NCH-GSKAcetylcysteine 2% oral solution...Novartis Consumer Health Confidential Page 9of 43 Clinical...

Novartis Consumer Health Inc

Parsippany USA

Clinical Research and Biostatistics

NCH-GSK Acetylcysteine 2 oral solution

Clinical Study Protocol 719-A-102

A Randomized Open-Label Two-Period Crossover Bioequivalence Study in Healthy Adult Subjects after Single Oral Dosing of a NCH-GSK

Acetylcysteine 2 Oral Solution versus a Reference Fluimucilreg

Acetylcysteine 2 Oral Solution

Authors

Document type Clinical Study Protocol

EUDRACT number 2015-003518-25

Version number 00

Development phase I

Release date 11-Nov-2015

Template Version 21 September 2012

Property of Novartis Consumer HealthConfidential

May not be used divulged published or otherwise disclosedwithout the consent of Novartis Consumer Health

PPD

Novartis Consumer Health Confidential Page 2 of 43

Clinical Study Protocol (Version No 00) Protocol No 719-A-102

Table of contents

List of tables 4

List of figures 4

List of abbreviations 5

Glossary of terms8

Protocol synopsis9

1 Background15

2 Purpose and rationale 15

3 Objectives 17

31 Primary objective17

32 Secondary objective17

4 Study design 17

5 Population18

51 Inclusion criteria 18

52 Exclusion criteria 19

6 Treatment22

61 Investigational and reference drugs 22

62 Treatment arms 22

63 Treatment assignment 23

64 Treatment blinding23

65 Treating the subject23

651 Subject numbering 23

652 Dispensing the study drug23

653 Study drug supply storage and tracking 24

654 Instructions for prescribing and taking the study drug24

655 Permitted study drug dose adjustments and interruptions25

656 Rescue medication 25

657 Other concomitant treatment25

658 Study drug discontinuation and premature subject withdrawal 25

659 Emergency unblinding of treatment assignment26

6510 Study completion and post-study treatment26

6511 Premature study termination 26

7 Visit schedule and assessments 27

71 Information to be collected on screening failures28

72 Subject demographics and other baseline characteristics28

73 Treatment exposure and compliance 29



74 Efficacy29

75 Safety 29

751 Physical examination 29

752 Vital signs29

753 Height and Weight 30

754 Laboratory evaluations30

755 Electrocardiogram (ECG) 30

756 Pregnancy and assessments of fertility 30

757 Appropriateness of safety measurements31

76 Other assessments 31

761 Urine drug screen cotinine and alcohol assessments 31

762 Pharmacokinetics 31

8 Safety monitoring 32

81 Adverse events32

82 Serious adverse event reporting33

83 Pregnancies 34

9 Data review and database management35

91 Site monitoring 35

92 Data collection 35

93 Database management and quality control 36

10 Data analysis36

101 Populations for analysis 36


103 Treatments (study drug rescue medication other concomitant therapies compliance)37

104 Analysis of the primary objective37

1041 Variables 37

1042 Statistical model and method of analysis 38

1043 Handling of missing valuescensoringdiscontinuations38

105 Analysis of secondary objective 39

1051 Efficacy (secondary) 39

1052 Safety39

106 Sample size calculation39

107 Power for analysis of critical secondary variables 40

108 Interim analysis40

11 Ethical considerations40



111 Regulatory and ethical compliance40

112 Informed consent procedures40

113 Responsibilities of the investigator and IRBIECREB41

114 Quality Assurance Audits and Health Authority Inspections41

115 Publication of study protocol and results41

12 Protocol adherence 41

121 Protocol Amendments 42

13 References 42

List of tablesTable 7-1 Assessment schedule27

Table 10-1 PK variables 37

List of figuresFigure 4-1 Study design 17



List of abbreviations

AE Adverse Event

ALT Alanine Aminotransferase

AST Aspartate Aminotransferase

ATC Anatomical Therapeutic Chemical

AUCinf Area under the plasma concentration-time curve extrapolated to infinity

AUClast Area under the plasma concentration-time curve from time zero to the last quantifiable concentration point post dose

BA Bioavailability

BE Bioequivalence

BLOQ Below Limit of Quantitation

BMI Body Mass Index

BP Blood Pressure

bpm Beats Per Minute

BUN Blood Urea Nitrogen

CFR Code of Federal Regulations

CK Creatine Kinase

COM Clinical Operations Manager

COPD Chronic Obstructive Pulmonary Disease

CPL Clinical Project Leader

CRO Contract Research Organization

CSR Clinical Study Report

DM Data Management

DQF Data Query Forms

DSP Drug Safety amp Pharmacovigilance

eCRF Electronic Case ReportRecord Form

ECG Electrocardiogram

EDC Electronic Data Capture

FSH Follicle Stimulating Hormone

GCP Good Clinical Practice

GI Gastrointestinal

GLP Good Laboratory Practice



GSH Glutathione

GGT Gamma-Glutamyl Transferase

HBs-Ag Surface Antigen of the Hepatitis B Virus

HBc-Ab Hepatitis B Core Antibody

HBc-IgM IgM Antibodies specific to the Hepatitis B Core Antigen

HCV-Ab Hepatitis C Antibody

hCG Human Chorionic Gonadotropin

HIV Human Immunodeficiency Virus

IB Investigator Brochure

ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

IE InclusionExclusion

IEC Independent Ethics Committee

IMP Investigational Medicinal Product

IN Investigator Notification

IPF Idiopathic Pulmonary Fibrosis

IRB Institutional Review Board

LLOQ Low limit of quantitation

MedDRA Medical Dictionary for Regulatory Activities

mmHg Millimeter of Mercury

msec Millisecond(s)

NAC N-Acetylcysteine

NCH-GSK Novartis Consumer Health-GSK Consumer Healthcare company

pa Post-dose administration

PK Pharmacokinetics

QC Quality Control

REB Research or Regional Ethics Board

SAE Serious Adverse Event

SGOT Serum Glutamic Oxaloacetic Transaminase

SGPT Serum Glutamic Pyruvic Transaminase

SOP Standard Operating Procedures

SUSARs Suspected Unexpected Serious Adverse Reactions



tNAC Total N-acetylcysteine

WHO World Health Organization



Glossary of terms

Adverse Event (AE) Any untoward medical occurrence in a patient or clinical-trial subject administered a human medicinal product and which does not necessarily have to have a causal relationship with this treatment An adverse event can therefore be any unfavorable and unintended sign (eg an abnormal laboratory finding) symptom or disease temporally associated with the use of a medicinal product whether or not considered related to the medicinal product

Assessment A measurement

Control (or reference) drug A study drug used as a comparator to reduce assessment bias preserve blinding of investigational drug assess internal study validity andor evaluate comparative effects of the investigational drug

Early termination Termination prior to the planned completion of all study drug administration and assessments

Enrollment Pointtime of subject entry into the study the point at which informed consent must be obtained (ie prior to starting any of the procedures described in the protocol)

Investigational Medicinal Product (IMP)

A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the authorized form or when used for an unauthorized indication or when used to gain further information about the authorized form

Investigational drug The study drug whose properties are being tested in the study this definition is consistent with US CFR 21 Section 3123 and is synonymous with ldquoinvestigational new drugrdquo

Subject number A unique identifier assigned by the investigator to each trial subject to protect the subjectrsquos identity and to be used in lieu of the subjectrsquos name when the subject report adverse events andor other trial related data

SubjectTrial Subject An individual who participates in a clinical trial either as a recipient of the investigational product(s) or as a

control

Period A minor subdivision of the study timeline divides stages into smaller functional segments such as screening baseline titration washout etc

Study drug discontinuation Pointtime when subject permanently stops taking study drug for any reason may or may not also be the pointtime of early termination

Termination Pointtime at which the subject came in for a final evaluationvisit or when study drug was discontinued whichever is later

Variable Information used in the data analysis



Protocol synopsis

Title of study A randomized open-label two-period crossover bioequivalence study in healthy adult subjects after single oral dosing of a NCH-GSK acetylcysteine 2 oral solution versus a reference Fluimucil

regAcetylcysteine 2 oral solution

Purpose and rationale The plan is to register in the countries of European Union (EU) the NCH-GSK acetylcysteine 2 oral solution as a generic product of the acetylcysteine 2 oral solutionfrom Zambon In the present study the bioequivalence (BE) of total N-acetylcysteine (tNAC) in plasma will be evaluated between the NCH-GSK Acetylcysteine 2 oral solution and the reference Fluimucil

regAcetylcysteine 2 oral solution from Zambon after a single oral dosing of 200 mg N-

acetylcysteine (NAC) under fasting condition The tNAC includes all the NAC in plasma irrespective of the redox statues (the reduced and oxidized forms) Fluimucil

regacetylcysteine oral solution 200

mg is part of the global marketing authorization of Fluimucilreg

(Zambon) in several EU member states (Belgium France Germany Hungary Italy Netherlands Portugal and Spain) and is considered the appropriate reference product by the European Union with demonstrated safety and efficacy

Objectives

Primary Objective

To demonstrate the bioequivalence of NAC after single oral dosing of 200 mg NAC in a NCH-GSK Acetylcysteine 2 oral solution compared to a reference Fluimucil

reg2 oral

solution in terms of AUClast and Cmax on the PK analyzable population

Secondary Objective


reg2 oral

solution in terms of AUCinf RA (Residual Area) Lambda_z Tmax and T12 on the PK analyzable population

To assess the safety after a single oral dosing of 200 mg NAC in the test and the reference formulations on the safety population

Population The study population will consist of male and female healthy adult subjects aged from 18 to 45 years A total of 46 subjects will be randomized in order to obtain 40 subjects who will complete the study

InclusionExclusion criteria

Inclusion criteria

Subjects eligible for inclusion in this study must fulfill all of the following inclusion criteria

1 Subjects must understand and provide written informed consent before any assessment is performed understand the study procedures and be willing and able to complete allrequired assessments

2 Male and female volunteers of any ethnic origin between 18 and 45 years of age Body Mass Index (BMI) of 185 to 30 kgm

2 inclusive Minimal body weight of 50 kg inclusive

3 Normal vital signs as follows

Oral body temperature between 350 and 375 ordmC inclusive

Sitting systolic blood pressure between 90 and 140 mmHg inclusive

Sitting diastolic blood pressure between 55 and 90 mmHg inclusive

Sitting pulse rate between 50 and 100 bpm (beats per minute) inclusive

Novartis Consumer Health Confidential 0 of 43


4 In general good physical health as judged by the investigator and determined by medicalsurgical history physical examination electrocardiogram (ECG 12-lead) and clinical laboratory (clinical chemistry and hematology) findings

Exclusion criteria

1 Use of other investigational drugs within 3 months or 10 half-lives of enrollment whichever is longer

2 History of or known hypersensitivity to any of the study drugs excipients or to drugs of similar chemical or pharmacological classes

