Hypertension Clinical Trials. in China. Liu Lisheng

Transcription

1 Hypertension Clinical Trials in China Liu Lisheng

2 Necessity of Conducting Large-scale Clinical Studies using Chinese Subjects RCT in China Discussion Experience Pharmacogenetics & individualized medicine Role of specialists in complicated RCTs Closer FU & dose flexibility

3 1/100,000 Mortality in Urban Area in China CVD Cancer Resp. Injury/poi son GI (yr)

4 Chronic Disease in China CVD Report of China 1. CVD patients: 230 million 2. New onset stroke: 2million/yr,Survived stroke:13 million 3. New onset MI: 0.5 million,survived MI: 3 million; CHD: 8 milllion 4. Patients with chronic diseases in 2003: 574 million : DM: 33 million-- Cancer: 46 million Cerebrovascular diseases: 93 million Cardiac disease: 165 million Hypertension: 237 million

5 Mortality in China, Japan, UK, USA USA UK Japan China Rural China Urban CHD Stroke OtherCVD Other Mortality 1/ Male WHO statistics

6 Mortality in China, Japan, UK, USA USA UK Japan China Rural China Urban CHD Stroke Other CVD Other Mortality 1/ Female WHO statistics

7 Necessity of Conducting Large-scale Clinical Studies using Chinese Subjects RCTs in China Discussion Experience Pharmacogenetics & individualized medicine Role of specialists in complicated RCTs Closer FU & dose flexibility

8 International Trials Trials Year Contributions PROGRESS The Perindopril Protection Against Recurrent Stroke Study CREATE Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation ADVANCE Action in diabetes & Vascular Disease: Preterax and Diamicaron Mr Controlled Evaluaton 2001 Post stroke antihypertensive treatment effectively reduced the recurrence of stroke in patients suffered from stroke 2005 Post MI : use of reviparin is beneficial 2006 Antihypertensive tr. reduce the events of macro- and micro-vascular events in patients with DM (blood pressure arm)

9 International Trials Trials Year Contributions & problems WAVE The Warfarin Antiplatelet Vascular Evaluation Study OASIS-6 Organization for the Assessment of Strategies for Ischemic Syndromes-6 POISE Effects of extendedrelease metoprolol succinate in patients undergoing non-cardiac surgery more hemorrhagic side effects in Chinese

10 International Trials Trials Year Contributions ONTARGET/TRANSEND Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint trial/telmisartan Randomized Assessment Study in ACE Intolerant Subjects with CVD HYVET The Hypertension in the Very Elderly Tri 2008 RAS blocade treatment effectively reduce CVD events with either ACEI or ARB rather than both 2008 Antihypertensive treatment reduced major CVD events and mortality in very elderly (>=80 yrs) hypertensive patients

11 Necessity of Conducting Large-scale Clinical Studies using Chinese Subjects RCTs in China Discussion Experience Pharmacogenetics & individualized medicine Role of specialists in complicated RCTs Closer FU & dose flexibility

12 Experience (1/2) Easier to recruit participants from clinics or communities. Concommitant drug treatment are less. large simple trials are feasible in China.

13 Example:Chinese subjects in HYVET (40% of total sample) Slightly younger, lighter & shorter. Smoked more but drank less alcohol. Less previous episodes of MI, more previous stroke Had lower blood urea, uric acid and Cr, higher HDLC. Blood glucose & TC, Na & K, blood haematocrit & Hb were all lower. Much easier to recruit, less concomitant tr. More compliant to tr. Easier to FU.

14 Experience (2/2) CHL was established on top of Syst.-China & PATs Collaborative group (31 medical universities) in 1989 & continuing on organizing RCTs both nationally & internationaly Established good relationship with world well known RCT Centers, implicating RCT results in Chinese population successfully. For ex. CCB based tr.used widely in ISH,captopril in post MI after Syst-China and CCS1 trials.

