China Stroke Primary Prevention Trial 2 for Participants With H-type Hypertension and MTHFR 677 CC/CT Genotype (CSPPT2-CC/CT)

Официальное название

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

Обзор

This is a multi-center, randomized, double-blind, double-dummy, controlled clinical trial. This trial will include 32,000 Chinese men and women with hypertension (H-type hypertension), MTHFR 677 CC or CT genotype, elevated plasma total homocysteine (tHcy ≥10µmol/L), and insufficient serum folate levels (\<12ng/mL). The participants will be first stratified by their MTHFR 677 genotype (CC vs. CT), then randomized to one of two treatment groups in a 1:1 ratio. 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. The treatment period is five years and primary endpoint is first ischemic stroke.

Подробное описание

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 first 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 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 randomized, double-blind, double-dummy, controlled treatment with a total of 5-years. At each of the participating centers, participants who remain eligible for participation at V1 will first be stratified by MTHFR genotypes: CC vs. CT. Within each genotype stratum, participants will then be randomized into 2 treatment groups: either an amlodipine-only tablet (5mg/d) with a dummy tablet or an amlodipine folic acid tablet (5.8mg/d) with a dummy tablet in a 1:1 ratio, using randomization and trial supply management (RTSM) platform.

During the treatment period, other antihypertensive drugs can be added to achieve the target 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 every 3 months during the five-year treatment period, and the treatment drugs will be distributed at each visit.

A total of 32,000 participants will be randomly assigned to one of the two treatment groups: Group A: amlodipine 5.0mg (n=16,000) and Group B: amlodipine-folic acid 5.8mg (n=16,000). Based on published data from CSPPT (Huo et al, JAMA, 2015), the 5-year cumulative incidence of ischemic stroke is around 2.9%. Assuming the 5-year cumulative incidence of ischemic stroke is 2.5% in the amlodipine-only group, this trial has 80% power to detect a 20% difference between group A and group B 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 cumulative incidence of ischemic stroke in the amlodipine-only group is 3.5%, this trial has 80% power to detect a 16% difference between group A and group B (HR ≤0.84).

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.

Вмешательства

• Препарат Amlodipine besylate
  The amlodipine used in this study is a listed product. Amlodipine tablets and amlodipine folic acid (dummy) are provided in aluminum-plastic blisters packaging. Each package includes 100 days of treatment drug (including 10 extra days of treatment for the follow-up window). A package of medication consists of 20 plates, each plate includes a total of 10 tablets arranged as follows: amlodipine 5mg/tablet x5 tablets + amlodipine-folic acid (dummy) x5 tablets. Affixed to the medication package is t
• Препарат 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. Amlodipine-folic acid tablets and amlodipine (dummy) are provided in aluminum-plastic blisters packaging. Each package includes 100 days of treatment drug (including 10 extra days of treatment for the follow-up window). A package of medication consists of 20 plates, each plate includes a total of 10 tablets arranged as follows: amlodipine-fol
• Препарат Amlodipine placebos
  An amlodipine placebo is a dummy pill of an amlodipine tablet with an identical appearance.
• Препарат Amlodipine-folic acid placebos
  An Amlodipine folic acid placebo is a dummy pill of an amlodipine folic acid tablet with an identical appearance.

Первичные конечные точки

• First ischemic stroke [Срок оценки: By the end of the fifth year from baseline]

Вторичные конечные точки (8)

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

Критерии участия

Критерии включения

• 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 CC or CT 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);
• Plasma total homocysteine ≥10 µmol/L;
• Serum folate level <12 ng/mL;
• Has voluntarily agreed to participate and provided 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.

Критерии исключения

• 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.).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Китай · 20 центров

• First Affiliated Hospital of Bengbu Medical University — Bengbu
• Bozhou — Бочжоу
• Chizhou People's Hospital — Chizhou
• Taihe County People's Hospital — Fuyang
• Peking University First Hospital — Пекин
• Yangjiang People's Hospital — Yangjiang
• The Affiliated Hospital Of Guizhou Medical University — Guiyang
• The First Affiliated Hospital of Hunan University of Medicine — Huaihua
• … и ещё 12 центров

Публикации

• 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

Идентификаторы

NCT: NCT04974138 · CSPPT2-CC/CT_2020

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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