3 Diagnosis of long QT syndrome or QTc (Fridericia preferred but Bazett acceptable) ge 450 msec for males and ge 470 msec for females at screening

4 History of malignancy or neoplastic disease of any organ system (except for localized basal cell skin carcinoma) treated or untreated within the past 5 years prior to screening regardless of whether there is evidence of local recurrence or metastases

5 Pregnant or breastfeeding women where pregnancy is defined as the state of a female after conception and until the termination of gestation confirmed by a positive human chorionic gonadotropin (hCG) serum test

6 Women of child-bearing potential defined as all women physiologically capable of becoming pregnant UNLESS they are

women whose career lifestyle or sexual orientation precludes intercourse with a male partner at the judgment of the investigator

women who have been surgically sterilized or whose partners have been sterilized by vasectomy or other means

using a highly effective method of birth control (ie one that results in a less than 1 per year failure rate when used consistently and correctly such as implants injectables combined oral contraceptives and some intrauterine devices (IUDs)) Periodic abstinence (eg calendar ovulation symptothermal post-ovulation methods) is not acceptable means of contraception

Reliable contraception should be established at least 3 months before administration of study medication and maintained throughout the study and for 30 days after study drug discontinuation

A woman who is postmenopausal must have a negative blood pregnancy test at screening but will not need to comply with an acceptable method of contraception Women are considered post-menopausal and not of child bearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg age appropriate history of vasomotor symptoms) or six months of spontaneous amenorrhea with known serum follicle stimulating hormone (FSH) levels gt 40 mIUmL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago In the case of oophorectomy alone only when the reproductive status of the woman has been confirmed by follow up hormone level assessment

7 Any surgical or medical condition which may significantly alter the absorption distribution metabolism or excretion of any drug substance including but not limited to any of the following

History of major gastrointestinal tract surgery such as gastrectomy gastroenterostomy bowel resection gastric bypass gastric stapling or gastric banding (note this is not applicable for minor abdominal surgery without significant tissue resection eg appendectomy and herniorrhaphy)

History (within 5 years prior to study start) of inflammatory bowel syndrome

History (within 5 years prior to study start) or evidence of renal disease or impaired renal function at screening as indicated by abnormal levels of serum creatinine (ge 14 mgdL) or BUN (blood urea nitrogen ge 25 mgdL) or the presence of clinically significant abnormal urinary constituents (eg albuminuria)



Evidence of ongoing hepatic disease or impaired hepatic function at screening A candidate will be excluded if more than one of the following lab value deviations are found 1) ASTSGOT (ge 12 ULN) ALTSGPT (ge 12 ULN) 2) GGT (ge 12 ULN) alkaline phosphatase (ge 12 ULN) 3) bilirubin (ge 10 mgdL) or CK (creatine kinase ge 3 to 5 ULN) A single deviation from the above values is acceptable and will not exclude the candidate unless specifically advised by the Investigator

History (within 5 years prior to study start) or clinical evidence at screening of pancreatic injury or pancreatitis

Evidence of urinary obstruction or difficulty in voiding at screening

Evidence of symptomatic prostatic hypertrophy

8 History (within 5 years prior to study start) of clinically significant gastritis pyloric channel stenosis peptic ulcer or duodenal ulceration gastro-esophageal reflux gastrointestinal bleeding rectal bleeding or other clinically significant GI abnormalities

9 History (within 5 years prior to study start) of orthostatic hypotension cardiovascular disease stroke transient ischemic attack (TIA) fainting or blackouts

10 Clinically relevant chronic or acute infectious illnesses or febrile infections within 2 weeks prior to start of the study

11 Newly occurred (within 2 weeks of screening visit) cutaneous and mucosal alterations

12 Patients with histamine intolerance

13 Any evidence of clinically significant cardiovascular pulmonary renal hepatic gastrointestinal hematological endocrinological metabolic autoimmune neurological psychiatric or other diseases at screening

14 History during the last five years of clinically significant metabolic pulmonary neurological hematological autoimmune psychiatric or endocrine disorders

15 Other clinically significant laboratory findings at screening in the opinion of the Investigator

16 Positive results in any of the virology tests for HIV-Ab HCV-Ab HBsAg and HBc-Ab (if positive to be verified by test for HBc-IgM)

17 Subject has used any medication (including over-the-counter medications) within 2 weeks before first scheduled study drug administration or within lt 10 times the elimination half-life of the respective drug (whichever is longer) or is anticipated to require any concomitant medication during that period or at any time throughout the study

Allowed treatments are systemic contraceptives and hormone replacement therapy as long as the female subject is on stable treatment for at least 3 months and continues treatment throughout the study and occasional use of paracetamol 500 mg (up to 2000 mg daily)

Single intake of other drugs is only allowed if judged by the investigator to have no clinical relevance and may not confound the interpretation of the study results

18 Subject reports consumption of any drug metabolizing enzyme (eg CYP3A4 or other cytochrome P450 enzymes) inducing or inhibiting aliments beverages or food supplements (eg broccoli Brussels sprouts grapefruit grapefruit juice star fruit St Johnrsquos Wort etc) within two weeks prior to the first scheduled study drug administration or is anticipated to consume such products during that two-week period or at any time throughout the study

19 Any history of drug hypersensitivity asthma urticaria or other significant allergic diathesis Subjects with uncomplicated seasonal allergic rhinitis can be accepted if expected allergy season is clearly outside enrollment treatment period

20 Subject has a history of illicit drug abuse or investigator suspects current drug abuse with drug classes that include but are not limited to barbiturates amphetamines benzodiazepines cocaine opiates cannabis or any other illicit drugs (verified by urine drug screen) (within 5 years prior to study start)



21 Subject shows evidence for current alcohol abuse or reports a regular average alcohol consumption exceeding 10 Uw of alcohol (1U = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor) within 6 months before screening

22 Smokers defined as the use of tobacco products during the 3 months prior to screening or urine cotinine levels gt 200 ngmL at screening

23 Not willing to fully comply with the following lifestyle restrictions throughout the study

No consumption of alcohol-containing products within 24 hours before and throughout each in-house study period

No consumption of caffeinetheophylline-containing products (ie coffee green tea black tea cola cacao) within 24 hours before and throughout each in-house study period

Acceptance of standardized food and beverages throughout each in-house study period

No performance of unaccustomed strenuous physical exercise (body building high performance sports) from 1 weeks prior to start of the study and throughout the entire study

No consumption of herbsfruits that have an influence on pharmacokinetics such as St Johns Worth star fruit seville orange or seville orange containing foods and beveragesgrapefruit or grapefruit-containing food or beverages from 2 weeks prior to start of the study and throughout the entire study

No planned consumption of concomitant medications from 2 weeks prior to start of the study throughout the entire study except those allowed in criterion 17 above

24 Any condition not identified in the protocol that in the opinion of the Investigator would confound the evaluation and interpretation of the study data or may put the subject at risk

25 Participation in a previous clinical study with or without another investigational product and with ~470 ml blood drawn or blood donation within the last 3 months prior to screening or previous enrollment into the current study

26 Persons directly or indirectly involved in the execution of this protocol including the Investigator in the current study or a first-degree relative of a study investigator the employees of the contract research organization (CRO) investigational site and persons related to them

27 ldquoVulnerablerdquo individual (as defined by the institutional review board (IRB) eg incarcerated person)

Investigational and reference therapy

Each subject will receive a single oral dose of each of the following two treatments on separate occasions according to the randomization schedule supplied by the sponsor During each period each subject will receive either

Treatment A (reference) Fluimucilreg

Acetylcysteine 2 oral solution 200 mg NAC in 10 mLby Zambon SPA or

Treatment B (test) NCH-GSK Acetylcysteine 2 oral solution 200 mg NAC in 10 mL

Study design

The study design follows the EMA guideline on the investigation of bioequivalence (CPMP 2010)

This is a randomized open-label single-center single-dose 2-period 2-treatment crossover study in adult male and female healthy volunteers Subjects will undergo screening evaluations to determine eligibility within 21 days prior to study enrolment All subjects will be admitted to the unit at ~500 pm on each of the 2 evenings before study drug administration and will receive the same standardizedmeal Subjects are required to fast (nothing to eat or drink except non-carbonated water) from 10 hours prior until 4 hours after study drug administration Subjects must not drink water one hour before and after study drug administration except with dosing After an overnight fast at approximately 800



am subjects will receive either treatment A Fluimucilreg

Acetylcysteine 2 oral solution 200 mg NAC in 10 mL or treatment B NCH-GSK Acetylcysteine 2 oral solution 200 mg NAC in 10 mL The 10 mL dose of the oral solution will be administered to the study subjects Thereafter subjects will be administered 230 mL of water to completely swallow the solution administered A part of this volume will be used to rinse the cup used for administration (further details on drug preparation and administration will be provided in the pharmacy manual provided by the phase I unit) There will be a standardized lunch approximately 4 hours after dosing standardized dinner approximately 8 hours after dosing and a snack approximately 12 hours after dosing Additional liquid intake during the 48hours post-dose will also be standardized (only water will be allowed) No concomitant medication will be permitted except for medications to treat adverse events at the discretion of the investigator

Blood sampling will be collected pre-dose at -45 -30 and -15 minutes (to determine individual endogenous baseline tNAC plasma concentrations) and post-dose at 5 10 20 30 40 50 minutes 1 15 2 4 6 8 10 12 24 36 and 48 hours in each period

Subjects will return to the clinic after at least 1 week wash-out (but le 10 days) for the second treatmentperiod at which time they will be administered the alternative formulation Exactly the same procedures as applied in treatment Period 1 will be followed

After completion of the second study period (ie last pharmacokinetic (PK) sample on Day 3 of Period 2) subjects will be discharged from the clinic

The total duration of the study is approximately 31 days (up to 34 days) which includes a maximal 21-day screening inclusion period plus 2 treatment periods with a 63 hour in-house confinement period prior to and after study drug administration (including 3 overnight stays) and a 48-hour blood sampling in each treatment period There will be at least 7 (but le 10) days wash-out interval between treatments

Analyses of tNAC concentration in plasma samples will be performed using a validated bioanalyticalmethodology in a laboratory with GLP and GCP certification Method validation has to be conducted in full compliance with the respective guidance documents (CHMP 2012 FDA 2001)

Efficacy assessments Not applicable

Other assessments

Pharmacokinetic (PK) assessments (in plasma) The following single dose PK variables will be calculated based on actual sampling times using non-compartmental methods from the actual individual baseline corrected plasma drug concentration versus time profiles during both treatment periods Cmax Tmax AUClast AUCinf RA Lambda_z and T12 The plasma concentrations of tNAC will be corrected with baseline levels which will be the average of three pre-dose baseline time points

