Clinical Trial Protocol for Antibacterial Drug

8/14/2019 Clinical Trial Protocol for Antibacterial Drug

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ASSIGNMENT NO: 01

TO GIVE AN OVER VIEW AND PROTOCOL FORTHE CONDUCT OF CLINICAL TRIAL FOR AN ANTI BACTERIAL DRUG

(MODEL DRUG)

SUBMITTED TOProf. Gautam SinghviInstructor-in-chargeSUBMITTED BY:

Sr.

NO.

NAME ID NO.

1. Gunja Chaturvedi 2008H1461012. R.Vidya 2008H146102

Submitted for the partial fulfillment of the requirements of the

course

CLINICAL RESEARCH (PHA G543)

BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCEPILANI (RAJASTHAN)AUGUST, 2009


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INDEXA. Study detailsB. Introduction & Objectives1. Background2. Introduction3. Preclinical data for the Model drug4. Mechanism of action5. Bioequivalence requirement6. Pharmacology

6.1.1 Absorption6.1.2 Distribution6.1.3 Metabolism6.1.4 Excretion6.1.5 Adverse drug events6.1.6 Dosage

7. Study design7.1.1 Summary7.1.2 No. of subjects planned7.1.3 No. of subjects enrolled7.1.4 No. of subjects included in primary analysis & safety datasheet7.1.5 Gender7.1.6 Mean (SD) of age7.1.7 Diagnosis and main criteria for eligibility7.1.8 Investigational product, dose and mode of administration7.1.9 Washout periods


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7.1.10 Duration of treatment8. Restrictions

8.1.1 Medications8.1.2 Diet8.1.3 Activity

9. Study population9.1.1 Screening assessments (lab tests and general examinations)9.1.2 Inclusion criteria9.1.3 Exclusion criteria

10.Study endpoints10.1.1 Primary endpoints10.1.2 Secondary endpoints

11.Schedule of assessment12.Study medication

12.1.1 Handling, storage & accountability procedure12.1.2 Return or Destruction of Study Drug

13.Analytical procedures , Pharmacokinetic studies and assessment of patient compliance13.1.1 Microbiological assessment13.1.2 Pharmacokinetic Characteristics13.1.3 Assessment of compliance

14.Safety:14.1.1 Clinical safety measurement

15.Handling of safety parameters15.1.1 Adverse drug events management15.1.2 Reporting of Serious Adverse Events


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16.Statistical considerations17.Deviations18.Ethical Considerations19.Subject Compensation for Participating in the study20.Termination of the Study21.Study Documentation22.Quality Assurance Audits23.Confidentiality of Data24.Archives25.Publication Policy


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STUDY DETAILS

Protocol title: A multicenter, Randomized, Double-Blind, Active Control, Parallel Assignment,Safety/Efficacy Study for the Model drug monotherapy versus comparator treatment

(vancomycin & vancomycin + ceftazidime)

Investigational product: Model drug Category: Antibacterial Indication: skin & complicated skin structure infections and Nosocomial pneumonia Brief description: This study is a multicenter, randomized, Double-Blind, Active Control, Parallel

Assignment, Safety/Efficacy Study and the purpose of this study is to (1) compare the clinical

cure rate of Model drug monotherapy versus a comparator (vancomycin & vancomycin +

ceftazidime) in the treatment of patients with complicated skin and skin structure infections and

(2) in the treatment of patients with nosocomial pneumonia.

Study sponsor: .. Protocol no: 2009011OFB IND no: The study is not conducted under an IND. Study phase: Phase III Study initiation date: October 2009(the first subject enrolled) Study completion date: February 2011(last subject off the study) Clinical study manager: .. Good Clinical practice: This study is carried out in accordance with (US FDA) regulations &

international conference or harmonization (ICH) Good Clinical Practice (GCP) guidelines.

Essentials documents will be retained in accordance with ICH GCP.


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INTRODUCTION AND OBJECTIVES

1. Background: Skinandskin-structureinfections are common,and range fromminor pyodermasto severe necrotizing infections. Complicated

infections are defined as involving abnormal skin

or wounds,occurring in compromised hosts, or requiring surgical intervention.

Classification

schemes for these infections are varied andconfusing.Distinguishing characteristics include the

etiological agent(s),clinical context and findings, depth of tissue involvement and rate of

progression. The most common pathogens are aerobic Gram-positivecocci, but complicated

infections frequently involve Gram-negativebacilli and anaerobic bacteria. Initial antibiotic

therapy is usually empirical, and later modified by the results ofstains and cultures of wound

specimens. Broad-spectrum coverage isfrequently needed for complicatedinfections. This study

is basically a randomized, doubleblind, multicenter trial involving patients with a broad range of

complicated skin and skinstructure infections due to either grampositive or gramnegative

bacteria is conducted to compare Model drug monotherapy with treatment with vancomycin

plus ceftazidime.

