CLINICAL

MODULE TRIAL PROTOCAL

7 ASSIGNMENT
Clinical Evaluation I-
Practical & Scientific Perspectives
TITLE:

PROTOCOL WRITING
This study is phase II, multicentric, randomized, placebo
controlled, triple blind, dose ranging study to demonstrate the
safety and efficacy parameters of HIV-1 integrase inhibitor
Submitted By: Jatin Gala
raltegravir (AB-0324) in treatment with patients experiencing
Roll number: 620850434
MSc
multi drug Clinical Research & Regulatory
resistance.
Affairs (MSc CRRA)
PROTOCAL NUMBER: BatchNCT001345
2008 – 2010

VERSION: 1

DATE: 11/08/2006

21
Sponsor:
Toro Pharmaceuticals Ltd.
L. B. Lamington,
North Jujus, Japan.
P. O. Box No: - 327.

Medical Expert:
Brian Martin. PhD
St. Joseph University of medicine
USA.
E. mail id: - martin.b@stj.co.org.

Principle Investigator:-
Dr. Sadanand Gaikwad. PhD
Indian Institute of Medicine
India.
E. mail id: - anandg@iim.org

3
 TABLE OF CONTENTS

1. PROTOCOL SUMMARY ................................................................................................6

2. INTRODUCTION ............................................................................................................ 8-9

3. TRIAL OBJECTIVES ......................................................................................................10

3.1 PRIMARY OBJECTIVES ...........................................................................................10

3.2 SECONDARY OBJECTIVES .....................................................................................10

4. TRIAL DESIGN ................................................................................................................10

5. PATIENT SELECTION.................................................................................................. 11

5.1 INCLUSION CRITERIA.............................................................................................11

5.2 EXCLUSION CRITERIA............................................................................................11

5.3 PATIENT WITHDRAWAL........................................................................................11

6. RANDOMISATION..........................................................................................................12

7. TREATMENTS.................................................................................................................10

8. INVESTIGATIONS / PROCEDURES...........................................................................13

9. ADVERSE EVENTS .......................................................................................................14

4
 9.1 TOXICITY....................................................................................................................14
9.2 SAE................................................................................................................................14

10. DISCONTINUATION OF THE STUDY......................................................................14

11. FOLLOW-UP OF PATIENTS .......................................................................................15

12. STATISTICS....................................................................................................................15

13. MONITORING................................................................................................................16

14. STUDY RECORD……………………………………………………………………….16

15. QUALITY CONTROL AND QUALITY ASSURANCE............................................17

16. ETHICS............................................................................................................................17

17. DATA HANDLING AND RECORD KEEPING...........................................................18

18. PUBLICATION POLICY................................................................................................18

19. FUNDING………………………………………………………………………………...18

20. STYDY ORGANIZATION AND IMPLEMENTATION ….........................................19

21. LOCATION FOR STUDY………………………………………………………………...20

22. REFERENCES…………………………………………………….………………………21

5
1. PROTOCAL SUMMARY

1.1 Title:

This study is phase II, multicentric, randomized, placebo controlled, triple blind, dose ranging
study to demonstrate the safety and efficacy parameters of HIV-1 integrase inhibitor raltegravir
(AB-0324) in treatment with patients experiencing multi drug resistance.

1.2 Objectives:

• Primary: - To check the safety parameters of various dosage of raltegravir against HIV- 1
infection, and to determine minimum therapeutic safe dose for phase II study.

• Secondary: - To check the efficacy parameters of raltegravir among HIV-1 infected patients, and
to check efficacy of raltegravir in combination with atazanavir.

1.3 Design of the study:

Randomized, Triple-Blind, Placebo Control, Parallel Assignment, dose ranging Safety/Efficacy

Study.

1.4 Investigator End Point

• Primary: Change in viral load.

• Secondary: Proportion between patients and change in viral load.

6
1.5 Study Objective:

• Primary: To review effect of various therapeutic doses of raltegravir on patient with HIV-1
infection.

• Secondary: To evaluate the effect of raltegravir against other antiretroviral therapy and to attain
significant and continuous immunological response of a drug.

1.6 Trial Design:

• Design: Triple blind, randomized, dose ranging, placebo controlled study.

1.6 Primary End Point:

• To assess antiretroviral activity, this will be measured by calculating differences in viral load
from base line for certain duration. Also to assess safety parameters of drug on patients.

1.7 Estimated Enrollment: 400 patients

1.8 Sample Size: 361 patients

1.9 Treatment regimens:

Study has been divided into two parts, in each part there are four treatment groups. In each part
patients from first three groups will receive different dosage of raltegravir and fourth group will
receive placebo but in part two patients will receive additional dose of atazanavir along with
regular dose of raltegravir and placebo.