The AUClast and Cmax values will be considered as the primary PK variables The other PK variables will be considered as secondary

Safety assessments

Safety assessments include recording of adverse events vital sign measurements physical examinations and clinical laboratory tests

Data analysis

Plasma concentrations at each time point will be summarized descriptively and graphed by treatment versus time for individual subjects and for the mean

All pertinent PK variables (AUClast AUCinf Residual Amount Lambda_z Tfrac12 and Cmax) will be calculated after first correcting baseline plasma concentrations based on the average of three pre-dose baseline time points of tNAC from each individual (ie calculated value = measured value ndashbaseline value) The post-dose plasma tNAC concentrations that equal or fall below the baseline concentrations (ie zero or negative values) will not be brought into the PK calculation The PK



variables (except Tmax) will then be summarized by descriptive statistics (N arithmetic means median standard deviations minimum maximum and coefficients of variation) and presented by treatment for all variables Tmax will be summarized using median Q1 Q3 minimum and maximumAdditionally geometric means will be calculated for log-transformed PK variables (AUClast AUCinf and Cmax)

Log-transformed AUClast AUCinf and Cmax will be compared between treatments using an ANOVA including terms for sequence formulation and period and subject nested within sequence as fixedeffects Sequence will be tested using subject nested within sequence as the error term The presence of a statistically significant sequence effect will be noted and its implications will be discussed A 90 CI on the ratio of untransformed PK variables to assess the hypothesis of bioequivalence with AUClastand Cmax will be derived through reverse transformation of the 90 CI for the difference in the log scale

The absence of any relevant difference in the rate and extent of absorption will be demonstrated in case that the respective 90 confidence intervals are entirely contained in the range of 80 - 125 for AUClast and for Cmax Under these conditions the bioequivalence between the test and reference formulations will be declared



1 Background

Acetylcysteine (N-acetylcysteine NAC) a precursor of cysteine and glutathione (GSH) is an important mucolytic agent that can reduce the viscosity of pulmonary secretions (Sadowska et al 2006) It has been used for the treatment of acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus (Sadowska et al 2006 Grandjean et al 2000)

The free sulfhydryl groups of NAC are capable to break the disulphide bridges present in the mucus when in direct contact with respiratory airways following inhalation or nebulization Orally administered NAC is thought to indirectly regulate mucus viscosity by normalizing the secretion of fucosylated mucins NAC may also act as an antioxidant that is capable of facilitating intracellular GSH biosynthesis and a free-radical scavenger against endogenousfree radicals or xenobiotics contributing to its protective action on the respiratory system

NAC has been in clinical use for many years limited to inhalation or intravenous injection therapy In the past decades however it has been reported that oral administration of NAC can effectively reduce the viscosity of bronchial mucus (Sadowska et al 2006 Grandjean et al 2000 Atkuri et al 2007) and most indications for NAC therapy can be achieved by oral administration (Atkuri et al 2007)

After oral administration NAC is rapidly absorbed from the gastrointestinal tract and theobserved maximum exposure (Cmax) is achieved at approximately 30 minutes to 1 hour post dose Because of extensive first-pass metabolism in the gut wall and liver the oral bioavailability (BA) of unchanged total NAC (tNAC) is approximately10 (Borgstrom et al 1986 Olsson et al 1988 No metabolite included for tNAC measure for the definition of tNAC see Section 2 for details) In humans orally administered NAC is mainly metabolizedto cysteine and the reported mean plasma half-life (T12) values of tNAC range from 1 hour to74 hours (Olsson et al 1988 Liu YM et al 2010) The varied values of the reported Tfrac12 are likely due to the differences in the sample collection periods from different studies and the multi-compartmental profiles of the NAC elimination Renal clearance may account for about 30 of tNAC elimination (Holdiness 1991)

The endogenous plasma concentrations of tNAC range between approximately 13 to 28ngmL (Gabard and Mascher 1991 Liu YM et al 2010) The levels were found to be fairly constant over a 24 hour interval ie no apparent circadian variations (Liu YM et al 2010)

NAC has a favorable tolerability and safety profile with a wide therapeutic window Daily doses in controlled clinical studies in adults with COPD or idiopathic pulmonary fibrosis (IPF) over 6 to 12 months range from 600 to 1800 mg With these doses NAC treatment wasnot associated with serious adverse events (SAEs) or a dose-dependent change of the established safety profile (Dekhuijzen and van Beurden 2006)

2 Purpose and rationale

In the present study the bioavailability (BA) of NAC in a new liquid formulation (NCH-GSKNAC 2 oral solution) will be examined to assess whether the rate and extent of NAC



absorption is comparable to those from a reference product (Fluimucilreg NAC 2 oral solution) after a single oral dosing of 200 mg under fasting condition

For the secretolytic therapy in acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus the recommended dose for NAC 2 oral solution in adults the elderly and children 12 years of age and above is 200 mg (10 ml) two to three times a day Since the recommended single dose unit in the claimed label for the test and the reference products is 200 mg a single dose of 200 mg is selected in the present BE study

The tNAC as defined in the protocol herein and throughout this document includes the reduced form and the oxidized (disulfide) forms of NAC in plasma The oxidized forms are disulfides of NAC with labile bond to plasma and low molecular weight proteins Both the reduced form and oxidized forms of NAC are instable in plasma and are interchangeable between the redox statuses In the present study by adding a reductant to the plasma samples the NAC as reduced form in plasma will be stabilized and all oxidized NAC will be converted to reduced form The tNAC will then be measured as reduced form and be representative of the total amount of NAC entering into the body for the BE assessment (Borgstrom et al 1986 Olsson et al 1988 Gabard and Mascher 1991 Liu YM et al 2010) NAC metabolites (eg cysteine cysteine and glutathione as well as their disulfides etc) will not be measured

The NCH-GSK formulation is essentially similar to the Fluimucilreg NAC oral solution formulation except for differences in the flavoring agents (le02) and the presence of propylene glycol (5) as solubilizer of the flavors The NCH-GSK product may provide a unique warming sensation in the throat The flavoring agents and 5 propylene glycol at the concentration presented are not considered to significantly impact the drug absorption (Hamid et al 2009) Therefore no significant differences in NAC BA between the tested and the reference formulations are anticipated

The upper age range of 45 years is selected to correspond the endogenous levels and pharmacokinetic characteristics of NAC in the previous PKBE studies (Gabard and Mascher 1991 Liu YM et al 2010) The PK sampling time points were selected following trial simulations based on tNAC PK and the endogenous tNAC levels from the healthy subjects The 48-hour post-dose PK collection period is designated based on the simulated PK profiles for plasma tNAC after 200 mg single dose which start to approach baseline tNAC levels after 48 hours of dosing The 48 hours post-dose PK collection period will cover more than 5 half-lives of tNAC and the ratio of AUClastAUCinf will be more than 90 (Olsson et al 1988Brown et al 2004 Liu YM et al 2010) The 7-day washout period will be gt10 times of the estimated Tfrac12 and therefore eliminates the likelihood of any carry-over effect from period to period

NCH-GSK considers that NCH-GSK acetylcysteine 2 oral solution meets the conditions of a generic application as per Article 10(1) of directive 200183EC Fluimucilreg acetylcysteine oral solution 200 mg10 mL is part of the global marketing authorisation of Fluimucil (Zambon) in several EU member states (Belgium France Germany Hungary Italy Netherlands Portugal and Spain) and is considered the appropriate reference product with demonstrated safety and efficacy (CHMP 2010)



3 Objectives

31 Primary objective

To demonstrate the bioequivalence of NAC after single oral dosing of 200 mg NAC in a NCH-GSK Acetylcysteine 2 oral solution compared to a reference Fluimucilreg 2 oral solution in terms of AUClast and Cmax on the PK analyzable population

32 Secondary objective

To demonstrate the bioequivalence of NAC after single oral dosing of 200 mg NAC in a NCH-GSK Acetylcysteine 2 oral solution compared to a reference Fluimucilreg 2 oral solution in terms of AUCinf RA (Residual Area) Lambda_z Tmax and T12 on the PK analyzable population


4 Study design

The study design follows the EMA guideline on the investigation of bioequivalence (CHMP 2010)

Each study subject will receive the test and reference treatment according to an open-labelrandomized single-center 2-period 2-sequence single-dose crossover design

The overall study design is illustrated in Figure 4-1

Figure 4-1 Study design

Screening Study Period 1 Clinical furlough Study Period 2 End-of-Study

Days -21 to -2 63 hour in-house

Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b

Visit 1 Visit 2 Visit 3 Visit 4a Washout period of at least 7 days but not more than 10 days including in-house study period and

clinical furlough period between each study drug administrationb End of Study assessments will occur at day 10 48 hours after the last IMP administration in Period

2 and after the last PK sample collection or after withdrawal if not completing the study

After screening eligible subjects will be admitted to the study center at ~500 pm on each of the 2 evenings before study drug administration and will receive the same standardized meal Subjects will remain there until the 48 hour blood sampling and discharge assessments arecompleted

The medications (either the test or the reference formulation according to randomization) will be given at between 700 and 1000 am after an overnight fasting period of at least 10 hoursSubjects must not drink water one hour before and after study drug administration except with dosing The 10 mL dose of the oral solution 2 will be administered to the study subjects Thereafter subjects will be administered 230 mL of water to completely swallow the solutionadministered A part of this volume will be used to rinse the cup used for administration



(further details on drug preparation and administration will be provided in the pharmacy manual provided by the phase I unit) There will be a standardized lunch approximately 4 hours after dosing standardized dinner approximately 8 hours after dosing and a snack approximately 12 hours after dosing Additional liquid intake during the 48 hours will also be standardized (only water will be allowed no fluid intake from -1 hour until 1 hour pa 150 ml of non-carbonated water at room temperature will be given every hour from 1 hour until 4hours pa ie 150 ml will be given four times After this time interval fluid intake of non-carbonated water is ad libitum) No concomitant medication will be permitted except for medications to treat adverse events at the discretion of the investigator

Blood sampling will be done pre-dose at -45 -30 and -15 minutes (to determine individual endogenous tNAC plasma concentrations) and post-dose at 5 10 20 30 40 50 minutes 1 15 2 4 6 8 10 12 24 36 and 48 hours in each period

Subjects will return to the clinic after at least 1 week wash-out (but le 10 days between each study drug administration) for the second treatment period at which time they will be administered the alternative formulation Exactly the same procedures as applied in treatment Period 1 will be followed

After completion of the second study period (ie last PK sample on Day 3 of Period 2) subjects will be discharged from the clinic An end of study examination will be performed at 48 hours post last IMP administration and after the last PK sample collection before discharging or after subject withdrawal if not completing the study which will verify that subjects display uncompromised health conditions and overall well-being and to screen for exclude possibly ongoing adverse events or remarkable safety laboratory deviations that may require follow-up