2. Introduction: Model drug is a prodrug, a prototypical cephalosporin with bactericidal activityagainst a broad spectrum of gram-positive bacteria, including methicillin-resistant

staphylococcus species. It is also active against many gram-negative bacteria, including many

Enterobacteriaceae.

3. Preclinical data for the Model drug:Pharmacokinetic and Pharmacodynamic characteristics of the Model drug


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4. Mechanism of action: Model drug has a bactericidal mode of action that involves tight bindingto many common essential penicillin-binding proteins (PBPs) in both gram-positive & gram-

negative bacteria. It has distinctive bactericidal activity against methicillin-resistant

staphylococci primarily due to its novel strong binding to the staphylococcal PBP2a, the PBP that

is chiefly responsible for -lactum resistance in methicillin-resistant staphylococci including

methicillin-resistant S.aureus (MRSA).

5. Bioequivalence requirement:The requirement of the following study is to compare the efficacyof the Model drug to that of Vancomycin & vancomycin +ceftazidime combination in patients

with primarily complicated skin and skin structure infections(cSSSIs) caused by gram- positive

bacteria and secondly for nosocomial pneumonia. The primary objective is to assessnoninferiority on the basis of the cure rates 7 to

14 days after the completion of therapy in

patients.

6. Pharmacology:6.1.1 Absorption: Model drug is administered intravenously and therefore has 100%

bioavailability.

6.1.2 Distribution: Model drug binds minimally (16%) to plasma proteins & binding isindependent of the concentration. Its steady-state volume of distribution (18L)

approximates extracellular fluid volume in humans.

6.1.3 Metabolism: Conversion from the prodrug (Model drug) to the active moiety occursrapidly and is mediated by plasma esterase.Prodrug concentrations are negligible and

measurable in plasma and urine only during infusion. The active Model drug undergoes

minimal metabolism to the open-ring metabolite, which is microbiologically inactive.Systemic exposure of the open-ring metabolite was considerably lower than for Model

drug, accounting for approximately 45 of the parent exposure.

6.1.4 Excretion: Model drug is eliminated primarily unchanged by renal excretion and thepredominant mechanism responsible for the elimination is glomerular filtration, with

some active reabsorption .In preclinical studies probenecid did not affect the

pharmacokinetics of the Model drug, thereby indicating no involvement of active tubular

secretion mechanisms. Elimination half life of the open-ring metabolite was slightly

longer, approximately 5 hours compared with Model drug, which was approximately 3

hours. Following single dose administration, approximately 89% of the administered dose

is recovered in the urine as active Model drug (83%), the open-ring metabolite (5%) and

prodrug (Model drug) (


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hypersensitivity to penicillin, to pregnant and breast-feeding women, to patients younger

than 18 years of age and to the patients with renal impairment or severe hepatic

impairment. As with all antibiotics that affect normal gastrointestinal flora, Model drug

may increase the risk for C. difficile infection.

6.1.6 Dosage: 500mg i.v. (equivalent to q12h over 60 min) of the Model drug or 1g Vancomycin q12h

for 7 14 days.

500mg equivalents of the Model drug given as i.v. infusion q8hr over 120 min plusplacebo q12hr over 60 min or 1g Vancomycin q12hr over 60min plus 1g ceftazidime

q8hr over 120 min for 7 -14 days.

7. Study design:7.1.1 Summary:In this study the patients are randomized (2:1) to receive intravenous infusions

of the Model drug 500mg over 120 minutes every 8 hours and placebo over 60 minutes

every 12 hours, or Vancomycin 1g over 60 minutes every 12 hours plus ceftazidime 1g

over 120 minutes every 8 hours for 7 14 days.Vancomycin dose is adjusted based on

the serum concentrations according to local practices.

7.1.2 No. of subjects planned: 10007.1.3 No. of subjects enrolled: .7.1.4 No. of subjects included in primary analysis & safety datasheet: .7.1.5 Gender:Male =.. & Female = (No. of males and females)7.1.6 Mean (SD) of age: The age of the enrolled subjects should be mentioned in terms of

mean (standard deviation) of the age.

Note: Subjects withdrawn or dropped out subsequent to dosing will not be replaced.

Data will be presented on all the subjects who completed the study. If necessary, an

unequal number of subjects per sequence will be used, and data will be presented on all

the subjects who completed the study.

