Phase 1 protocol
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This phase 1 clinical trial protocol aims to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a new investigational bronchodilator drug, CF-021, in healthy adult volunteers. The study is a randomized, open-label, single ascending oral dose trial. It will enroll approximately 30 subjects in sequential dose cohorts to determine the maximum tolerated dose of CF-021. Safety monitoring, pharmacokinetic profiling and bronchodilator effects will be assessed after single oral doses. The study aims to establish a safe clinical dosing range to enable further evaluation of CF-021 in phase 2 trials for chronic obstructive pulmonary disease.
![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 47
in any
information released to third parties or published. [ ]](https://image.slidesharecdn.com/phase1protocol-141004130402-conversion-gate02/85/Phase-1-protocol-47-320.jpg)
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Phase 1 protocol
- 1. PHASE 1 PROTOCOL Dr.RENJU.S.RAVI
- 2. OVERVIEW PROTOCOL – Definition Phases of Human Research Pre- Clinical Studies and its relevance IND PHASE 1 CLINICAL TRIAL PHASE 1 PROTOCOL DESIGN
- 3. 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 3
- 4. 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.
- 6. 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 6
- 7. 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)
- 8. 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. 8
- 9. 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
- 10. 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 10
- 11. 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. 11
- 12. New drug development Chemistry(discovery) (Identification, Isolation, Purification) Preclinical studies ( Animals) Clinical trials ( Human) 12
- 13. Preclinical studies(animals) Pharmacodynamic studies Pharmacokinetic studies Systemic toxicity studies Local toxicity studies 13
- 14. 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
- 15. Relevance of animal studies 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/ED50 15
- 16. Relevance of animal studies 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 16
- 17. 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
- 18. Phase I trial Goal How well the drug is tolerated in small number of subjects Toxicity screening and determination of Maximum Tolerated Dose(MTD) 18
- 19. Maximum tolerated dose Highest possible dose with an acceptable rate of dose limiting toxicities(DLT) Acceptable toxicities set by the investigators 19
- 20. 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 20
- 21. 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. 21
- 22. 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, or 1/3rd 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 22
- 23. 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 level 1 of 3 experience DLT : enroll additional 3 subjects >1 of 3 experience DLT: Stop , MTD was the previous one If <2/ 6 experience DLT : dose If 2 or more out of 6 experience DLT: MTD was the previous one 23
- 24. Design a protocol for phase I trial for a new molecule which is found to have a bronchodilator action in animal studies. 24
- 25. 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 25
- 26. 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. 26
- 27. 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. 27
- 28. 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 28
- 29. 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. 29
- 30. 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) 30
- 31. 2. Aim To determine Safety,Tolerability,Pharmacokinetic and Pharmacodyanamic properties of CF-021 after a single oral dose escalation in healthy adult human volunteers. 31
- 32. 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) 32
- 33. 3.0.Objectives 3.2 Secondary : To determine pharmacokinetics of the drug (AUC, Cmax tmax,bioavailabilty) , Pharmacodynamic parameter after single oral dose escalation. 33
- 34. 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 34
- 35. 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 35
- 36. 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 36
- 37. 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. 37
- 38. 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 38
- 39. 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 39
- 40. 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 4 3 mg to match 3 mg oral dose GROUP 5 10 mg to match 10 mg oral dose GROUP 6 30 mg to match 30 mg oral dose GROUP 7 100 mg to match 100 mg oral dose GROUP 8 300 mg to match 300 oral dose 40
- 41. 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) 41
- 42. 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 42
- 43. 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. 43
- 44. 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
- 45. 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. 45
- 46. 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 46
- 47. 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 47 in any information released to third parties or published. [ ]
Editor's Notes
- #11: in which it has to be administered to human beings
- #28: Caused by abnormal response to inhalation of tobacco smoke or other toxic agents
- #33: Coagulation studies
- #40: trial will be stopped which is the 1/10 th of the maximum tolerated dose in animals.(20 mg)
- #41: Doses are increased till maximum tolerated dose is reached. out of 6 subjects ,3 subjects randomly will receive 2 mg oral single dose of cf 021 and 3 subjects willl receive placebo equivalent to 2 mg oral single dose. Similarly in cohort 2,3sed,4,5,6,7,8 will received doubling incremental doses. When ADEs or PD effect are observed, linear increment doses will be
- #42: Every reported symptom will be recorded separately ,.duration, severity
- #45: All adverse events occuring during the course of study shall be managed and due compensation for injuries arising from study will be given as per the approval of IRB.Confidentality of individuals shall be ensured