A Randomized, Double-Blind, Multi-Center, Phase III Trial to Evaluate the Efficacy and Safety of KDF1901 in Patients With Essential Hypertension Inappropriately Controlled on KDF1901-R0 Treatment
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 286
- 试验地点
- 2
- 主要终点
- Change in Mean Sitting Systolic Blood Pressure (MSSBP) from baseline to Week 8
研究概览
简要总结
This randomized, double-blind, multicenter phase 3 clinical trial evaluated the efficacy and safety of KDF1901, a single-pill triple combination of valsartan, amlodipine, and chlorthalidone, in patients with essential hypertension inadequately controlled with dual therapy. A total of 286 patients who remained uncontrolled after a 4-week run-in period with valsartan/amlodipine were randomized to receive either KDF1901 (valsartan/amlodipine/chlorthalidone 160/10/25 mg) or a dual combination of valsartan/amlodipine (160/10 mg) for 8 weeks.
The primary endpoint was the change in mean sitting systolic blood pressure (MSSBP) from baseline at week 8. Secondary outcomes included changes in diastolic BP (MSDBP), blood pressure normalization rate, and response rate. KDF1901 demonstrated significantly greater reductions in both MSSBP and MSDBP, with higher normalization and response rates compared to dual therapy. The treatment was well tolerated, and the incidence of adverse events was comparable between groups.
详细描述
Achieving optimal blood pressure control remains a clinical challenge, especially in patients who do not respond adequately to dual antihypertensive therapy. This study assessed the clinical benefit of adding chlorthalidone to a fixed-dose combination of valsartan and amlodipine to form KDF1901, a triple combination therapy.
The study included 286 patients with essential hypertension who did not reach target blood pressure after a 4-week run-in period with valsartan/amlodipine (80/5 mg). They were randomized 1:1 to receive either KDF1901 (160/10/25 mg) or valsartan/amlodipine (160/10 mg) for 8 weeks.
At week 8, the KDF1901 group showed significantly greater reductions in MSSBP (-21.2 ± 9.3 mmHg vs. -15.4 ± 8.7 mmHg, p<0.001) and MSDBP (-12.2 ± 6.5 mmHg vs. -8.6 ± 6.2 mmHg, p<0.001) than the dual therapy group. Blood pressure normalization and response rates were also significantly higher with KDF1901.
Subgroup analyses revealed consistent efficacy in elderly and diabetic patients. The incidence of TEAEs was similar between groups, and most adverse events were mild and not drug-related. These results suggest the potential clinical utility of chlorthalidone-based triple therapy in high-risk hypertensive patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female participants aged ≥19 years at the time of screening.
- •Participants who meet one of the following blood pressure criteria at screening:
- •If not currently receiving antihypertensive medication for at least 4 weeks (treatment-naïve):
- •Mean Sitting Systolic Blood Pressure (MSSBP) ≥160 mmHg and <200 mmHg
- •If currently receiving antihypertensive medication:
- •MSSBP ≥140 mmHg and <200 mmHg
- •For participants with cardiovascular disease, diabetes mellitus, or microalbuminuria (e.g., persistent proteinuria or hematuria), the range is:
- •MSSBP ≥130 mmHg and <200 mmHg
- •Willing and able to provide written informed consent prior to participation in the study.
- •At baseline (Visit 3), participants must have MSSBP ≥140 mmHg and <200 mmHg.
- •For participants with cardiovascular disease, diabetes mellitus, or microalbuminuria: MSSBP ≥130 mmHg and <200 mmHg
- •At least 70% compliance with run-in period medication, as assessed by tablet count.