7.1.7 Diagnosis and main criteria for eligibility: Complicated skin and skin structureinfections(cSSSI),including non-limb threatening diabetic foot infections without

concomitant osteomylitis caused by Enterobacter cloacae, Escherichia coli,Klebsiella

pneumonia,Proteus mirabilis, Staphylococcus aureus (including methicillin-resistant

isolates) and Streptococcus pyogenes.


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7.1.8 Investigational product, dose and mode of administration: Model drug, 500 mg andintravenous.

7.1.9 Washout periods: 2 weeks7.1.10 Duration of treatment: 7 14 days

8. Restrictions:8.1.1 Medications - Subjects should not have received any medication (except vitamins

preparations) including over the counter medications (OTC) during the 3 weeks period

prior to the onset of the study. They will be instructed during screening not to take any

prescription and OTC medications until the completion of the study. If drug therapy

other than that specified in the protocol is required during the study or in the washout

period, decisions to continue or discontinue the subject will be based on the following:

The pharmacology and pharmacokinetics of the non-study medication. The likelihood of a drug-drug interaction, thereby affecting pharmacokinetic

comparison of the study medication.

The time of administration of the non-study medication.8.1.2 Diet No special dietary restrictions are there as such.8.1.3 Activity If any special activity has to be restricted of performed will be instructed to

the subjects on the spot while administering the drug.

9. Study population:9.1.1 Screening assessments (lab tests and general examinations):

HEMATOLOGY

Haemoglobin Total leukocyte count Differential leukocyte

count

Platelet countBIO-CHEMISTRY

Blood Urea Nitrogen Creatinine Total bilirubin Alkaline phosphatase AST ALT Glucose Sodium Potassium

URINALYSIS

PHYSICAL

EXAMINATION

Colour Appearance pH Specific gravity Protein Glucose Glomerular filtration

rate

Renal ClearanceMICROSCOPIC

EXAMINATION

RBC WBC Epithelial Cells

ADDITIONAL TESTS

HIV I & II HBsAg HCV VDRL


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Chloride Calcium Magnesium Uric acid

Crystals Casts Others

Note: The underlined tests are important test from the study point of view. All the samples during screening will be collected and analyzed at Clinical laboratory

situated at BITS Clinical Pharmacology Unit.

9.1.2 Inclusion criteria :1. Diagnosis of an infection consistent with complicated skin and skin structure infections

caused by gram-positive bacteria.

2. Age range should be in 18 92 years.3. Any kind of surgical site infection within 30 days of surgery or trauma with purulent

drainage or 3 or more signs of infection.

4. Abscess for less than 7 days with purulent drainage or aspirate and evidence of loculatedfluid.

5. Erythema and/or induration of 20 mm or more in diameter.6. Cellulitis for less than 7 days with advancing edema, erythema or induration and one other

sign of infection.

9.1.3 Exclusion criteria :1. Known or suspected hypersensitivity to any study medication (especially cephalosporin or

vancomycin allergy)

2. If the renal clearance is less than 30ml/min or Oliguria less than 20ml/hr in response to fluidchallenge.

3. Alanine aminotransferase /aspartate aminotransferase levels 3 times the upper limit of thenormal.

4. Patient who is pregnant or lactating, neutropenic or HIVinfected with CD4+ count less than0.2 X 10

9/L.

5. Any known or suspected condition or concurrent treatment contraindicated by theprescribing information

6. Previous enrollment in this study7. Treatment with any investigational drug within 30 days before enrollment.

10. Study endpoints:10.1.1 Primary endpoints: Noninferiority of the Model drug group when compared with the

Vancomycin-Ceftazidime group on clinical cure rates at the test-of-cure visit of clinically

evaluable and intent-to-treat populations.


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10.1.2 Secondary endpoints: Microbiological eradication rate at 7-14 days after the end oftherapy; Clinical cure rate and microbiological relapse at late follow-up visit; All deaths

due to pneumonia within 30 days after randomization.

11.Schedule of assessment:The clinical evaluations (at the baseline, during treatment, and aftertreatment) will include a microbiological assessment of the site of infection, evaluation of the

signs and symptoms of infection, and at the Test-of-cure(TOC) and Late-follow-up(LFU) visits, an

evaluation of the clinical outcome. The clinical outcome at the TOC visit, 7 to 14 days following

the End-oftherapy(EOT) visit, will be categorized as cure, failure, or not evaluable. Cure is

defined as a resolution of all signs and symptoms of the infection or improvement to such an

extent that no further antimicrobial therapy will be necessary. Failure is defined as a need for

further treatment with a nonstudy antibiotic and discontinuation of the study drug due to a

treatment-related Adverse Event (AE) or due to a lack of efficacy of the study drug after at least

3 days of study therapy. Patients assessed for failing therapy at the EOT visit will be considered

failures at the TOC visit. Patients who will deviate from the protocol-defined treatment orevaluation procedures will be considered not evaluable.

