Phase 1 protocol

PHASE 1 PROTOCOL

Dr.RENJU.S.RAVI

OVERVIEW

PROTOCOL – Definition

Phases of Human Research

Pre- Clinical Studies and its relevance

IND PHASE 1 CLINICAL TRIAL

PHASE 1 PROTOCOL DESIGN

PROTOCOL

It is a brief outline of what the study is & how it is to be carried out.

Main reference tool for

the investigator

For submission to the Ethics committee to obtain permission to conduct the study

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CLINICAL TRIALS

Clinical trials are studies performed with human subjects to test new drugs or combinations of drugs, new approaches to surgery or radiotherapy or procedures to improve the diagnosis of disease and the quality of life of the patient.

PHASES of Human research

Phase I: Establish safety, PK studies

Phase II : Establish efficacy ,dose ranging

Phase III : Randomized comparison of treatments

Phase IV : Long term surveillance in broader

population

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INVESTIGATIONAL NEW DRUG (IND) APPLICATION

IND application is the result of a successful preclinical development program

The IND is also the vehicle through which a sponsor advances to the next stage of drug development known as clinical trials (human trials)

When a new compound passes preclinical

pharmacological screening ,manufacturer files

Investigational New Drug (IND) with the DCGI

Testing in humans is done only after completion ofsufficient acute and subacute animal toxicity studies.

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INVESTIGATIONAL NEW DRUG (IND) APPLICATION

Includes data and information areas: Animal Pharmacology and Toxicology

Studies Manufacturing Information Clinical Protocols and Investigator

Information Composition and source of drug

PRE -REQUISITES

The IND includes Chemical structure ,its source ,its

manufacturing data with details of its purity Preclinical data about PD, PK and

toxicological studies with ED 50 and LD 50 data

Specification of dosage forms A detailed description of the investigational

protocol including - dose and route of administration

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PRE -REQUISITES

The names and qualifications of each investigator and the facilities available to them

An agreement from the sponsors to submit annual progress report

A certification that “ informed consent” will be obtained from human volunteers and that “ethics of research in human beings “ will be strictly followed.

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New drug development

Chemistry(discovery)

(Identification, Isolation, Purification)

Preclinical studies ( Animals)

Clinical trials ( Human)

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Preclinical studies(animals)

Pharmacodynamic studiesPharmacokinetic studiesSystemic toxicity studiesLocal toxicity studies

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Relevance of animal studies

Pre-clinical toxicology studies will generate basically three types of findings

1. Overt toxicity

e.g. Clinical signs, macro and microscopic lesions

2. Surrogate markers of toxicity

e.g., Hematological/LFT or serum liver enzyme levels/urine tests, etc.

3. Exaggerated pharmacodynamic effects 14


Minimum lethal dose (MLD): minimum dose that produce 10% lethality (LD10)

Threshold toxic dose (TTD): the lowest dose that produce an adverse effect

Maximal tolerated dose (MTD)

The highest daily dose of a chemical that does not cause overt toxicity in a ninety-day study in laboratory mice or rats

Therapeutic index : LD50/ED5015


No-Observed-Adverse-Effect-Level (NOAEL) is the greatest concentration or amount of a substance, found by experiment or observation, which causes no detectable adverse alteration of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions of exposure

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Calculation of Human equivalent dose(HED)

HED = Animal NOAEL x (Wanimal / Whuman)1-b

where W is the weight in Kg and b is a correction factor (equal to 0.67) used to convert mg/kg to mg/m2

For example, if the NOAEL of an investigational drug in relevant species (monkey of 3 kg) is 50 mg/kg, then

HED = 50 mg/kg x (3 kg/65 kg)0.33

= 50 mg/kg x 0.3624

= 18 mg/m2

This value should be divided by a safety factor

Phase I trial

Goal How well the drug is tolerated in small

number of subjects

Toxicity screening and determination of Maximum Tolerated Dose(MTD)

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Maximum tolerated dose

Highest possible dose with an acceptable rate of dose limiting toxicities(DLT)

Acceptable toxicities set by the investigators

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Phase I Study

Phase IA : on Healthy subjects Phase IB : Patients / failure on

conventional therapy The total number of subjects included

varies with the drug, but is generally in the range of 20 to 80

Dose escalation study Efficacy is measured but not the main

objective

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Phase I Cont…

Usually nonblind or "open label" Alternatively, they may be "blinded"

and placebo-controlled. Conducted in centers having necessary

facilities to closely observe and monitor the subject

Carried out by investigators trained in clinical pharmacology

May be carried out in one or two centers.