15 Necessity of Conducting Large-scale Clinical Studies using Chinese Subjects RCTs in China Discussion Experience Pharmacogenetics & individualized medicine Role of specialists in complicated RCTs Closer FU & dose flexibility

16 Pharmacogenetics & individualized medicine Warfarin dosage in Asian people Can folic acid prevent stroke? China Stroke Primary Prevention Trial

17 Types of Adverse Drug Reactions Type A: dose dependent, usually predictable, common, monogenic or oligogenic model (example: excessive bleeding with warfarin Inter-individual difference in warfarin sensitivity) Type B: dose independent, unpredictable, rare, polygenic model (example: penicillin anaphylaxis, Stevens-Johnson syndrome)

18 Warfarin, an anti-coagulant is widely used to prevent and treat blood clots. Warfarin Heart Valve Replacement Pulmonary Embolism (PE) Warfarin treatment is problematic: Narrow therapeutic index. Wide inter-individual and inter-ethnic in dose response. INR needs to be monitored closely.

19 Warfarin maintenance doses vary among different populations: Asians require lower doses Ethnicity Warfarin dose References Asian Chinese 3.3 (mg/day) Q. J. Med. 89, Japanese 3.3 (mg/day) Clin. Pharmacol. Ther. 63, Caucasian American 5.1 (mg/day) JAMA, 287, Italian 5.5 (mg/day) Blood, 105,

20 Warfarin metabolism and Vitamin K cycle

21 Genotype frequencies of VKORC1 promoter polymorphism (-1639 G>A) in Chinese and Caucasians.

22 Genotype frequencies of VKORC1 & CYP2C9 varients in Chinese (Fu Wai Hospital) Number of samples : 92 VK, 91 CY VKORC GG 1.09% AG AA CYP2C9 *1/* *1/* *2/*2 - *1/* *3/*3 -

23 Promoter SNP in VKORC1(-1639 G>A) is associated with warfarin dosage Human Molecular Genetics, 14: , The polymorphism abolished an E-box and was found to regulate VKORC1 expression. Promoter analysis demonstrated that the G allele has approximately 50% higher activity than the A allele This functional polymorphism underscores the inter-ethnic and inter-individual differences in warfarin dosage

24 Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes Clinical Pharmacology & Therapeutics, 2008 Academia sinica Taiwan

25 Purpose of prospective Study To determine whether an individual s VKORC1 and CYP2C9 genotypes can be used to predict warfarin dosage To reduce/prevent adverse bleeding complications for warfarin sensitive patients To shorten the time to therapeutic INR thus reducing the burden of constant INR monitoring

26 Suggested Starting dose based on genotypes VKORC G>A CYP2C9 Starting Dose (mg/d) Expected frequency (%) Actual Frequency (n=108) GG *1/* (2.8%) GG *1/* GG *3/* < AG *1/* (15.7%) AG *1/* (0.9%) AG *3/*3 2.5 < AA *1/* (76.9%) AA *1/* (3.7%) AA *3/* <

27 Adverse Events With pharmacogenetic dosing, 10 % patients had INR > 4.0, however none had clinical bleeding or developed venous thrombosis or pulmonary embolism Without pharmacogenetic dosing, the incidence of AE is as high as 39% (Historical controls)

28 Conclusions Warfarin Prospective Study Time to therapeutic INR is shortened (1-2 weeks vs > 3-4 weeks) No serious adverse events Dosage prediction based on genotypes alone can achieve high sensitivity (69%) This sensitivity may increase when other factors are used in the prediction Future study: A randomized, controlled trial utilizing the algorithm incorporating other nongenetic factors Dose = x predicted dose x age x BSA x HT

29 The scientific and clinical evidence that supports lower warfarin doses for paitents with certain genetic variations in CYP2C9 and in the VKORC1 has recently moved the US Food and Drug Administration (FDA) to change the labeling of warfarin recommending genetic testing to guide warfarin dosing.

30 Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin.

31 Ethnically Different Dose Recommendation Description of current changes to the Crestor label In a pharmacokinetic study involving a diverse population of Asians residing in the United States, rosuvastatin drug levels were found to be elevated approximately 2-fold compared with a Caucasian control group. As a result of these findings, the Dosage and Administration section of the label now states that the 5 mg dose of Crestor should be considered as the start dose for Asian patients and any increase in dose should take into consideration the increased drug exposure in this patient population. Results of this pharmacokinetic study are further discussed under the Clinical Pharmacology and Precautions section of labeling.