12.Study medication:12.1.1 Handling, storage & accountability procedure:Upon receipt of the of the study

treatment supplies, an inventory must be performed and a drug receipt log filled out and

signed by the person accepting the shipment. It is important that the designated study

staff counts and verifies that the shipment contains all the items noted in the shipment

inventory. Any damaged or unusable study drug in a given shipment (active drug or

comparator) will be documented in the study files. The investigator must notify studysponsor of any damaged or unusable study treatments that were supplied to the

investigators site.

12.1.2 Return or Destruction of Study Drug:At the completion of the study, there will be a finalreconciliation of drug shipped, drug consumed, and drug remaining. This reconciliation

will be logged on the drug reconciliation form, signed and dated. Any discrepancies

noted will be investigated, resolved, and documented prior to return or destruction of

unused study drug. Drug destroyed on site will be documented in the study files.

13.Analytical procedures , Pharmacokinetic studies and assessment of patient complaince:13.1.1 Microbiological assessment: The microbiological assessments will include pathogen

identification and susceptibility testing of all specimens, in addition to genotypic

characterization of staphylococci (by testing for Panton-Valentine leukocidin [PVL] and

mecA genes). Patients will be assessed for microbiological outcome at the TOC visit, and

this outcome will be determined by Gram stain and culture of any discharge or infected

tissues. The microbiological outcome for the patients will be categorized as eradication,

presumed eradication, colonization, persistence, presumed persistence, super infection,


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or not evaluable. Patients will be considered to have an eradicated microbiological

outcome if no pathogen is isolated from any culture (fluid or tissue) taken at the original

site of infection and to have a presumed eradicated microbiological outcome if no

material suitable for culture is obtained from the primary site of infection in the absence

of clinical signs or symptoms of infection. Patients will be considered not evaluable with

regard to microbiological outcome if no pathogen is isolated at the time of entry into the

trial, no clinical evaluation is done at the TOC visit, no data related to microbiological

outcome is collected at the TOC visit, or protocol-defined procedures is not conducted.

Only patients with a microbiological outcome of eradication or presumed eradication at

the TOC assessment will be evaluated for relapse at the LFU assessment.

13.1.2 Pharmacokinetic Characteristics: The following pharmacokinetic parameters will becalculated for the Model drug by using suitable software like Win Nonlin .

Parameters Description

AUC0tThe area under the plasma concentration versus time

curve, from time zero to the last measurable

concentration, as calculated by the linear trapezoidalmethod.

AUC0

The area under the plasma concentration versus time

curve, from time zero to infinity. AUC0is

calculated as thesum ofAUC0t plus the ratio of the

last measurable plasma concentration to the

elimination rate constant.

AUC0t/ AUC0 The ratio ofAUC0t/ AUC0

C maxMaximum plasma concentration over the time span

specified.

Tmax Time of the maximum measured plasma

concentration. If the maximum value occurs at more

than 1 time point, Tmax is defined as the first time

point with this value.

Kel

Apparent first order terminal elimination rate constant

calculated from a semi-log plot of the plasma

concentration versus time curve. The parameter will

be calculated by linear least-square regression analysis

using the maximum number of time points in the

terminal lig- linear phase(e.g three or more non-zero

plasma concentrations)

T1/2

The apparent first-order terminal elimination half life

will be calculated as 0.693/ Kel .


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13.1.3 Assessment of compliance: Patient compliance will assessed by checking for anyhypersensitivity reactions occurring after the administration of the drug. Events involving

exacerbations or the worsening of preexisting illnesses will be recorded.

14.Safety:14.1.1 Clinical safety measurement: It is the responsibility of the Principal Investigator to

oversee the safety of the study at his/her site. This safety monitoring will include careful

assessment and appropriate reporting of adverse events as noted above, as well as the

construction and implementation of a site data and safety-monitoring plan (see section 9

Auditing, Monitoring and Inspecting). Medical monitoring will include a regular

assessment of the number and type of serious adverse events.

15.Handling of safety parameters:15.1.1 Adverse drug events management:

At each contact with the subject, the investigator must seek information on adverseevents by specific questioning and, as appropriate, by examination. Information on all

adverse events will be recorded immediately in the source document, and also in the

appropriate adverse event module of the case report form (CRF). All clearly related

signs, symptoms, and abnormal diagnostic procedures results will be recorded in the

source document, though grouped under one diagnosis.