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Phase I Study

Determination of dose

Starting dose will be selected based on preclinical toxicity and dose response curve. 1/10th of the LD10 in rodents, or1/3rd of the minimal toxic dose in large animals

Expressed as mg/m2

Maximum tolerated dose will be the one incremental dose less than dose producing unacceptable toxicity

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Traditional 3+3 design

Patients enrolled in groups of 3 each for each dose level

None of 3 experience DLT( Dose Limiting Toxicities)

the dose level1 of 3 experience DLT : enroll additional 3 subjects>1 of 3 experience DLT: Stop , MTD was the previous

one If <2/ 6 experience DLT : doseIf 2 or more out of 6 experience DLT: MTD was the

previous one

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Design a protocol for phase I trial for a new molecule which is found to have a bronchodilator action in animal studies.

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Title

A phase I, open label study for evaluating Safety,Tolerability,Pharmacokinetic and Pharmacodyanamic properties of CF 021 after single oral dose escalation in healthy adult volunteers

Protocol No: ASDW223

Version : 1.0

Date: 01/07/2014

IND No: CF 021

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Chief Investigator: Dr. Vivek Clinical Pharmacologist MCH, Tvpm Phone: 985177660

Co-investigator: Dr. Chandrashekar Assistant Professor, Respiratory

Medicine MCH, Tvpm Phone: 9995678828

Sponsor : Doctor Reddy’s laboratories Hyderabad, India. Ph no. 0992378654.

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1.Background and Introduction

Chronic obstructive pulmonary disease (COPD) is a disease of increasing public health importance around the world.It is the fourth leading cause of death in the United States.

Irreversible inflammatory response to an inhaled environmental stimuli.

Bronchodilators produce improvement in airflow in patients with COPD ,whose lungs have become hyperinflated.

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1.1. Investigational product

CF-021 a novel bronchodilator drug has shown its efficacy in animals .

Pharmacological profile of the drug was studied in animals.

Toxicological studies-Acute toxicity (LD50),

subacute toxicity ,chronic toxicity was studied on animals.

Pharmacokinetic studies –A,D,M,E,Bioavailability

Pharmacodyanamic studies-receptor activity at cellular level

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As preclinical studies predicted that this drug holds promise ,we are undertaking phase 1 study for evaluating safety and tolerability of this drug in healthy adult human volunteers.

Study will be conducted as per GCP guidelines.

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Permission was sought from DCGI by IND application filing containing all the prerequisites .(preclinical data, Chemical structure , manufacturing data, Specification of dosage forms, investigational protocol,ethical committee clearance)

The trail has been registered in clinical trial registry of India (CTRI)

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2. Aim

To determine Safety,Tolerability,Pharmacokinetic and Pharmacodyanamic properties of CF-021 after a single oral dose escalation in healthy adult human volunteers.

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3.0.Objectives

3.1 Primary: To determine safe and maximum

tolerated dose .( safety parameters -adverse drug

events,clinical laboratory test,changes in blood pressure,heart rate,blood glucose ,serum potassium,FEV1,12 lead ECG)

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3.0.Objectives

3.2 Secondary :To determine pharmacokinetics of

the drug (AUC, Cmax tmax,bioavailabilty) ,

Pharmacodynamic parameter after single oral dose escalation.

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4. Methodology

Study design : Randomized, open label, single oral dose escalation study.