7
PART I

• 1st group: Standard dose of raltegravir (200 mg)

• 2nd group: Standard dose of raltegravir (400 mg)
• 3rd group: Standard dose of raltegravir (600 mg)
• 4th group: Standard dose of placebo

PART II

• 1st group: Standard dose of raltegravir (200 mg) plus additional dose of atazanavir
• 2nd group: Standard dose of raltegravir (400 mg) plus additional dose of atazanavir
• 3rd group: Standard dose of raltegravir (600 mg) plus additional dose of atazanavir
• 4th group: Standard dose of placebo plus additional dose of atazanavir

2. INTRODUCTION:

There is great need of an antiretroviral agent with an innovative mechanism to treat patients who
have infected with HIV 1 and have very little available treatment option with them. Raltegravir is
new agent of a pharmaceutical class of antiretroviral drug known as integrase inhibitor. It has
shown vital activity against HIV-1 and different variants of HIV-1 which has shown resistance to
other available antiretroviral. It has also been regarded as class one HIV integrase inhibitors.
Metabolism of raltegravir takes place with the help of glucuronidation.

Result of phase one studies has proven that raltegravir is well tolerated, has a limited tendancy
for drug-drug interaction, and has pharmacokinetic effect that supports twice a daily dosing
irrespective of food intake. Atazanavir helps in inhibition of UAT32C, the basic pathway of
clearance of raltegravir and enhance process of pharmacokinetic. Study will also focus on
combination dose of raltegravir with other antiretroviral drug.

8
Mechanism:-

Raltegravir basically targets an HIV enzyme that integrates viral genetic material into human
chromosome. Raltegravir and other integrase inhibitors are also know as strand transfer inhibitor.
Raltegravir block the strand transfer step of integration and thus blocks viral replication
Result of the pre-clinical study has proven that raltegravir had a guarantee to be clinically
effective HIV integrase inhibitor with wide activity against circulating variants of HIV-1.
Raltegravir inhibits final, integrase strand transfer reaction and hence has a novel mechanism of
action than other drugs.

Biomedically raltegravir has proven its efficacy; it shows less than 1000 fold selectivity for
integrase with respect to human DNA polymerase. Study on mechanism of raltegravir by which
it hinders HIV-1 replication has been carried out in cell culture.

Early and late HIV-1 reverse transcriptase and various integrated and unintegrated forms of HIV-
1 DNA have been studied with the help of quantitative PCR assay. Mutation in integrase either
in vitro or in vivo may result in change in susceptibility of drug.

Pre-clinical pharmacokinetic and toxicological studies of raltegravir have been carried out on rat,
dog, rabbit and other species. In addition to this toxicological effect has been studied in rodents,
rats and dogs.

Source: Raltergavir_ACM_BGPK_1.doc Version 9.2

9
3. TRIAL OBJECTIVE:

3.1 Primary objective:

• To estimate minimum therapeutic dose of a study drug based on safety and efficacy ratio.

3.2 Secondary objective:

• To decide suitable effective dose of a drug based on safety and efficacy ratio.

• To achieve significant therapeutic, immunological effect of a drug on patient showing

resistance to other HIV drug.

4. TRIAL DESIGN:

4.1 Primary end point:

• Reduced level of viral load with specific time interval along with safety parameters of
drug.

4.2 Secondary end point:

• Virologial end point: HIV RNA value <400 and < 50 copies/ ml.

• Reduced ratio between patient and viral load.

4.3 Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, dose
ranging Safety/Efficacy Study.

10
5. PATIENT SELECTION

Approximately 400 patients with HIV-1 infection who satisfy the inclusion criteria will be
enrolling into the study. They will be randomly assigned one of the study arms.

5.1 Inclusion criteria

1. HIV-1 seropositive patient with age more than 20 years

2. HIV-1 RNA (concentration) should be more than 5500 copies/ml
3. Density of CD4 cell count should be more than 100 cells/µl.
4. Patient showing resistance to other antiretroviral drugs.
5. Non pregnant HIV positive women.
6. For women – Hemoglobin level should be more than 80 g/L.
For men- Hemoglobin level should be more than 100 g/L.

5.2 Exclusion criteria

1. Patient less than 20 years.

2. Patient with previous treatment on integrase inhibitors.
3. Patient with past history of hepatitis.
4. Patient with drug abuse
5. Additional exclusion criteria will be discussed and identified by the study investigator
during study.