All adverse events occurring during the study period must be recorded. The clinicalcourse of each event will be followed until resolution, stabilization, or until it is

determined that the study treatment or participation is not the cause. Serious adverse

events continuing throughout the study period will be followed up to determine thefinal outcome. Any serious adverse event that occurs after the study period and is

considered to be possibly related to the study treatment or study participation will also

be recorded and reported immediately.

15.1.2 Reporting of Serious Adverse Events:Study Sponsor Notification by Investigator: A serious adverse event will be reported to

the study sponsor by telephone within 24 hours of the event. A Serious Adverse Event

(SAE) form will be completed by the investigator and faxed to the study sponsor within

24 hours. The investigator will keep a copy of this SAE form on file at the study site.


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This protocol and any amendments will be submitted to a properly constituted independentEthics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal

prescriptions, for formal approval of the study conduct. The decision of the EC/IRB concerning

the conduct of the study will be made in writing to the investigator and a copy of this decision

will be provided to the sponsor before commencement of this study. The investigator should

provide a list of EC/IRB members and their affiliate to the sponsor.

All subjects for this study will be provided a consent form describing this study and providingsufficient information for subjects to make an informed decision about their participation in

this study. The consent form will be submitted with the protocol for review and approval by

the EC/IRB for the study. The formal consent of a subject, using the EC/IRB-approved consent

form, must be obtained before that subject is submitted to any study procedure. This consent

form must be signed by the subject or legally acceptable surrogate, and the investigator-

designated research professional obtaining the consent.

- Drop-out/Withdrawal of Subjects from Study: Subjects will be informed that they are free todropout from the study at any time without stating any reason. The investigator may withdraw

a subject from the study for any of the following reasons:

a) The subject suffers from significant intercurrent illness or undergoes surgery during thecourse of the study.

b) The subject experiences adverse event, when withdrawal would be in the best interest ofthe subjects.

c) The subject fails to comply with the requirements of the protocol or if the subject isuncooperative during the study.

Details of reasons for withdrawal of subjects will be recorded and reported. Every effort will bemade to obtain a complete follow-up for any withdrawn subject.

19. Subject Compensation for Participating in the study:The subjects will be adequately compensated on account of their participation in the study. In

case of drop-out/withdrawal of a subject before completion of the study, the guidelines issued

by the Institutional Review Board of the concerned hospital will be final and binding on both

BITS Research Laboratories and the study subjects. The compensation in this study will be Rs.

10,000/- per completed subject.

20. Termination of the Study:BITS Research Laboratories reserves the right to discontinue the trial at any time. Reasons forthis termination will be provided to the subjects. The Principal Investigator reserves the right to

discontinue the study for safety reasons at any time.


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21.Study Documentation:All data generated during the conduct of the study will be directly entered in the raw data

recording forms as governed by the SOPs of Department of Clinical Pharmacology and

Development and/or Clinical Pharmacology & Pharmacokinetics, BITS Research Laboratories

except the analytical data of clinical laboratory of the Clinical Pharmacology Unit, which will be

transcribed into the study related forms and the raw data retained by the laboratory for

records. The computer-generated chromatograms will also be treated as raw data. All raw data

and transcribed data forms will be completed by the study personnel assisting in the study and

will be checked wherever applicable for completeness and logistics by the Clinical Investigator

or his designate Research Scientist for clinical data and the Laboratory Supervisor for the bio-

analytical data. The Clinical Investigator and the Laboratory Supervisor will supervise

compilation of data until ready for archiving.

22.Quality Assurance Audits:The raw data generated during the course of the study, including the clinical and analytical

operations and the final reports will be liable for inspection and quality audit for conformance tothis protocol and all the governing SOPs by an auditor from the Corporate Quality Assurance

Department of BITS Research Laboratories.

23.Confidentiality of Data:The data identifying each study subject by name will be kept confidential and will be accessible

to the study personnel, Quality Assurance Auditor during audits and if necessary, to the

Institutional Review Board of the concerned hospital and various regulatory agencies.

24.Archives:A representative sample of the drug supplies used in the study will be retained at the BITS

Clinical Pharmacology Unit.

All data generated in connection with this study, together with the original copy of this protocol

and the final report will be archived.

25.Publication Policy:Neither the complete nor any part of the results of the study carried out under this protocol, nor

any of the information provided by the sponsor for the purposes of performing the study, will be

published or passed on to any third party without the consent of the study sponsor. Anyinvestigator involved with this study is obligated to provide the sponsor with complete test

results and all data derived from the study.

Clinical Trial Protocol for Antibacterial Drug

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