Setting : Dept of respiratory medicine

MCH, Trivandrum

Duration : Aug-October 2014( 3 months)

Sample size : Around 30

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5.1. Inclusion criteria

1.Healthy adults of either sex aged 18 -50 yrs

2.Those having normal spirometry (fev1 -80% of predicted, fev1/fvc - 70%)

3.Non smokers,non alcoholics

4.No h/o of drug intake last 3 mths which have effect on liver enzymes

5.No h/o of drug allergy, drug abuse

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5.2. Exclusion criteria

Abnormal lung function (FEV1 <80% predicted)

H/o breathing problem Clinically significant medical history

or condition which precludes participation

Clinically significant ECG abnormality Use of any investigational drug within

past 90 days

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6.0. Study Procedure

All healthy volunteers first will undergo screening medical tests.

Those who satisfy the inclusion criteria will be enrolled into study .

Signed and dated written informed consent will be obtained

They should be hospitalized Base line lab investigations of

cardiovascular , renal, hepatic, hematopoietic function and Pulmonary function test, will be done in ACR lab, Mch ,Tvm.

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6.1. Randomization

Subjects will be divided into 8 groups. Each group containing 3 subjects . Single oral dose with increasing dosage will be

given to subjects

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Procedure cont…

Starting dose of the drug is 0.1 mg Successive cohorts will receive (logarithmic)

incremental doses (1,3,10,30,100). Doses increased till maximum tolerated dose

is reached Maximum tolerated dose is the one

incremental dose less than dose producing unacceptable toxicity

Stopping rule: If there is unacceptable serious ADR and poor bioavailibilty

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Group Drug dose(3 subjects)

Placebo (3 subjects)

GROUP 1 (3 subjects)0.1 mg to match 0.1 mg oral dose

GROUP 2 0.3 mg to match 0.3 mg oral dose

GROUP 3 1 mg to match 1 mg oral dose





GROUP 8 300 mg to match 300 oral dose40

7.0. Safety parameter

Information will be sought at specified intervals.

Starting from the 1st day ,the individuals will be observed for adverse events and changes (compared to baseline) in vital signs, physical examination, pulmonary function tests until drug is completely eliminated from the body.( depending on t1/2)

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8.0. Pharmacokinetic parameter

Pre dosing plasma and urine sample and sample after giving the drug ,after 1 st hr, 4 th hr,6 th hr and 24 th hr will be taken daily until drug is completely eliminated.

Auc, Cmax, tmax, bioavailability will be recorded

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9.0 Analysis

Approriate statistical test will be used to analyse the data.

Expert statistician advice will be sought.

Data will be entered in Microsoft Excel sheet.

SPSS version 16 will be used to analyse the data.

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10.0 Ethical aspects

The study will be conducted acc to the declaration of Helsinki 2008, after taking approval from the Institutional ethics committee, Medical College, Tvm.

A written informed consent will be taken from all the subjects participating in the study.

The study subjects will be appropriately managed for any drug related adverse event during the study period.

Insurance for volunteers. 44

11.0. Expected outcome

This phase 1, randomized, open label study will help to evaluate safe, max tolerated dose, clinical dose range, pharmacokinetic, pharmacodynamic parameter of the above bronchodilator drug in healthy human volunteers so that drug can be further evaluated in phase 2 trial.

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12.0. References

1.Craig WA,Oman SJ,Shaw WR,Ramgopal v Dhingra texbook of respiratory diseases and drug therapy fourth edition;32-6:243-252

2.Kvnin CM .Effect of bronchodilator on animals,Br J clinical pharmacology 2008;26: 624 -630

3.Gupta S, Ravishankar G. A novel bronchodilator showing promising results in animal models.BMJ,2006;2(4):330-40

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Informed consent form Study Title:

Study Number:

Subject’s Initials: _______________ Subject’s Name: ______________

Date of Birth / Age: _____________

Please initial box (Subject)

(i) I confirm that I have read and understood the informations heet dated ___ for the above study and have had the opportunity to ask questions.

(ii) I understand that my participation in the study is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected.

(iii) I understand that the Sponsor of the clinical trial, others working on the Sponsor’s behalf, the Ethics Committee and the regulatory authorities will not need my permission to look at my health records both in respect of the current study and any further research that may be conducted in relation to it, even if I withdraw from the trial. I agree to this access. However, I understand that my identity will not be revealed in any information released to third parties or published. [ ]

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Phase 1 protocol

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