The total duration of the study is approximately 31 days (up to 34 days) which includes a 21-day screening inclusion period plus 2 treatment periods with a 63 hour in-house confinement period prior to and after study drug administration and a 48-hour blood sampling in each treatment period

5 Population

The study population will consist of a representative group of healthy male and female adult subjects 18 to 45 years of age Enrollment of approximately 46 healthy subjects is planned in order to yield at least 40 completers for analysis based on an approximately 10 drop out rate

51 Inclusion criteria


1 Subjects must understand and provide written informed consent before any assessment is performed understand the study procedures and be willing to complete the required assessments

2 Male and female volunteers of any ethnic origin between 18 and 45 years of age Body Mass Index (BMI) of 185 to 30 kgm2 inclusive Minimal body weight of 50 kg inclusive







Sitting pulse rate between 50 and 100 bpm inclusive


52 Exclusion criteria





5 Pregnant or breastfeeding women where pregnancy is defined as the state of a female after conception and until the termination of gestation confirmed by a positive hCG serumtest






A woman who is postmenopausal must have a negative blood pregnancy test at screening but will not need to comply with an acceptable method of contraception Women are considered post-menopausal and not of child bearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg age appropriate history of vasomotor symptoms) or six months of spontaneous amenorrhea with known serum FSH



levels gt 40 mIUmL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago In the case of oophorectomy alone only when the reproductive status of the woman has been confirmed by follow up hormone level assessment


History of major gastrointestinal tract surgery such as gastrectomygastroenterostomy bowel resection gastric bypass gastric stapling or gastric banding(note this is not applicable for minor abdominal surgery without significant tissue resection eg appendectomy and herniorrhaphy)


History (within 5 years prior to study start) or evidence of renal disease or impaired renal function at screening as indicated by abnormal levels of serum creatinine (ge 14mgdL) or BUN (ge 25 mgdL) or the presence of clinically significant abnormal urinary constituents (eg albuminuria)

Evidence of ongoing hepatic disease or impaired hepatic function at screening A candidate will be excluded if more than one of the following lab value deviations are found 1) ASTSGOT (ge 12 ULN) ALTSGPT (ge 12 ULN) 2) GGT (ge 12 ULN) alkaline phosphatase (ge 12 ULN) 3) bilirubin (ge 10 mgdL) or CK (ge 3 to 5 ULN) A single deviation from the above values is acceptable and will not exclude the candidate unless specifically advised by the Investigator

















18 Single intake of other drugs is only allowed if judged by the investigator to have no clinical relevance and may not confound the interpretation of the study results Subject reports consumption of any drug metabolizing enzyme (eg CYP3A4 or other cytochrome P450 enzymes) inducing or inhibiting aliments beverages or food supplements (eg broccoli Brussels sprouts grapefruit grapefruit juice star fruit St Johnrsquos Wort etc) within two weeks prior to the first scheduled study drug administration or is anticipated to consume such products during that two-week period or at any time throughout the study

19 Any history of drug hypersensitivity asthma urticaria or other significant allergic diathesis Subjects with uncomplicated seasonal allergic rhinitis can be accepted if expected allergy season is clearly outside enrolment treatment period


21 Subject shows evidence for current alcohol abuse or reports a regular average alcohol consumption exceeding 10 Uw of alcohol (1U = 150 mL of wine or 360 mL of beer or 45mL of hard liquor) within 6 months before screening







No consumption of herbsfruits that have an influence on pharmacokinetics such as St Johns Worth star fruit seville orange or seville orange containing foods and beverages grapefruit or grapefruit-containing food or beverages from 2 weeks prior to start of the study and throughout the entire study







27 ldquoVulnerablerdquo individual (as defined by the IRB eg incarcerated person)

6 Treatment

61 Investigational and reference drugs

Each subject will receive a single oral dose of each of the two treatments on separate occasions according to the randomization schedule supplied by the sponsor During each treatment period each subject will receive either

Treatment A (reference) Fluimucilreg Acetylcysteine 2 oral solution 200 mg NAC in 10 mL by Zambon SPA or

Treatment B (test) Acetylcysteine 2 oral solution 200 mg NAC in 10 mL by NCH-GSK

The reference therapy contains 2 g NAC per 100 ml (200 mg acetylcysteine per 10 ml dose ie 2 of NAC in vw) in a 100 mL amber glass bottle The excipients include Carmellose Sodium (Sodium CMC) Sodium Benzoate Methyl Paraben Sodium EDTA Sodium Saccharin Sodium Hydroxide Raspberry Flavor and Purified Water

The investigational therapy contains 2 g NAC per 100 ml (200 mg acetylcysteine per 10 ml dose ie 2 of NAC in vw) in a 100 mL amber glass bottle The excipients include Carmellose Sodium (Sodium CMC) Sodium Benzoate Methyl Paraben Sodium EDTA Sodium Saccharin Sodium Hydroxide Propylene Glycol IFF Flavor 316282 Peppermint Flavor Purified WaterThe selection of Fluimucilreg acetylcysteine oral solution (reference product) will be based on assay content to ensure that the batch of the test product does not differ by more than 5 from that of the batch used as reference product according to the European Guideline on the investigation of bioequivalence (CPMPEWPQWP140198 Rev 1(2010))

62 Treatment arms

At Visit 2 (Day 1) subjects will be randomly assigned to one of the following two treatment sequences AB or BA



63 Treatment assignment

At Visit 2 (Study Day 1 Period 1) subjects who fulfill all the inclusionexclusion (IE) criteria will be given the lowest available number on the randomization list This number assigns them to one of the two sequences

The randomization numbers will be generated following NCH-GSK procedures related to the production and distribution of randomization lists A randomization list will be produced by Novartis Pharmaceuticals Drug Supply Management using a validated system that automates the random assignment of treatment orders to randomization numbers The randomization scheme will be reviewed and approved by the Integrated Information Sciences Audit Readiness Validation amp Randomization group and locked by them after approval

64 Treatment blinding

As this is an open-label study treatment blinding procedures are not applicable However personnel performing the bioanalytical analysis of plasma samples will be blinded to the randomization

65 Treating the subject

651 Subject numbering

Each subject is uniquely identified in the study by the site number and the screening number

Upon signing the informed consent form the subject is assigned a site and a screening number by the investigator The first subject is assigned screening number 001 and subsequent subjects are assigned consecutive numbers Once assigned to a subject a screening number will not be reused If the subject fails to be randomized for any reason the reason for not being randomized will be entered on the Screening Log and the Demography electronic case report form (eCRF) should also be completed At the time of randomization eligible subjects will receive a unique randomization number according to the randomization list starting with the lowest available number Randomization numbers will not be reused The randomizationnumber will be recorded on the respective fields of the eCRF

652 Dispensing the study drug

The study medications will be provided by NCH-GSK to the study site The reference marketed products will be packed and shipped in their original commercial packages and the test product will be packed and shipped in 100 ml glass amber bottles containing 2 g NAC per 100 ml

One individual bottle of study medication will be used for one individual only for a single study period The bottles for the test and reference products will be appropriately labeled Immediately prior to dosing a 10 mL dose of the oral solution will be metered from the bottle to the cup The study subjects will be asked to drink the content of the measuring cupThereafter subjects will be administered 230 mL of water to completely swallow the solution administered A part of this volume will be used to rinse the cup used for administration (further details on drug preparation and administration will be provided in the pharmacy manual provided by the phase I unit) Investigator staff will verify the study drug using the



randomization number and the visit number on the label A witness at the phase I unit will confirm that the correct study drug is being administered Immediately before administering study drug to the subject investigator staff will detach the outer part of the label from the packaging and affix it to the source document for that subject The randomization number must also be recorded on the Randomization Number field of the eCRF

Further details on drug dispensing can be found in the pharmacy manual provided by the phase I unit

653 Study drug supply storage and tracking

Study drugs must be received by a designated person at the study site handled and stored safely and properly and kept in a secured location to which only the investigator and designated assistants have access Upon receipt all study drugs should be stored according to the instructions specified on the drug labels Clinical supplies are to be dispensed only in accordance with the protocol Upon receipt all study drugs should be stored at a controlled room temperature not more than 25 degC

Medication labels will be in the local language and comply with the legal requirements of each country They will include storage conditions for the drug but no information about the subject except for the randomization number

The investigator must maintain an accurate record of the shipment and dispensing of study drug in a drug accountability ledger Monitoring of drug accountability will be performed by the field monitor during site visits and at the completion of the trial At the conclusion of the study and as appropriate during the course of the study the investigator will ship all used and unused study drug packaging drug labels and a copy of the completed drug accountability ledger to the address provided to the investigator

654 Instructions for prescribing and taking the study drug

Subjects will be randomized to study medication on Day 1 of Period 1 only A single dose of study medication will be taken orally on Day 1 of each period at around 800 am Trained study personnel will administer each dose

All dosages prescribed and dispensed to the subject and all dose changes during the study must be recorded on the Dosage Administration Record eCRF page

The Investigational medicinal product (IMPs either the test or the reference formulation according to randomization) will be administered after an overnight fasting period of at least 10 hours with subjects in upright posture The solutions of the IMPs will be metered by the site personnel immediately prior to administration from the bottle to the cup The study subjects will be asked to drink the content of the measuring cup The IMP administration will be performed by suitably qualified site personnel under the instruction and supervision of the investigator or sub-investigator(s) Thereafter subjects will drink 230 ml water in order to remove residual IMP from oral-mucosal surfaces A part of this volume will be used to rinse the cup used for administration (further details on drug preparation and administration will be provided in the pharmacy manual provided by the phase I unit) After administration the oral cavity of the subjects will be examined to ensure the subjects swallow the dose The subjects will be monitored for 1 hour post dosing to ensure there is no regurgitation of water or studied



drug There will be a standardized lunch approximately 4 hours after dosing dinner approximately 8 hours after dosing and a snack approximately 12 hours after dosing From one hour after the morning administration of the IMPs liquid intake (only non-carbonated water at room temperature) at customary amounts will be allowed but will be standardized during the 48 hours post-dose period (see Section 4 for details) Subjects will remain in sitting position for the first 4 hours after dose administration However one hour after study drug administration subjects are allowed to walk to the bathroom as necessary

Further details on prescribing and taking the study drugs can be found in the pharmacymanual provided by the phase I unit

655 Permitted study drug dose adjustments and interruptions

Study drug dose adjustments andor interruptions are not permitted

656 Rescue medication

The study is conducted in healthy adult subjects Hence there is no requirement for rescue medication provisions

657 Other concomitant treatment

No concomitant treatment is allowed during the entire period of the study (for exceptions see exclusion criterion 17) No PK interaction is anticipated between NAC and low dose paracetamol therefore occasional use of paracetamol 500 mg (up to 2000 mg daily) is allowed (Miller et al 1983) If concomitant therapy is required during the study a decision for the subjectrsquos continuation will be made by the investigator with consultation of NCH-GSKclinical project leader (CPL) based on the time the medication was administered and on the pharmacology and pharmacokinetics of the study drug and the concomitant medication

