China Stroke Primary Prevention Trial 2 for Participants With Hypertension and MTHFR 677 TT Genotype

Official title

Comparative Efficacy of Amlodipine Folic Acid vs. Amlodipine on the Risk of First Ischemic Stroke Among Participants With Hypertension and MTHFR 677 TT Genotype: A Multi-center, Randomized, Double-blind, Triple-dummy, Controlled Clinical Trial

Overview

This is a multi-center, randomized, double-blind, triple-dummy, controlled trial in 24,000 Chinese men and women with hypertension and MTHFR 677 TT genotype. The study participants will be randomized to one of the three treatment groups: Group A: amlodipine tablet (5mg), taken orally, once daily, serving as active comparator. Group B: amlodipine folic acid 5.8mg tablet (5mg amlodipine and 0.8mg folic acid), taken orally, once daily. Group C: amlodipine folic acid 5.8mg tablet plus 5-methyltetrahydrofolate (5-MTHF, 0.4mg), taken orally, once daily. The primary endpoint is first ischemic stroke.

Detailed description

This study consists of 3 periods: Screening, Run-in, and Randomized treatment.

Period I: Screening (V0)

The purpose of Period I is to obtain informed consent and screen for eligible participants.

After obtaining written informed consent, at the screening visit (V0), participants will complete a face-to-face interview and clinical evaluation and measurements. Their biological samples will be collected for laboratory analyses. Collectively, these information will help to determine eligibility for inclusion in the study.

Period II: Run-in Period (VD)

The purpose of Run-in is to assess participants' compliance for following the amlodipine treatment regimen as well as to observe participants' tolerance to amlodipine, so as to screen out those with poor compliance or intolerance to amlodipine treatment.

The run-in phase lasted 2 to 4 weeks, during which oral administration of Amlodipine tablets (5 mg) was given once daily.

Period III: Randomized Treatment (V1-V21)

This is a 5-year period of randomized, double-blind, triple-dummy, controlled treatment. At each of the research centers, participants who remain eligible for participation in the study will be randomized into 3 treatment groups:

A. Amlodipine-only (5mg/d) with an amlodipine folic acid placebo and 5-MTHF placebos.

B. Amlodipine folic acid tablet (5.8mg/d) with amlodipine placebo and 5-MTHF placebo.

C. Amlodipine folic acid tablets (5.8mg/d) and 5-MTHF (0.4mg/d) with an amlodipine placebo in a 1:1:1 ratio, using the randomization and trial supply management (RTSM) platform.

During the treatment period, other antihypertensive drugs can be added to achieve blood pressure control (BP ≤140/90mmHg), including Valsartan (80mg/d), or/and Indapamide (1.5mg/d), or/and metoprolol tartrate tablets (25mg/d). Participants will be followed up every 3 months during the treatment period, and the treatment drugs will be distributed at each visit.

A total of 24,000 participants will be randomly assigned to one of three treatment groups (Group A n=8,000, Group B n=8,000, Group C n=8,000). Based on published data from CSPPT (Huo et al, JAMA, 2015), the 5-year cumulative incidence of first ischemic stroke in the amlodipine-only group is 3.5%. Assuming the 5-year cumulative incidence of first ischemic stroke in the amlodipine-only group is around 3.5%, this trial has 80% power to detect a 20% difference between group A and group B+C in the observed hazard ratio (HR) for incident ischemic stroke (HR≤0.80), at a two-sided significance level of α=0.05. If instead, the 5-year incidence of ischemic stroke in the amlodipine-only group is 2.5%, this trial has 80% power to detect a 23% difference between the treatment groups (A vs B+C) (HR≤0.77).

There are two planned interim analyses, one at the end of the third year, and another at the end of the fourth year. The O'Brien-Fleming alpha-spending function will be used to define the significance level of each interim analysis to ensure that the final overall two-sided significance level of α=0.05 is met.

