1. PHASE III PROTOCOL
Dr.RENJU.S.RAVI

2. 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
2

3. 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.

5. 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. Phase-III Clinical Trial
 Multicentric study
 Conducted by clinicians
 Several hundred to few thousand
patients
 Lasts for 1 - 5 years
 Study design-RCT
 expensive, time-consuming and
difficult trial to design.

7. Contd.......
Document comparative efficacy
and safety of new drug
Document special characteristics
of new drug Vs standard drug
Determine optimum dosage
schedule
Document population kinetics if
possible

8. Requirements - For permission to
conduct phase III trial from DCGI
1. Introduction of drug
2. Chemical &Pharmaceutical information
3. Animal Pharmacology data
4. Details of Phase II Trial
5. Protocol of the proposed trial
6. Names& details of investigators
7. Details of institutions
8. Case report forms
9. Ethical clearance from IRB

9. Animal pharmacology data
 Long term toxicity studies in
animals
 Three generation fertility studies
 Peri/post natal studies in animals
 Teratogenicity studies
 Life span studies in mice and rats

10. “ Pharmaceutical company has
marketed a novel CCB cardex for
the treatment of mild to moderate
essential hypertension. This drug
has also been found to have
additional antiplatelet property. You
want to know whether it is safe and
more efficacious than Nifedipine.
Design a protocol for this study.”

11. Title
A multicentric Parallel group
double blind randomized control
trial to compare the efficacy and
safety of Cardex Vs Nifedipine in
stage1 hypertension
Protocol No: ASDW223
Version : 1.0
Date: 1/9/14
IND No: AK 0021

12. Chief Investigator: Dr. Ajay
Assistant Professor,
Dept of Internal Medicine
MCH, Tvpm
Phone: 9895005685
Co-investigator: Dr. Watson
Assistant Professor,
Dept of Internal Medicine
MCH, Tvpm
Phone: 9995678828
Sponsor: Glen mark
Washington USA
Ph :7680964765

13. INTRODUCTION
Hypertension is one of the leading causes
of morbidity and mortality in India. Chronic
hypertension results in the development of
coronary artery disease, cerebrovascular
disease and end organ damage.
Coronary artery disease is the most
important long term complication of systemic
hypertension. Patients are usually prescribed
an antiplatelet drug like aspirin along with an
antihypertensive like nicardipine to prevent
re-occlusion.

14. Cardex is a novel calcium
channel blocker with additional anti-platelet
activity. Hence administering
an antiplatelet drug separately is not
required.
In this context we are
undertaking a study comparing the
efficacy and safety of cardex with
cardio selective CCB nifedipine.

15. Investigational product
 Cardex is a novel calcium channel
blocker with additional antiplatelet
action. Phase I & Phase II trial has
been done and data shows it is safe
in humans.
 Pharmacokinetic studies –
A,D,M,E,Bioavailability
 Pharmacodyanamic studies-receptor
activity at cellular level

16. AIM:
To compare the efficacy and
safety of cardex vs nifedipine in patients
with stage I hypertension

17. OBJECTIVES:
Primary objective
1. To assess the efficacy and safety of
cardex and its comparison with nifedipine
in patients with stage I
hypertension(JNCVIII)
2. To study the antiplatelet activity of
cardex in patient with stage 1 HTN
Secondary objective:
1. To study population kinetics

18. METHODOLOGY
Study design: Double blind randomized control parallel
group study to compare the efficacy and safety of
cardex Vs Nifedipine
Setting : Medicine OPD,MCH ,Tvpm. Total of 15 centers all
over India
Duration: 2 years
Case definition: A case of stage I hypertension is a
person having a BP greater than 140/90 mm hg but below
160/100 mm of Hg on three or more occasions.

19. Selection criteria
 Inclusion criteria:
a. Patients with newly diagnosed stage I hypertension
acc. to JNC VIII
b. Age group 20-65 yrs
c. Patient not on any medications
 Exclusion criteria
a. Pregnant women
b. Persons with hepatic or renal dysfunction
c. severely ill patients
d. Patients with bleeding disorders

20. Sample size:
Total of 600 subjects. 300 in each arm
Randomization :
The study subjects are selected randomly
using a computerized random table from
newly diagnosed stage I hypertension
patients attending the medicine OPD
(Done from the trial Co-ordinator office)

21. Study Procedure
 Selection of 600 Patients with with
stage 1 hypertension
Written informed consent obtained
 Randomized to two groups of 300 each
 Prior to the initiation of treatment, the
systolic and diastolic BP will be assessed
using syphgmomanometer .