5.3 PATIENT WITHDRAWAL

• Withdrawal of the patient will depend on any unexpected ADR.

• Depend on patient’s choice to withdraw from study.

11
 • Any adverse event due to study medication.
• Breaking of study code.

6. RANDOMIZATION:

• Patients contributing to trial will be assigned to chronological trial number.

• During randomization all study personnel (Investigator, monitors, patients, study site
personnel, laboratory personnel) will be kept blinded.
• Process of randomization will be carried out by certified statistician with the help of
computer generated randomised allocation schedule.
• Interactive voice response service (IVRS) will enhance the process of central
randomization, in which patients will be randomized in equal ratio to one of three doses
of raltegravir or placebo. Dose will be given twice daily with 10-14 hrs apart.
• Before randomization investigator will check patients optimal background regimen on the
basis of patients antiretroviral treatment history, reason behind this is to develop best
possible treatment schedule.(During randomization patients were stratified with in each
substudy by enfuvirtide)

12
7. TREATMENT:

• Complete study has been divided into two parts. Each part of the study has two arms i.e.
treatment arm and interventional arm.
• In each part patient will be divided into 4 groups.
• In each part patients from first 3 groups will receive study medication where as fourth
group will receive placebo.
• In part one first three groups will receive different dosage of raltegravir but in part two
patients will receive additional dose of atazanavir in addition to raltegravir.

8. INVESTIGATIONS/PROCEDURE:

8.1 Safety assessment

• Safety assessment will be based on physical examination of patient in every single week.
• Safety will be assessed with placebo even in the light of study population who were in
advance stage of disease with several related medical condition and who receive many
different medication.
• Blood sample and urine sample will be checked periodically.
• Patients will be assessed to free medical check up camp at every single week.
• In spite of withdrawal from trial patient will receive free treatment of antiretroviral drug.

8.2 Efficacy assessment

• After completion of every treatment cycle patient will be tested for viral load.

• For detection of viral load COBAS Amplicor monitor test will be used.

13
9. ADVERSE EVENT:

• Toxicity:

Monotherapy of raltegravir will result in resistance, hence to avoid this

monotherapy should be strictly avoided.
Conditions like fever, chill, local skin infection should be treated with standard
medication.
Excessive dose of raltegravir may result in mild nausea and vomiting, in such
condition standard medication should be given.

• Serious Adverse Event:

Increase blood pressure, dyspnea may induce in some patient and is associated
with dose of a drug and patients physical condition.
May lead to a short-term worsening of pre-existing depression which may be
treated standard dose of antidepressants and anti-psychotic drugs.

10. DISCONTINUATION OF STUDY:

• Ethical violation with protocol compliance will lead to the discontinuation of study.
• Serious ADR due to treatment regimens
• Infringement in medical coding.

14
11. PATIENT FOLLOWUP:

• Follow up of patient will be done for 16 months; this duration is divided into 2 sets. Each
set is divided into cycle of 14 days in which patient will be treated with various
diagnostic tests.
• Follow up period for all study subjects will be same.

12. STATISTICS:

• The primary analysis used to review the efficacy will be based on principle modified
intension to treat.

• In MITT patient included in treatment arm will be randomised in spite of their treatment
they received.

• Patients who will not receive study medication will be excluded from efficacy analysis.

• Result from non compliance =failure (NC=F) will be used to determine patients with HIV
RNA< 400copies/ ml<50 copies/ml.

• For efficacy analysis between raltegravir and placebo logistic regression model will be
used.

• GSS and PSS score will be used to determine the contribution of OBT in study.

15
 • Interim analysis will not be carried out through out study.

13. MONITORING

• Monitoring of a trial by expert will be done periodically.

• Regular monitoring will be done by study monitor.
• Monitoring of ADR should be done strictly.
• CD4+, T cell counts will be monitored by central laboratory.
• COBAS Amplicor HIV-1 monitor test will be used for monitoring of plasma HIV-1 RNA
viral load.
• Monitoring for expected efficacy of drug will be done by Principle investigator.

14. STUDY RECORD

• SECRACY

All necessary privacy regarding patient identification will be maintained

throughout study by every study personnel.
Secrecy regarding treatment arm and interventional arm will be assured.
Identification of patient will kept confidential as per the regulatory guidelines.

• STORAGE

ALL study records will be stored for next 15 years.

16
15. QUALITY CONTROL AND QUALITY ASSURANCE:

• Quality of clinical trial will be monitored at each and every step.