The investigator should instruct the subject to notify the study site about any new medications heshe takes after the start of the study drug All medications and significant non-drug therapies (including physical therapy and blood transfusions) administered after the subject starts treatment with study drug must be listed on the Concomitant MedicationsSignificant non-drug therapies after start of study drug eCRF page An Adverse Event Form should be completed for any subject starting a concomitant medication following the start of the study

658 Study drug discontinuation and premature subject withdrawal

Study drug must be discontinued and the subject withdrawn from the trial if the investigator determines that continuation of treatment would result in a significant safety risk for that subject The following circumstances require study drug discontinuation and premature subject withdrawal

Withdrawal of informed consent

Subject lost to follow-up

Pregnancy

Death



The following deviations from the prescribed dose regimen for the study drug vomiting diarrhea or regurgitation of water or studied drug (within 60 min) after study drug administration

Use of concomitant medication as described in 657

Subjects may voluntarily withdraw from the study for any reason at any time They may be considered withdrawn if they state an intention to withdraw or fail to return for visits or become lost to follow up for any other reasons

If premature withdrawal occurs for any reason the investigator must determine the primary reason for a subjectrsquos premature withdrawal from the study and record this information on the Study Completion page of the eCRF

For subjects who are lost to follow-up (ie those subjects whose status is unclear because they fail to appear for study visits without stating an intention to withdraw) the investigator should show due diligence by documenting in the source documents steps taken to contact the subject eg dates of telephone calls registered letters or other reasonable best efforts to contacting the subject in order to establish the reason for discontinuation and to check presence of any AEs

Subjects who are prematurely withdrawn from the study will not be replaced

659 Emergency unblinding of treatment assignment

As this is an open-label study no provisions for emergency unblinding procedures are required

6510 Study completion and post-study treatment

Completion of study for individual study subjects will be defined as completion of all visits through Visit 4 Every attempt will be made to perform a final follow up visit on prematurely withdrawn subjects The subjects upon completionearly termination will be referred back totheir primary care physician if necessary

To ensure subject safety every SAE occurring after the subject has signed the informed consent and until the subject has stopped his participation in the study must be reported regardless of suspected causality see Section 82 Serious adverse event reporting

6511 Premature study termination

The study can be terminated at any time for an ethical reason by NCH-GSK an IRBIEC or a Health Authority Should this be necessary all subjects should be seen as soon as possible and treated as described in Section 7 for a prematurely withdrawn subject The investigator may be informed of additional procedures to be followed in order to assure that adequate consideration is given to the protection of the subjectrsquos best interest

The investigator will be responsible for informing the IRBIEC of the early termination of the trial



7 Visit schedule and assessments

Table 7-1 lists all of the assessments and indicates with an ldquoxrdquo the study days visits when therespective assessments are performed Subjects should be seen for all visits exactly on the designated days without any allowed ldquovisit windowrdquo

Subjects who discontinue study drug before completing the study and those who prematurely withdraw from the study for any reason should be scheduled for an End-of-Study Examination as soon as possible at which time all of the assessments listed for the End-of-Study Examination will be performed

Table 7-1 Assessment schedule

Screening

Period 1 Clinical furloughInterval

Period 2 End-of-Study Examination

7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10

Obtain informed consent

1x

Review IE criteria x x x

Medical History x

Physical Exam(including weight and height)

X x

Vital signs2

X x x x x x

Brief Physical Exam2

x x

12-lead ECG x

Safety Clinical Laboratory

x x

Urinalysis x x

Virology x

Urine illicit drug screen x x x

Alcohol breath test x x x

Urine cotinine test x x x

Blood Pregnancy test4

x x x x

In house confinement5

x x x x x x x x

Randomization x

Administration of study medication

x x

PK blood sampling6

x x x x x x

Concomitant medication record

x x x x x x x x x x x

AE record x x x x x x x x x x x

Study Completion form x

All AEs must be collected from time of informed consent 1

The study start will count from the point when the subject signs the informed consent



Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 102Vital sign measure at day -1 (day 7) and day 1 (day 8) of period 1 (period 2) within 30 minutes prior

to study drug administration3

Brief physical exam includes examination of general appearance heart and lung will be performed on day -1 (day 7)4

For females only5

Evening of the day prior each treatment period until the morning of 48-hour blood sampling is completed ie 3 overnight stays6

pre-dose at -45 -30 and -15 minutes and post-dose at 5 10 20 30 40 50 minutes 1 15 2 4 6 8 10 12 24 36 and 48 hours post-dose7

The end-of-study examinations (physical exam including weight only) will be performed at 48 hours post last IMP administration and after the last PK sample collection or after withdrawal from the study before study completion

71 Information to be collected on screening failures

Subjects may discontinue from the study prior to randomization from Visit 1 prior to any medication being administered

Subjects discontinuing prior to randomization are considered screening failures

If a subject discontinues before entering the treatment period only the Screening Log entry including the primary reason for discontinuation and only selected information as specified for each study should be completed in the eCRF if applicable It is not necessary to complete all the required evaluations at the time of discontinuation unless medically indicated

The following information is to be collected for screening failures

Screening number

Date of screening

Date of inform consent

Subject initials if applicable

Race

Ethnicity

Date of birth

Sex

Primary reason for screening failure

Occurrence of Serious Adverse Events (SAE) Adverse events that are not SAEs will

be followed by the investigator and collected only in the source data

72 Subject demographics and other baseline characteristics

Subject demographic and baseline characteristic data to be collected on all subjects as appropriate for the study goals and the population being studied and includes date of birth



sex race ethnicity height and weight Relevant medical historycurrent medical condition data includes data until the time of informed consent Where possible diagnoses and not symptoms will be recorded

73 Treatment exposure and compliance

The compliance for drug administration will be recorded by the site staff who will administer the drug and observe the subject swallowing and perform mouth check

74 Efficacy

None

75 Safety

751 Physical examination

A complete physical examination will be performed according to assessment schedule in Table 7-1 It will include the examination of general appearance skin neck (including thyroid) eyes ears nose throat lungs heart abdomen back lymph nodes extremities vascular and neurological If indicated based on medical history andor symptoms rectal external genitalia breast and pelvic exams will be performed

A brief physical exam will be conducted according to assessment schedule in Table 7-1 A brief physical exam will include the examination of general appearance heart and lung

Information for all physical examinations must be included in the source documentation at the study site Significant findings that are present prior to signing the ICF must be included in the Relevant Medical HistoryCurrent Medical Conditions eCRF page Significant findings made after signing the ICF which meet the definition of an Adverse Event (AE) must be recorded on the Adverse Event eCRF page

752 Vital signs

Vital signs will be assessed according to assessment schedule in Table 7-1 This will include BP and pulse measurements After the subject has been sitting for five minutes with back supported and both feet placed on the floor systolic and diastolic blood pressure will be measured three times within 30 minutes prior to study drug administration using an automated validated device eg OMRON with an appropriately sized cuff The repeat sitting measurements will be made at 1 - 2 minute intervals and the meanaverage of the three measurements will be used If the cuff sizes available are not large enough for the subjects arm circumference a sphygmomanometer with an appropriately sized cuff may be used

Normal vital signs are as follows oral body temperature between 350 and 375 ordmC systolic blood pressure between 90 and 140mmHg diastolic blood pressure between 55 and 90 mmHg pulse rate between 50 and 100 bpm



753 Height and Weight

Height in centimeters (cm) and body weight (to the nearest 01 kilogram [kg] in indoor clothing but without shoes) will be measured according to assessment schedule in Table 7-1(End-of-Study Examination for weight only)

BMI should be calculated using the following formula weight (kg) height2 (m2)

754 Laboratory evaluations

A laboratory will be used for analysis of all specimens collected Details on the collections shipment of samples and reporting of results by the laboratory are provided to investigators in the laboratory manual

7541 Hematology

Hemoglobin hematocrit red blood cell count white blood cell count with differential and platelet count will be measured according to assessment schedule in Table 7-1

7542 Virology

The following virology tests will be performed at screening only HIV-Ab HCV-Ab HBsAg and HBc-Ab (if positive to be verified by test for HBc-IgM)

7543 Clinical chemistry

BUN creatinine total bilirubin CK AST ALT GGT alkaline phosphatase sodium potassium chloride calcium phosphorous total protein albumin uric acid triglycerides and FSH (for female only see exclusion criteria6) will be measured according to assessment schedule in Table 7-1

7544 Urinalysis

Dipstick measurements for specific gravity protein glucose and blood and WBC and RBC sediments will be measured according to assessment schedule in Table 7-1

755 Electrocardiogram (ECG)

After resting for 5 minutes in a supine position a standard 12 lead ECG will be performed at screen visit Interpretation of the tracing must be made by a qualified physician and documented on the ECG section of the eCRF Each ECG tracing should be labeled with the study number subject initials subject number date and kept in the source documents at the study site Only clinically significant abnormalities should be reported in the eCRF Clinically significant abnormalities should also be recorded on the Adverse Event eCRF page at the baseline visit Clinically significant findings must be discussed with the NCH-GSK clinical project leader (CPL) prior to enrolling the subject in the study

756 Pregnancy and assessments of fertility

All females including women of non-child bearing potential will have a blood pregnancy test according to assessment schedule in Table 7-1 A positive pregnancy test requires immediate



interruption of study medication until repeated serum β-hCG is performed and found to be negative If positive the subject must be discontinued from the trial

757 Appropriateness of safety measurements

The safety assessments selected are standard for this indicationsubject population

76 Other assessments

761 Urine drug screen cotinine and alcohol assessments

A urine drug screen will be performed according to assessment schedule in Table 7-1 for amphetamines barbiturates benzodiazepines cocaine opiates phencyclidine (phenylcyclohexalpiperidine) tetrahydrocannabinol methadone methamphetamine tricyclic antidepressants oxycodone and propoxyphene

Subjects with a confirmed positive urine drug screen will not be randomized into the study (see Section 52 exclusion criterion No 20) or will be discontinued from the study

Cotinine is a metabolite of nicotine which is excreted in the urine from 2 to 4 days after tobacco or nicotine use Urine cotinine will be measured according to assessment schedule in Table 7-1 In case of urine cotinine level gt 200 ngmL the subject will not be randomized into the study or will be discontinued from the study

Alcohol will be measured according to assessment schedule in Table 7-1 through breathalyzer test In case of a positive finding in the alcohol test (as indicated by an alcohol breathalyzer test result ge 001) the subject will not be randomized into the study or will be discontinued from the study