32 Pharmacogenetics & individualized medicine Warfarin dosage in RCT Can folic acid prevent stroke? China Stroke Primary Prevention Trial

33 Enalapril Maleate and Folic Acid Tablets for Primary Prevention of Stroke in Chinese Hypertensive Patients: a Post-marketing Double-blind Randomized Controlled Trial China Stroke Primary Prevention Trial (CSPPT) XP Xu Anhuei Med Un

34 RATIONALE Case control study of subj in China: CVD events strongly associated with thcy Folic acid supplement.reduce primary stroke 25% C677T gene polymorphism of 5,10-methylenetetra hydrofolate reductase (MTHFR),is a genetic determinator of plasma thcy. TT genotype has higher thcy & CVD risk.

35 Objective Endpoints Objectives of CSPPT To evaluate the long-term efficacy of Enalapril Maleate and Folic Acid Tablets (EMFAT) in prevention of stroke in Chinese hypertensives, as compared to Enalapril alone as anti-hypertension treatment Primary Endpoints F,NF stroke Secondary Endpoints Stroke subtypes» Ischemic» Hemorrhage F,NF MI CVD Mortality All-cause mortality Other Endpoints CHF, unstable angina pectoris hospitalization Coronary revascularization, peripheral arterial revascularization

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37 Enrollment Criteria Age M & F( premenopausal women who agree to use a reliable contraceptive method during the trial) Mild to moderate essential hypertension 140 mmhg SBP 180 mmhg; and/or 90 mmhg DBP 110 mmhg; or Currently under treatment for hypertension Informed consent Voluntary participation Signed written informed consent

38 Exclusion Criteria Any medical history of Stroke Myocardial infarction Heart failure Allergic or non-tolerant to ACEI Post-revascularization Pregnant and breast-feeding women Long-term use of Vitamin B (including folate) Mental retardation or other mental diseases Low compliance due to other reasons

39 Screening Phase Genotype Identification Study Flow Chart run-in Phase (3 weeks) Tolerance in Enalapril Therapy TT CT Trial Phase (208 weeks) A: Enalapril and Folic Acid Tablet 10mg/0.8mg Enalapril Tablet 10mg B: Enalapril and Folic Acid Tablet 10mg/0.8mg Enalapril Tablet 10mg CC C: Enalapril and Folic Acid Tablet 10mg/0.8mg Enalapril Tablet 10mg

40 Screening phase The Flow of Study Verification of eligibility, informed consent and enrollment of eligible patients Run in phase (3 wks) Enalapril 10mg q.d. MTHFR C677T genotyping Trial phase (4 yrs) Double-blind, randomized Treatment: EMFAT (10mg enalapril + 0.8mg folate) Control: 10mg enalapril If necessary for optimal BP control, non-acei anti-hypertensive drugs can be added. FU every 3 mons

41 Follow-up Visits Every three months Blood pressure and Pulse Endpoint events Other adverse events Compliance of medication If necessary, adding other anti hypertensive drug End of the first year Plasma Hcy; CRP, liver, kidney function End of the fourth year Plasma Hcy; CRP, Urine microalbumin; Liver, kidney functions; % body fat; EKG; Pulse wave velocity; Ankle-brachial index; Carotid intima-media thickness; Retina fundus image

42 Data Collection at Baseline Medical history and questionnaire Physical examination, including height, weight, waist circ. BP and resting heart rate EKG Pulse wave velocity Ankle-brachial index Carotid intima-media thickness Retina fundus image % body fat using BIA Laboratory tests Plasma Hcy CRP K +, Na +, and other electrolytes Liver, kidney function Urine Microalbumin

43 Statistical Power >80% of power, assuming Sample size (n=20,000) An annual incident rate of 0.5% for the primary endpoint event in the control 4 years of follow-up 15% reduction of the incident rate in the treatment group Two-sided alpha value of 0.05

44 Necessity of Conducting Large-scale Clinical Studies using Chinese Subjects RCTs in China Discussion Experience Pharmacogenetics & individualized medicine Role of specialists in complicated RCTs Closer FU & dose flexibility

45 Role of specialists in complicated trials In high risk patients trial, closer FU and careful dose titrating is important. Experienced clinicians are necessary for conducting complicate trials.

46 Conclusion In China, Simple Large Scale Clinical Trials can be accomplished in communities with low cost Group of doctors and nurses have been trained by taking parts in national and International Clinical Trials in past 20 years

47 Since CVD is the leading cause of death, with experienced trial investigators, China will continuously work in this field Ethnic difference and pharmancogenetics need to be considered in designing future trials

48 Thank You!