• Quality of all medicines used during trial will be maintained throughout study.
• Auditing of trial will be done by certified auditor at regular interval.
• Auditing will help to maintained efficacy and transparency during trial.
• All QA/QC procedure will be carried out in compliance to GLP guidelines.
• Accuracy of data generated by statistician will monitored periodically at every step.
• Every single data generated during trial will be reported only on CRF form provided by
trial steering committee.
• Supervision of AE and SAE will be done by data monitoring committee.

16. ETHICS:-

• During trial period all study procedure will be carried out according to guidelines as
mentioned in ‘Declarations of Helsinki’.
• Whole study procedure will be carried out in compliance with GCP.
• Since this trial is multicentric, at each site ethical approval will be taken from local
ethical committee.
• Written, signed, documented informed consent form will be taken from all subjects
enrolling into study. In case of vulnerability consent will be obtain from legal
representative. Procedure of informed consent and other necessary information is listed in
appendix II.
• Process of informed consent will be carried out under strict observation of investigator.
• Patients will make aware of all study treatment (Drug and Placebo).
• Any infringement during study (AE and SAE) will be reported with 24 hrs to regulatory
authority.

17
 • Informed consent form will be submitted to ethical committee at the time of approval.

17. REPORTING AND DATA HANDLING:

• Data archiving and reporting will be done by qualified personnel.

• Reporting of patient information on CRF will be done in anonymous format, (only
number) to keep secrecy in patient identification.
• All the necessary information for the trial along with past history of patient will be
reported on CRF form and that same information will be transcribed in database in
electronic format.
• Record data and patient file will be maintained in source document.

18. STUDY PLBLICATION POLICY:-

• Study results will be published periodically to peer- review journals for publication.
• Before submission results will be reviewed by protocol committee.
• All publication should fulfill the criteria for authorship, disclosure, scientific integrity and
other necessary requirement of peer- reviewed scientific journal.
• Name of all study personnel who have contributed towards study will be listed as co-
authors.
• Confidentiality of patient’s identification will maintain.

19. FUNDING:

Funding for complete study will be done by Toro pharmaceuticals.

18
20. STUDY ORGANIZATION AND IMPLEMENTATION:

Investigator:-
P. Flintoff. M.D, Ph.D.
B.Cook. M.D. Ph.D.

Study Coordinator:-
F. Anderson, Msc, Ph.D.

Study Protocol:-
H. Harmission, M.D.
Waugh S, M.D.

Patient Assessment:-
M. Purohit, M.D, Ph.D.
Naresh Goyal, M.D, Ph.D.

Patient Recruitment:-
Prashant Sawant, M.D, Ph.D.

Monitoring and management of ADR:-

Priti Sawant M.D, Ph.D.

Coding and statistical analysis:-

Atul Shanbhag, Msc (Stat.), Ph.D.

19
21. LOCATION FOR STUDY:
Since this study is multicentric, study will be carried out at four different places i.e. USA, Latin
America, Europe and Asia.

Study will be carried at following hospitals:-

In USA: - Abbott Northwestern Hospital, Minneapolis

800, East 28th street.

Minneapolis, MN 55407.
(612) 863-4000

In Latin America: - Shrines Hospital

Mexico D.F.
011-52-654-764-987

In Europe: - Atkinson Morley Hospital

31, Copse hill, Wimbledon,
London, Greater London, SW20 ONE.
020-89467711

In Asia: - Bhagwati Hospital.

Borivali (w), Mumbai 67.
+91-022-28971572.

20
22. REFERENCES

1. Grinsztejn B, Chen J, Harvey C, et:al; Safety and efficacy of HIV-1 integrase inhibitor
raltegravir (MK-0518) in treatment experiencing patient with multidrug resistance virus:
a phase II randomized control trial. Lancet 2007; 369: 1261-69.

2. Martin M, Yen B, Hong W, et:al; Rapid and durable antiretroviral effect of HIV-1
integrase inhibitor raltegravir as a part of combination therapy in treatment naïve patient
with HIV-1 infection: Result of 48 week controlled study JAIDS Journal of aquirede
immune deficiency syndrome: Volume 46(2)1 October 2007pp 125-133.

3. Iwamato M, Petry A, Laethem M, et:al; Safety, Tolerability and Pharmacokinetic of

raltegravir after single and multiple doses in healthy subjects. Clinical pharmacology and
therapeutics (2008) doi: 10.1038/ sj. Cipt 6100281.

4. John M, Anthony D, Chen M, et:al; Antiretroviral therapy with the integrase inhibitor
raltegravir alters decay kinetics of HIV, significantly reducing the second phase.
AIDS volume 21(17) November 2007 p 2315-2321

21