762 Pharmacokinetics

Blood samples for the determination of tNAC plasma concentrations [5 ml each] will be taken in sitting position starting on Study Day 1 of each treatment period at the following times baseline (at -45 -30 and -15 minutes before study drug administration) and 5 10 20 30 40 50 minutes 1 15 2 4 6 8 10 12 24 36 and 48 hours post-dose in each period The blood collection vials must be labeled with the following randomization code sampling number and drug name A blood volume of 5 mL per time point from pre-dose to 12 hours post dose will be collected via a venous catheter and 5 mL blood for 24 36 and 48 hours will be collected via direct venipuncture Taken together a total of 20 blood samples will be taken for tNAC PK in each period resulting in a total blood volume draw for PK assessments to be approximately 200 ml over the two treatment periods

Blood will be taken during the trial 200 mL for PK samples and 30 mL for safety laboratory tests plus 10 ml for pregnancy test Therefore a total of approximatively 230 ml of blood will be taken for male and 235 ml for female

Time zero (ldquo0rdquo) as reference for post-dose PK samplings is defined as the time after swallowing of the study drug by the respective study subject The time after swallowing of the study drug and the time for complete ingestion of the 230 ml water will be recorded in eCRF



Documentation and timing of PK sample collection Actual times of PK-blood sampling will be documented The following deviations from the scheduled blood sampling time points exceeding the indicated acceptance ranges below will be recorded and commented as protocol deviations

Scheduled time Deviation (absolute values)

-45 min to 1 h gt 1 min

15 h to 2 h gt 3 min



All actual dates and actual times of blood sampling must be recorded on the eCRF page

Further details on collecting handling labeling of the PK samples and shipment instructions can be found in the laboratory manual provided by the bioanalytical laboratory to the study site

Bioanalytics will be performed by a specific and highly sensitive LC-MSMS methodology in a laboratory with GLP certification Method validation will have to be conducted in full compliance with the respective guidance documents EMA 2012 ([EMEACHMPEWP1922172009 Guideline on bioanalytical method validation July 2011]) A bioanalytical protocol and a Method Validation Report will be prepared to describe respectively the analytical plan and the method validation The estimated limits of quantification for tNAC will be confirmed during the method validation

8 Safety monitoring

81 Adverse events

An adverse event (AE) is the appearance or worsening of any undesirable sign symptom or medical condition occurring after signing the informed consent form even if the event is not considered to be related to study drug Study drug includes the investigational drug under evaluation and the comparator drug that is given during any period of the study Medical conditionsdiseases present before starting study drug are only considered AEs if they worsen after signing the informed consent form Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or symptoms are considered clinically significant or require therapy

The occurrence of AEs should be sought by non-directive questioning of the subject at each visit during the study AEs also may be detected when they are volunteered by the subject during or between visits or through physical examination laboratory test or other assessments All AEs must be recorded on the Adverse Events eCRF page with the following information

1 The severity grade [mild moderate severe]

2 Its relationship to the study drug(s) (suspectednot suspected)

3 Its duration (start and end dates or if continuing at final exam)

4 Whether it constitutes a serious adverse event (SAE)



An SAE is defined as an event which

Is fatal or life-threatening

Results in persistent or significant disabilityincapacity

Constitutes a congenital anomalybirth defect

Requires inpatient hospitalization or prolongation of existing hospitalization unless hospitalization is for

Routine treatment or monitoring of the studied indication not associated with any deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since the start of study drug

Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE given above and not resulting in hospital admission

Social reasons or respite care in the absence of any deterioration in the subjectrsquos general condition

Is medically significant ie defined as an event that jeopardizes the subject or may require medical or surgical intervention to prevent one of the outcomes listed above

Unlike routine safety assessments SAEs are monitored continuously and have special reporting requirements see Section 8-2

All AEs should be treated appropriately Treatment may include one or more of the following no action taken (ie further observation only) study drug dosage adjustedtemporarily interrupted study drug permanently discontinued due to this AE concomitant medication given non-drug therapy given subject hospitalizedsubjectrsquos hospitalization prolonged subject withdrawn from the study The action taken to treat the AE should be recorded on the Adverse Event eCRF page

Once an AE is detected it should be followed until its resolution or until it is judged to be permanent and assessment should be made at each visit (or more frequently if necessary) of any changes in severity the suspected relationship to the study drug the interventions required to treat it and the outcome

Information about common side effects already known about the investigational drug can be found in the Investigator Brochure (IB) or will be communicated between IB updates in the form of Investigator Notifications This information will be included in the subject informed consent and should be discussed with the subject during the study as needed

82 Serious adverse event reporting

To ensure subject safety every SAE regardless of suspected causality occurring after the subject has provided informed consent and until 30 days after the subject has stopped study participation (defined as time of last dose of study drug taken or last visit whichever is later)must be reported to the NCH-GSK Drug Safety and Pharmacovigilance (DSP) department within 24 hours of learning of its occurrence

Any SAEs experienced after this 30 day period should only be reported to the NCH-GSKDSP department if the investigator suspects a causal relationship to the study drug



Recurrent episodes complications or progression of the initial SAE must be reported as follow-up to the original episode regardless of when the event occurs This report must be submitted within 24 hours of the investigator receiving the follow-up information An SAE that is considered completely unrelated to a previously reported one should be reported separately as a new event

Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form The investigator must assess the relationship to study drug complete the SAE Report Form in English and send the completed signed form by fax within 24 hours to the NCH-GSK DSP Department

The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the CRF documentation at the study site

Follow-up information must be sent to the same person to whom the original SAE Report Form was sent using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report The follow-up information should describe whether the event has resolved or continues if and how it was treated whether the blind was broken or not and whether the subject continued or withdrew from study participation

The NCH-GSK DSP fax number is

International FAX

If a SAE is reported and not documented in the current IB and is thought to be related to the Novartis study drug a NCH-GSK DSP associate may require further information from the investigator for Health Authority reporting NCH-GSK will also perform an analysis of similar events and draft a dear investigator letter based on the findings and distribute to all investigators who participate in NCH-GSK sponsored NAC studies Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported to the competent authorities along with analysis of similar event report and relevant ethic committees in accordance with the applicable regulatory requirements Fatal or life-threatening and suspected SAEs are submitted within seven days of initial receipt date whereas non-fatal and non-life-threatening suspected SAEs and other reportable SAEs within 15 days of their initial receipt date or according to national reporting requirements All SUSARs submitted to HAs are also sent to the IRBsEthics Committees and the concerned investigators with an Investigator Notification (IN) letter by Clinical Operations

83 Pregnancies

To ensure subject safety each pregnancy in a subject must be reported to NCH-GSK within 24 hours of learning of its occurrence The pregnancy should be followed up to determine outcome including spontaneous or voluntary termination details of the birth and the presence or absence of any birth defects congenital abnormalities or maternal andor newborn complications

Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to NCH-GSK DSP Department (International FAX )

PPD

PPD



Pregnancy follow-up should be recorded on the same form and should include an assessment of the possible relationship to the Novartis study drug of any pregnancy outcome Any SAE experienced during pregnancy must be reported on the SAE Report Form

9 Data review and database management

91 Site monitoring

Before study initiation at a site initiation visit or at an Investigator Meeting a NCH-GSKrepresentative or the CRO will review the protocol and the eCRF with the investigators and their staff During the study the study monitor will visit the site according to the monitoring plan to check the completeness of subject records the accuracy of entries on the eCRF the adherence to the protocol and to Good Clinical Practice (GCP) the progress of enrollment and to ensure that study drug is being stored dispensed and accounted for according to specifications and related Standard Operating Procedures (SOPs) Key study personnel must be available to assist the study monitor during these visits Source data verification is done by direct inspection of the subjectrsquos original files by authorized persons

The investigator must maintain source documents for each subject in the study consisting of case and visit notes (hospital records or clinic outpatient charts) containing demographic and medical information laboratory data ECGs and the results of any other tests or assessments All information on eCRF must be traceable to these source documents in the subjects file The investigator must also keep the original informed consent form signed by the subject (a signed copy is given to the subject)

Trial documents including the Essential Documents collected in the Investigator File must bekept at the site for at least fifteen years or two years after regulatory submission whichever is longer It is the responsibility of NCH-GSK to inform the Investigator as to when these documents no longer need to be retained

The investigator must give the study monitor access to all relevant source documents to confirm their consistency with the eCRF entries NCH-GSK monitoring standards require full verification for the presence of informed consent adherence to the inclusionexclusion criteria documentation of SAEs and the recording of data that will be used for all primary and safety outcomes Additional checks of the consistency of the source data with the eCRF are performed according to the study-specific monitoring plan No information in source documents about the identity of the subjects will be disclosed

92 Data collection

Designated investigator staff will enter the data required by the protocol into the eCRF using a fully validated software that conforms to the FDA 21 CFR (code of federal regulations) Part 11 requirements Designated investigator site staff will not be given access to the electronic data capture (EDC) system until they have been trained and documented Automatic validation programs check for data discrepancies and by generating appropriate error messages allow the data to be confirmed or corrected before transfer of the data to the Data Management (DM) CRO working on behalf of NCH-GSK The Investigator must certify that the data entered into the eCRF are complete and accurate After database lock the investigator



will receive a CD-ROM or paper copies of the patient data for archiving at the investigational site

93 Database management and quality control

The DM CRO staff working on behalf of NCH-GSK review the data entered into the eCRFs by investigational site staff for completeness and accuracy and instruct the site staff to make any required corrections or additions Queries are sent to the investigational site using an electronic data query Designated investigator site staff is required to respond to the query and confirm or correct the data If the electronic query system is not used a paper Data Query Form (DQF) will instead be faxed to the site for resolution Responsible site staff will complete and sign the faxed copy and return it to the DM CRO who will make the correction to the database The signed copy of the Data Query Form is kept at the investigator site Routine Quality Control (QC) audits of all key safety efficacy and PK data in the database are performed prior to locking the database

Concomitant medications entered into the database will be coded using an internal validated medication dictionary Medical historycurrent medical conditions and AEs will be coded using current version of the Medical Dictionary for Regulatory Activities (MedDRA) terminology

Safety laboratory samples will be processed locally and the results will be sent electronically to the designated DM CRO for overall study database integration

A contract research laboratory that is in compliance with Good Laboratory Practices (GLP) and GCP will analyze blood PK samples collected during the study The raw data will be reviewed approved and audited by appropriate personnel of the analytical laboratory to ensure data completeness and accuracy The derived plasma PK data will be transferred electronically to the Data Management CRO and NCH-GSK for overall study database integration

At the conclusion of the study the occurrence of any protocol deviations will be determined After these actions have been completed and the database has been declared to be complete and accurate it will be locked and made available for data analysis Any changes to the database after that time can only be made by joint written agreement between the Clinical Project Leader the Project Statistician and the Project Data Manager with authorization from the Head of Clinical Research