22.  Base line investigations (Blood
routine examination, LFT, RFT, lipid
profile,Platelet count,BT,Platelet
aggregation study, RBS) will be done in
ACR lab, MCH Trivandrum
 All relevant data will be recorded in
prepared proforma.

23. Day 1
 All 300 patients will receive cardex
10mg twice daily orally (after
breakfast and after dinner)
 The second group will receive
nifedipine 20mg orally twice daily
(after breakfast and after dinner)

24. Day 2
 In all Patients BP measured in the morning
at 8am after breakfast and morning dose of
the drug
 All the patients will be given tablets for
the rest of the month to be taken at home
 Asked to report any occurrence of side
effects immediately to the investigators.

25. 2nd visit - At the end of one month
• BP of all the patients will be recorded
• 10 ml of blood - RBS, lipid profile,Platelet
count,BT and platelet aggregation study.
• If no significant side effect is noted the drugs
will be given for a further period of 2 months
• At the end of the period, patient will be asked
to report for a third visit

26. 3rd visit
 At the end of 3 months
 BP of all patients will be recorded
 10 ml of blood - estimate RBS, lipid profile
Platelet count,BT and platelet aggregation
study.
 If no significant side effect is noted the
drugs will be given for a further period of 3
months.

27. 4th visit
• At the end of 6 months.
• Recording of BP
• RBS, lipid profile,BT, and platelet
aggregation
• If no significant side effect is noted the
drugs will be given for a further period of
6 months

28. 5th visit
• At the end of 12 months, final evaluation
of the patients will be done.
• Recording of BP
• RBS, lipid profile,BT, and platelet
aggregation
6th visit
At the end of 18months
• Follow up done up to 24 months

29.  All adverse effects during the period of study will be
recorded in the adverse drug reaction form
 If any serious ADE occurs it should be reported
1. within 24hrs to the sponsor
2. With in 7 days to the EC
3. With in 14 calendar days to the DCGI - expert
committee. 30 days to decide upon compensation.
Stopping rules
 If patient develops any serious ADE
 Drug should be stopped and appropriate treatment is
started.

30. STATISTICAL ANALYSIS:
• At the end of the study, BP during each of
visits and platelet aggregatory studies will be
evaluated.
• SPSS version 16 will be used to evaluate the
data. Student ‘t’ test and ANOVA will be used
to estimate the significance.

31. ETHICAL ASPECTS
 The study will be conducted acc to the
declaration of Helsinki 2008,ICH& GCP
guidelines .
• After taking approval from the independent
ethics committee, Medical College, Tvpm
study will be started
• A written informed consent will be obtained
from all patients participating in the study.

32. INFORMED CONSENT
 I.............hereby give my consent to be included as
a subject in this study on “A multicentric parallel group double blind
randomized control study to compare the efficacy and safety of Cardex
Vs Nifedipine in Stage 1 Hypertension.” All the details regarding the
study including any side effects and complications have been explained
to me by Dr. Ajay , the principal investigator.
I wholeheartedly agree without any compulsion to
participate in this study. The principal investigator has explained to me
that he will be collecting the data of my symptoms and results of blood
tests & other investigations that has been done as part of the routine
evaluation of my condition. The maintenance of confidentiality of the
details has been assured.
I am assured that I can withdraw from the study at any time
and that my withdrawal from the study would not affect the treatment
given to me.I also understand that there wouldn’t be any financial burden
on me.
Name of the investigator: Dr.Ajay Name of the patient:
Signature and Date: Signature and Date:
Name of the witness:
Signature and Date:

33. OUTCOME
• Mean reduction in systolic and diastolic
BP by 10mmHg will be taken as the
expected outcome.
• A reduction in platelet aggregation as
compared to initial value will be the 2nd
expected outcome.

34. Patient with stage 1 HTN
Selection criteria
Not
satisfied
Out of
the study
satisfied
RCT
N=600 patients
Nifedipine 20mg
Cardex 10mg N=300
N=300
Reduction in BP
Reduced platelet aggregation
Reduction in BP
Reduced platelet aggregation
Comparison of
outcome
conclusion

35. REFERENCES
1. Cirzonna R, landmark L, frondoza GC. The new
cardioselective calcium channel blocker-nifedipine a
review. JAMA, 2005;8(2):125-32
2. Gupta S, Ravishankar G. A comparison of the
antihypertensive effects of nicardipine with
nifedipine.BMJ,2006;2(4):330-401.
3.Craig WA,Shaw WR,Ramgopal v Dhingra texbook
ofHypertension and drug therapy fourth edition;32-
6:243-252

36. THANK YOU