Interventions

• Drug Amlodipine besylate
  The amlodipine used in this study is a listed product.
• Drug Amlodipine besylate And Folic Acid
  The amlodipine besylate and folic acid tablets have been approved for listing by the China Food and Drug Administration, approval number: Zhunzi H20180020.
• Drug 5-methyltetrahydrofolate (5-MTHF)
  The 5-MTHF used in this study is a listed product.
• Drug Amlodipine placebo
  Amlodipine placebos are dummy pills of amlodipine with identical appearance.
• Drug Amlodipine folic acid placebo
  Amlodipine folic acid placebos are dummy pills of amlodipine folic acid with identical appearance.
• Drug 5-MTHF Placebos
  5-MTHF placebos are the dummy pills of 5-MTHF with identical appearance.

Primary outcome measures

• First ischemic stroke [Time frame: By the end of the fifth year of the study]

Secondary outcome measures (8)

• First ischemic stroke (for refined treatment group comparisons) [Time frame: By the end of the fifth year of the study]
• First stroke (ischemic and hemorrhagic) [Time frame: By the end of the fifth year from baseline]
• Composite cardiovascular endpoint (first non-fatal stroke, first non-fatal myocardial infarction, cardiovascular death) [Time frame: By the end of the fifth year from baseline]
• Kidney outcomes [Time frame: By the end of the fifth year from baseline]
• First hemorrhagic stroke [Time frame: By the end of the fifth year from baseline]
• First myocardial infarction [Time frame: By the end of the fifth year from baseline]
• First coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) [Time frame: By the end of the fifth year from baseline]
• Cardiovascular death [Time frame: By the end of the fifth year from baseline]

Eligibility criteria

Inclusion criteria

• Men and women, aged ≥45 and <75 years.
• Hypertension: Previously diagnosed with primary hypertension and has been taking antihypertensive medication within the past two weeks; OR has not been taking antihypertensive medications within the last two weeks, but meets the following criteria for hypertension: SBP≥140 mmHg and/or DBP≥90 mmHg (average of at least 2 measurements each time) at two separate (not on the same day) clinical visits.
• MTHFR 677 TT genotype (based on the test results from the central laboratory during the screening period or a previous official test report from a laboratory with medical testing qualifications).
• Voluntarily participates and has given signed informed consent.

Randomized-treatment phase inclusion criteria:

• Good compliance during the run-in period, and unlikely to discontinue treatment;
• No stroke or cardiovascular events during the run-in period;
• The participant voluntarily agrees to continue the study.

Exclusion criteria

• Previously diagnosed secondary hypertension;
• Previously diagnosed stroke;
• Previously diagnosed myocardial infarction;
• Previously diagnosed heart failure;
• Previously diagnosed atrial fibrillation;
• Cardio-cerebral-kidney revascularization and/or other large arterial stent;
• Currently on dialysis, or diagnosed with stage 4-5 chronic kidney disease, or eGFR <30 mL/ min/1.73m²;
• Known to have congenital (such as aortic stenosis) or acquired organic heart disease;
• Known to have any of the following severe diseases or conditions:

• Digestive system: i. Previously diagnosed with any form of viral hepatitis that is currently still in the active phase; ii. Abnormal liver function test before enrollment (any of ALT, AST, GGT, TBIL, DBIL test 3 times higher than normal, or ALB≤30g/L); iii. Subtotal gastrectomy and/or gastrojejunostomy;
• Respiratory system: previously diagnosed with pulmonary heart disease;
• Presence of malignant tumors or other severe diseases;
• Presence of long-term gastrointestinal symptoms such as ; anorexia, decreased appetite, nausea, and abdominal bloating;
• Previously diagnosed with vitamin B12 deficiency and/or its related diseases.
• Participant, at the investigator's discretion, is assessed to be unsuitable for the study, for reasons including but not limited to the presence of abnormal laboratory results, or clinical conditions;
• Prior history of significant intolerance due to adverse reactions resulting from usage of amlodipine or other CCBs, valsartan or other ARBs, indapamide or other similar diuretics, metoprolol tartaric acid or other beta-blockers, or any drugs or health products containing folate or folic acid;
• Regular consumption of folic acid or vitamin B compounds, or other compounds containing folic acid in the past 3 months;
• The presence of any of the following conditions that could negatively influence a participant's ability to consent or participate in the trial:

• Dementia;
• Severe mental disorders;
• Inability to express informed consent;
• Unlikely to complete the study follow-up as specified by the protocol, or plans to relocate outside of the study area in the near future;
• History of poor compliance when taking antihypertensive medications or is expected to have poor compliance during the study;
• Refusal to participate, or inability to modify current drug regimen;
• Women who are pregnant or breastfeeding; or subjects of childbearing potential who are unwilling or unable to use effective contraception during the study period.
• Within one month prior to the first visit, having participated in any clinical trial for a drug that has not yet been officially approved by the state or is not currently approved for sale; or currently participating in any clinical trial that could potentially impact the results of this study (medication use, drug efficacy, drug interaction, etc.).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 20 centers

• First Affillated Hospital of Bengbu Medical University — Bengbu
• Bozhou People's Hospital — Bozhou
• Chizhou People's Hospital — Chizhou
• Taihe County People's Hospital — Fuyang
• Peking University First Hospital — Beijing
• Yangjiang People's Hospital — Yangjiang
• The Affiliated Hospital of Guizhou Medical University — Guiyang
• The First Affiliated Hospital of Hunan University of Medicine — Huaihua
• … and 12 more centers

Publications

• Kjeldsen SE, Julius S, Hedner T, Hansson L. Stroke is more common than myocardial infarction in hypertension: analysis based on 11 major randomized intervention trials. Blood Press. 2001;10(4):190-2. doi: 10.1080/08037050152669684. No abstract available. PMID 11800055
• Collaboration HLT. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998 Mar 21;316(7135):894-8. PMID 9569395
• Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005 Oct;82(4):806-12. doi: 10.1093/ajcn/82.4.806. PMID 16210710
• Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Renlund M, Stoll C, Alembik Y, Dott B, Czeizel AE, Gelman-Kohan Z, Scarano G, Bianca S, Ettore G, Tenconi R, Bellato S, Scala I, Mutchinick OM, Lopez MA, de Walle H, Hofstra R, Joutchenko L, Kavteladze L, Bermejo E, Martinez-Frias ML, Gallagher M, Erickson JD, Vollset SE, Mastroiacovo P, Andria G, Botto LD. Geographical and ethnic variation of the 67 PMID 12920077
• Xu X, Li J, Sheng W, Liu L. Meta-analysis of genetic studies from journals published in China of ischemic stroke in the Han Chinese population. Cerebrovasc Dis. 2008;26(1):48-62. doi: 10.1159/000135653. Epub 2008 May 30. PMID 18511872
• Qin X, Li J, Cui Y, Liu Z, Zhao Z, Ge J, Guan D, Hu J, Wang Y, Zhang F, Xu X, Wang X, Xu X, Huo Y. MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults. Nutr J. 2012 Jan 10;11:2. doi: 10.1186/1475-2891-11-2. PMID 22230384
• Qin X, Li J, Cui Y, Liu Z, Zhao Z, Ge J, Guan D, Hu J, Wang Y, Zhang F, Xu X, Wang X, Xu X, Huo Y. Effect of folic acid intervention on the change of serum folate level in hypertensive Chinese adults: do methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms affect therapeutic responses? Pharmacogenet Genomics. 2012 Jun;22(6):421-8. doi: 10.1097/FPC.0b013e32834ac5e8. PMID 21869730
• Qin X, Li J, Zhang Y, Ma W, Fan F, Wang B, Xing H, Tang G, Wang X, Xu X, Xu X, Huo Y. Prevalence and associated factors of diabetes and impaired fasting glucose in Chinese hypertensive adults aged 45 to 75 years. PLoS One. 2012;7(8):e42538. doi: 10.1371/journal.pone.0042538. Epub 2012 Aug 3. PMID 22880024

Identifiers

NCT: NCT04974151 · CSPPT2-TT_2020

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