10 Data analysis

101 Populations for analysis

The safety population will consist of all randomized subjects who received at least one dose of the IMP

The PK-analyzable population will consist of all subjects who completed both treatment periods and who and who did not experience vomiting or diarrhea (within 60 min) after study drug administration Concentration data from those excluded subjects will be presented in the individual listings but will not be included in the summary statistics



Comprehensive justification for the classification of a protocol deviation as ldquomajorrdquo will be determined at the Data Review meeting and will be described in the statistical analysis plan (SAP) and the integrated clinical study report


Demographic and other baseline data will be presented using descriptive statistics for the safety and PK populations Demographic and other baseline data (including ECG pregnancy screens urine drug screen cotinine screen and breath alcohol assessment) will be listed

103 Treatments (study drug rescue medication other concomitant therapies compliance)

Exposure to Test and Reference IMPs will be listed in the safety and PK-analyzable populations and frequency tables will be provided Concomitant medications will be summarized by preferred term and the number and percentage of subjects who took any concomitant medication will be presented

104 Analysis of the primary objective

1041 Variables

In order to determine the PK profile of tNAC the following (see Table 10-1) single dose plasma PK variables will be determined from the baseline corrected plasma concentrations of tNAC using non-compartmental methods for which the baseline endogenous plasma tNAC levels will be determined by the average of the three (-45 -30 and -15 minutes) pre-dose plasma concentrations of tNAC

Table 10-1 PK variables

Parameter Descriptionderivation

Cmax The maximum observed post-dose concentration obtained without interpolation

AUClast The area under the plasma concentration versus time curve calculated from time 0 to the last measurable sampling time point t computed using the linear trapezoidal rule

AUCinf The area under the plasma concentration versus time curve calculated from time 0 to infinity where AUC = AUClast + Clastλz Clast is the concentration at the last measurable sampling time point and λz is the terminal elimination rate constant

RA (Residual Area) Percent extrapolated area (= (AUCinf ndash AUClast) AUCinf)100)

Lambda_z The terminal elimination rate constant computed as the slope of the regression line of ln (C(t)) on time The regression should generally involve at least 3 consecutive measurable concentrations that decrease over time

Tmax Time of maximum observed plasma concentration

Tfrac12 The elimination half-life computed as T12 = 0693 λz



Actual post-dose sampling times will be listed by treatment and subject Calculation of all PK variables will be based on actual sampling times rather than the scheduled sampling times


1042 Statistical model and method of analysis

All statistical analyses will be done in the PK-analyzable population

Plasma concentrations (without and with baseline correction) at each time point will be summarized descriptively and graphed by treatment versus time for individual subjects and for the mean

All PK variables listed in Table 10-1 will be calculated after first correcting plasma concentrations based on the average of the measures from the three baseline time points of tNAC (ie calculated value = measured value ndash baseline value) The post-dose plasma tNAC concentrations that equal or fall below the baseline concentrations (ie zero or negative values) will not be brought into the PK calculation For calculation of the Tfrac12 only the points in the terminal elimination phase that are linear in the ln (C(t)) on time scale will be brought into the calculation

The PK variables (except Tmax) will then be summarized by descriptive statistics (N arithmetic means median standard deviations minimum maximum and coefficients of variation) Tmax will be summarized using median Q1 Q3 minimum and maximum

Additionally geometric means will be calculated for log-transformed PK variables (AUClastand Cmax and AUCinf)

Log-transformed AUClast Cmax and AUCinf will be compared between treatments using an ANOVA including terms for sequence formulation and period and subject nested within sequence as fixed effects Sequence will be tested using subject nested within sequence as the error term The presence of a statistically significant sequence effect will be noted and its implications will be discussed A 90 CI on the ratio of untransformed PK variables to assess the hypothesis of bioequivalence will be derived through reverse transformation of the 90 CI for the difference in the log scale

If the respective 90 confidence intervals are entirely contained into the range of 80 - 125 for AUClast and for Cmax then the bioequivalence between the test and reference formulations will be declared

1043 Handling of missing valuescensoringdiscontinuations

AUClast and AUCinf will be computed by applying the linear trapezoidal rule to all non-missing concentrations

Since the expected bioanalytical LLOQ (1 ngmL) for plasma tNAC is well below the reported lowest basal tNAC plasma levels (approximately 13 ngmL) no below limit of quantitation (BLOQ) values are expected in this study All measured plasma tNAC concentrations below basal NAC levels obtained before Cmax for each subject will be



imputed as zero All measured plasma tNAC concentrations below basal tNAC levels obtained after Cmax for each subject will not be imputed

For other PK variables missing data will not be imputed

105 Analysis of secondary objective

1051 Efficacy (secondary)

Not applicable

1052 Safety

Safety variables will be summarized for the safety population

AEs will be summarized by presenting for each treatment the number and percentage of subjects having any AE in each MedDRA System Organ Class (SOC) and having each individual AE This will be done separately for all AEs and for AEs that are suspected to be drug-related All AEs will also be tabulated in corresponding fashion by severity Any other information collected (eg action taken duration) will be listed as appropriate Each AE will be attributed to the treatment taken most recently before the start of the AE

Vital signs and their changes from baseline will be summarized by time-point and treatment Baseline will be defined as the last pre-dose measurement Summary statistics will include mean standard deviation minimum median and maximum No inferential statistics will be presented

All safety data including Physical exam and Laboratory data will be listed with abnormalities noted

106 Sample size calculation

A recent BE study in healthy adult Chinese subjects (Liu YM et al 2010) using a 600 mg effervescent tablet as Reference product (Fluimucilreg 600 mg effervescent tablet Zambon Group Italy) and three NACreg 200 mg effervescent tablets as Test product (Hexal AG Holzkirchen Germany) demonstrated bioequivalence of both products based on a total sample size of N=24 male subjects with overall narrow confidence intervals for Cmax AUClast and AUCinf and an associated average relative BA of the Test formulation to the Reference formulation of 9625 (the same definition for tNAC as per our protocol was usedin this study) While the intra-subject CV from ANOVA for Cmax AUClast and AUCinf were not reported it was estimated that the CV could be as high as 32 for Cmax Assuming a departure of up to 4 from true bioequivalence to have 80 power for the CIs of AUClast and Cmax to be within 80 and 125 it is estimated that N=40 subjects are needed to complete the 2-way crossover study Therefore in total N=46 healthy subjects will be enrolled and randomized in order to have 40 evaluable subjects completing both periods taking into account an approximately 10 drop out rate



A sample size of 40 evaluable subjects (n=46 to allow for drop outs) based on an assumed intra-subject CV of 30 and 90 power was confirmed by trial simulation Other trial design features were also confirmed by simulation

107 Power for analysis of critical secondary variables

Not applicable

108 Interim analysis

Not applicable

11 Ethical considerations

111 Regulatory and ethical compliance

This clinical study was designed and shall be implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice with applicable local regulations (including European Directive 200120EC US Code of Federal Regulations Title 21 and Japanese Ministry of Health Labor and Welfare) and with the ethical principles laid down in the Declaration of Helsinki

112 Informed consent procedures

Eligible subjects may only be included in the study after providing written (witnessed where required by law or regulation) IRBIECREB-approved informed consent or if incapable of doing so after such consent has been provided by a legally acceptable representative of the subject In cases where the subjectrsquos representative gives consent the subject should be informed about the study to the extent possible given hisher understanding If the subject is capable of doing so heshe should indicate assent by personally signing and dating the written informed consent document or a separate assent form Informed consent must be obtained before conducting any study-specific procedures (ie all of the procedures described in the protocol) The process of obtaining informed consent should be documented in the subject source documents

NCH-GSK will provide to investigators in a separate document a proposed informed consent form that complies with the ICH GCP guideline and regulatory requirements and is considered appropriate for this study Any changes to the proposed consent form suggested by the investigator must be agreed to by NCH-GSK before submission to the IRBIECREB and a copy of the approved version must be provided to the NCH-GSK clinical operational manager (COM) after IRBIECREB approval

Women of child bearing potential should be informed that taking the study medication may involve unknown risks to the fetus if pregnancy were to occur during the study and agree that in order to participate in the study they must adhere to the contraception requirement for the duration of the study If there is any question that the subject will not reliably comply they should not be entered in the study



113 Responsibilities of the investigator and IRBIECREB

The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted IRBIECREB before study start A signed and dated statement that the protocol and informed consent have been approved by the IRBIECREB must be given to NCH-GSK before study initiation Prior to study start the investigator is required to sign a protocol signature page confirming hisher agreement to conduct the study in accordance with these documents and all of the instructions and procedures found in this protocol and to give access to all relevant data and records to NCH-GSK monitors auditors NCH-GSK Clinical Quality Assurance representatives designated agents of NCH-GSK IRBsIECsREBs and regulatory authorities as required

If an inspection of the clinical site is requested by a regulatory authority the investigator must inform NCH-GSK immediately that this request has been made SAEs will be reported by the investigator to the IRBIECREB as required

114 Quality Assurance Audits and Health Authority Inspections

The clinical investigator study site may be subject to quality assurance audits performed by NCH-GSK or its agents on behalf of NCH-GSK andor regulatory inspections by the appropriate health authorities The investigator and the institution will allow NCH-GSK its agents andor appropriate regulatory authorities direct access to study records including source records CRFs and other study relevant documentation for review Subject privacy and data confidentiality will be observed accordingly to the applicable regulatory requirements andor local laws

The investigator must immediately notify NCH-GSK if they have been contacted by a regulatory agency concerning an upcoming inspection It is important that investigators and their relevant personnel are available during audits andor inspections and that sufficient time is devoted to the process

115 Publication of study protocol and results

NCH assures that the key design elements of this protocol will be posted in a publicly accessible database such as clinicaltrialsgov In addition upon study completion and finalization of the study report the results of this trial will be either submitted for publication andor posted in a publicly accessible database of clinical trial results

12 Protocol adherence

Investigators ascertain they will apply due diligence to avoid protocol deviations Under no circumstances should the investigator contact NCH-GSK or its agents if any monitoring the trial to request approval of a protocol deviation as no authorized deviations are permitted If the investigator feels a protocol deviation would improve the conduct of the study this must be considered a protocol amendment and unless such an amendment is agreed upon by NCH-GSK and approved by the IRBIECREB it cannot be implemented All protocol deviations will be recorded by the Investigator and all important deviations will be reported in the clinical study report (CSR) as defined in the note for Guidance ICH E3



121 Protocol Amendments

Any change or addition to the protocol can only be made in a written protocol amendment that must be approved by NCH-GSK Health Authorities where required and the IRBIECREB Only amendments that are required for subject safety may be implemented prior to IRBIECREB approval Notwithstanding the need for approval of formal protocol amendments the investigator is expected to take any immediate action required for the safety of any subject included in this study even if this action represents a deviation from the protocol In such cases NCH-GSK should be notified of this action and the IRBIECREB at the study site should be informed within 10 working days

13 References

[Atkuri KR Mantovani JJ Herzenberg LA Herzenberg LA (2007)] N-Acetylcysteine ndash a safe antidote for cysteineglutathione deficiency Curr Opin Pharmacol 7 355ndash359

[Borgstroumlm L Kagedal B Paulsen O (1986)] Pharmacokinetics of N-acetylcysteine in man Eur J Clin Pharmacol 31 217-222

[Committee for medicinal products for human use (CHMP) European Medicines Agency (2010)] Guideline on the investigation of bioequivalence

[Committee for medicinal products for human use (CHMP) European Medicines Agency (2012)] Guideline on bioanalytical method validation

[Dekhuijzen PNR van Beurden WJC(2006)] The role for N-acetylcysteine in the managementof COPD Int J Chron Obstruct Pulmon Dis 1 99ndash106

[Food and Drug Administration US Department of Health and Human Services (2001) ]Guidance for Industry Bioanalytical Method Validation

[Gabard B Mascher H (1991)] Endogenous plasma N-acetylcysteine and single dose oral bioavailability from two different formulations as determined by a new analytical method Biopharm Drug Dispos 12 343ndash353

[Grandjean EM Berthet P Ruffmann R Leuenberger P (2000)] Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease A meta-analysis of published double-blind placebo-controlled clinical trials Clin Ther 22 209ndash221

[Hamid KA Katsumi H Sakane T Yamamoto A (2009)] The effects of common solubilizing agents on the intestinal membrane barrier functions and membrane toxicity in rats Int J Pharm 379100-108

[Holdiness MR (1991)] Clinical pharmacokinetics of N-acetylcysteine Clin Pharmacokinet 20 123ndash134

[Liu YM Liu Y Lu C Jia JY et al (2010)] Relative bioavailability of generic and branded acetylcysteine effervescent tablets A single-dose open-label randomized-sequence two-period crossover study in fasting healthy Chinese male volunteers Clin Ther 32 2097-105

[Miller LF Rumack BH (1983)] Clinical safety of high oral doses of acetylcysteine Semin Oncol 10(1 Suppl 1)76-85

[Olsson B Johansson M Gabrielsson J Bolme P (2006)] Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine Eur J Clin Pharmacol 34 77-82



[Sadowska AM Verbraecken J Darquennes K De Backer WA(2006)] Role of N-acetylcysteine in the management of COPD Int J Chron Obstruct Pulmon Dis 1 425ndash434

Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background

2Purpose and rationale

3Objectives

31Primary objective

32Secondary objective

4Study design

5Population

51Inclusion criteria

52Exclusion criteria

6Treatment

61Investigational and reference drugs

62Treatment arms

63Treatment assignment

64Treatment blinding

65Treating the subject

651Subject numbering

652Dispensing the study drug

653Study drug supply storage and tracking

654Instructions for prescribing and taking the study drug

655Permitted study drug dose adjustments and interruptions

656Rescue medication

657Other concomitant treatment

658Study drug discontinuation and premature subject withdrawal

659Emergency unblinding of treatment assignment

6510Study completion and post-study treatment

6511Premature study termination

7Visit schedule and assessments

71Information to be collected on screening failures

72Subject demographics and other baseline characteristics

73Treatment exposure and compliance

74Efficacy

75Safety

751Physical examination

752Vital signs

753Height and Weight

754Laboratory evaluations

7541Hematology

7542Virology

7543Clinical chemistry

7544Urinalysis

755Electrocardiogram (ECG)

756Pregnancy and assessments of fertility

757Appropriateness of safety measurements

76Other assessments

761Urine drug screen cotinine and alcohol assessments

762Pharmacokinetics

8Safety monitoring

81Adverse events

82Serious adverse event reporting

83Pregnancies

9Data review and database management

91Site monitoring

92Data collection

93Database management and quality control

10Data analysis

101Populations for analysis


103Treatments (study drug rescue medication other concomitant therapies compliance)

104Analysis of the primary objective

1041Variables

1042Statistical model and method of analysis

1043Handling of missing valuescensoringdiscontinuations

105Analysis of secondary objective

1051Efficacy (secondary)

1052Safety

106Sample size calculation

107Power for analysis of critical secondary variables

108Interim analysis

11Ethical considerations

111Regulatory and ethical compliance

112Informed consent procedures

113Responsibilities of the investigator and IRBIECREB

114Quality Assurance Audits and Health Authority Inspections

115Publication of study protocol and results

12Protocol adherence

121Protocol Amendments

13References



Table 10-1PK variables

Novartis Consumer Health Confidential of 43


Table of contents

List of tables 4

List of figures 4

List of abbreviations 5

Glossary of terms8

Protocol synopsis9

1 Background15

2 Purpose and rationale 15

3 Objectives 17

31 Primary objective17

32 Secondary objective17

4 Study design 17

5 Population18

51 Inclusion criteria 18

52 Exclusion criteria 19

6 Treatment22

61 Investigational and reference drugs 22

62 Treatment arms 22

63 Treatment assignment 23

64 Treatment blinding23

65 Treating the subject23

651 Subject numbering 23

652 Dispensing the study drug23

653 Study drug supply storage and tracking 24

654 Instructions for prescribing and taking the study drug24

655 Permitted study drug dose adjustments and interruptions25

656 Rescue medication 25

657 Other concomitant treatment25

658 Study drug discontinuation and premature subject withdrawal 25

659 Emergency unblinding of treatment assignment26

6510 Study completion and post-study treatment26

6511 Premature study termination 26

7 Visit schedule and assessments 27

71 Information to be collected on screening failures28


73 Treatment exposure and compliance 29



74 Efficacy29

75 Safety 29


752 Vital signs29










81 Adverse events32


83 Pregnancies 34





10 Data analysis36





1041 Variables 37





1052 Safety39














13 References 42







AE Adverse Event






BA Bioavailability

BE Bioequivalence


BMI Body Mass Index

BP Blood Pressure




CK Creatine Kinase






DM Data Management








GI Gastrointestinal




GSH Glutathione



















msec Millisecond(s)




PK Pharmacokinetics

QC Quality Control













Glossary of terms











control







Protocol synopsis









Objectives

Primary Objective


reg2 oral


Secondary Objective


reg2 oral





Inclusion criteria













Exclusion criteria

























































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References






74 Efficacy29

75 Safety 29


752 Vital signs29










81 Adverse events32


83 Pregnancies 34





10 Data analysis36





1041 Variables 37





1052 Safety39














13 References 42







AE Adverse Event






BA Bioavailability

BE Bioequivalence


BMI Body Mass Index

BP Blood Pressure




CK Creatine Kinase






DM Data Management








GI Gastrointestinal




GSH Glutathione



















msec Millisecond(s)




PK Pharmacokinetics

QC Quality Control













Glossary of terms











control







Protocol synopsis









Objectives

Primary Objective


reg2 oral


Secondary Objective


reg2 oral





Inclusion criteria













Exclusion criteria

























































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References













13 References 42







AE Adverse Event






BA Bioavailability

BE Bioequivalence


BMI Body Mass Index

BP Blood Pressure




CK Creatine Kinase






DM Data Management








GI Gastrointestinal




GSH Glutathione



















msec Millisecond(s)




PK Pharmacokinetics

QC Quality Control













Glossary of terms











control







Protocol synopsis









Objectives

Primary Objective


reg2 oral


Secondary Objective


reg2 oral





Inclusion criteria













Exclusion criteria

























































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References







AE Adverse Event






BA Bioavailability

BE Bioequivalence


BMI Body Mass Index

BP Blood Pressure




CK Creatine Kinase






DM Data Management








GI Gastrointestinal




GSH Glutathione



















msec Millisecond(s)




PK Pharmacokinetics

QC Quality Control













Glossary of terms











control







Protocol synopsis









Objectives

Primary Objective


reg2 oral


Secondary Objective


reg2 oral





Inclusion criteria













Exclusion criteria

























































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References






GSH Glutathione



















msec Millisecond(s)




PK Pharmacokinetics

QC Quality Control













Glossary of terms











control







Protocol synopsis









Objectives

Primary Objective


reg2 oral


Secondary Objective


reg2 oral





Inclusion criteria













Exclusion criteria

























































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References










Glossary of terms











control







Protocol synopsis









Objectives

Primary Objective


reg2 oral


Secondary Objective


reg2 oral





Inclusion criteria













Exclusion criteria

























































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References






Protocol synopsis









Objectives

Primary Objective


reg2 oral


Secondary Objective


reg2 oral





Inclusion criteria













Exclusion criteria

























































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References







Exclusion criteria

























































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References













































Study design













Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References














Other assessments



Safety assessments


Data analysis










1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References











1 Background



















3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References














3 Objectives






4 Study design







Days -1 1 to 3a

Days 3 to 7a

63 hour in-house

Days 7 8 to 10

Day 10b













5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References











5 Population




































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References


































































6 Treatment







62 Treatment arms











































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References













































Pregnancy

Death























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References


























Screening



7

Visit 1 2 3 4

Day -21 to -2 -1 1 2 3 3-7 7 8 9 10 10


1x


Medical History x


X x

Vital signs2

X x x x x x


x x

12-lead ECG x


x x

Urinalysis x x

Virology x





x x x x


x x x x x x x x

Randomization x


x x

PK blood sampling6

x x x x x x









Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References






Screening



7

Visit 1 2 3 4




For females only5









Screening number

Date of screening



Race

Ethnicity

Date of birth

Sex











74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References









74 Efficacy

None

75 Safety





752 Vital signs










7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References











7541 Hematology


7542 Virology




7544 Urinalysis
































8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References






























8 Safety monitoring

81 Adverse events

































International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References






























International FAX


83 Pregnancies



PPD

PPD





91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References








91 Site monitoring





92 Data collection











10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References













10 Data analysis












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References












1041 Variables
































Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References

























Not applicable

1052 Safety











Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References








Not applicable


Not applicable
























13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References




















13 References

















Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References







Table of contents

List of tables

List of figures


Glossary of terms

Protocol synopsis

1Background


3Objectives

31Primary objective


4Study design

5Population



6Treatment


62Treatment arms



















74Efficacy

75Safety


752Vital signs



7541Hematology

7542Virology


7544Urinalysis




76Other assessments


762Pharmacokinetics

8Safety monitoring

81Adverse events


83Pregnancies


91Site monitoring

92Data collection


10Data analysis





1041Variables





1052Safety



108Interim analysis









13References




NCH-GSKAcetylcysteine 2% oral solution...Novartis Consumer Health Confidential Page 9of 43 Clinical...

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Transcript of NCH-GSKAcetylcysteine 2% oral solution...Novartis Consumer Health Confidential Page 9of 43 Clinical...