排除标准
- •Mean sitting diastolic blood pressure (MSDBP) ≥110 mmHg at screening (Visit 1) or baseline (Visit 3)
- •Difference in blood pressure between arms: MSSBP ≥20 mmHg and MSDBP ≥10 mmHg at screening
- •History or presence of secondary hypertension or suspected secondary hypertension, including:
- •Aortic coarctation, pheochromocytoma, Cushing's syndrome, hyperaldosteronism, polycystic kidney disease
- •Severe pulmonary, cardiac, or vascular conditions, such as:
- •Pulmonary hypertension, severe heart failure (NYHA class III or IV), hypertrophic cardiomyopathy, aortic aneurysm, thrombocytopathy
- •History of serious cardiovascular events or interventions within 24 weeks prior to screening:
- •Myocardial infarction, unstable angina, coronary revascularization (PCI/CABG)
- •History of cerebrovascular disorders within 24 weeks prior to screening:
- •Stroke, TIA, cerebral hemorrhage
- •History of ocular conditions within 24 weeks prior to screening:
- •Retinal hemorrhage, optic neuropathy, severe visual impairment
- •History of malignancy within 5 years prior to screening, except:
- •Successfully treated and in remission for ≥2 years, or
- •Basal cell carcinoma or squamous cell carcinoma of the skin
- •Hereditary blood disorders or history of angioedema related to ACE inhibitors or ARBs
- •History of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
- •Diagnosis of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) within 48 weeks prior to screening
- •Clinically significant conditions affecting drug absorption, distribution, metabolism, or excretion
- •Symptoms of orthostatic hypotension or risk of falls or syncope
- •Severe anemia, leukopenia, or thrombocytopenia at screening
- •Heart failure NYHA class III or IV
- •Known serious arrhythmias, including ventricular tachycardia or fibrillation
- •Known autoimmune disease or connective tissue disorder
- •Clinically significant renal, hepatic, or cardiovascular disease
- •eGFR <30 mL/min/1.73 m² or serum creatinine ≥2.0 mg/dL
- •ALT or AST >3× upper limit of normal (ULN)
- •Serum K+ <3.5 or >5.5 mmol/L, Na+ <135 mmol/L, Ca2+ >10.5 or <2.63 mmol/L
- •Requiring long-term immunosuppressive therapy or systemic corticosteroids
- •Clinically significant chronic inflammatory conditions
- •History of major surgery or active GI disorders
- •Type 2 diabetes mellitus with HbA1c ≥9.0%
- •Known edematous disorders (e.g., untreated nephrotic syndrome)
- •Requirement for prohibited medications (emergency drugs) during study period (Visit 1-6)
- •Use of lithium therapy
- •Use of terfenadine or astemizole
- •Hypersensitivity to study drugs, dihydropyridine-class CCBs, thiazide diuretics, or sulfonamides
- •History or suspicion of drug or alcohol abuse
- •Pregnancy or lactation
- •Women of childbearing potential or male participants not agreeing to use reliable contraception during study
- •Participation in other clinical trials or use of investigational products within 4 weeks prior to screening
- •Judged by the investigator to be otherwise unsuitable for study participation
研究组 & 干预措施
KDF1901 group
Run-in Period (4 weeks): KDF1901-R0, a fixed-dose combination tablet containing valsartan 80 mg and amlodipine 5 mg, administered once daily
Treatment Period 1 (2 weeks): KDF1901-L, containing valsartan 80 mg, amlodipine 5 mg, and chlorthalidone 12.5 mg, administered once daily
Treatment Period 2 (6 weeks): KDF1901, containing valsartan 160 mg, amlodipine 10 mg, and chlorthalidone 25 mg, administered once daily
干预措施: KDF1901-R0 (Drug)
KDF1901 group
Run-in Period (4 weeks): KDF1901-R0, a fixed-dose combination tablet containing valsartan 80 mg and amlodipine 5 mg, administered once daily
Treatment Period 1 (2 weeks): KDF1901-L, containing valsartan 80 mg, amlodipine 5 mg, and chlorthalidone 12.5 mg, administered once daily
Treatment Period 2 (6 weeks): KDF1901, containing valsartan 160 mg, amlodipine 10 mg, and chlorthalidone 25 mg, administered once daily
干预措施: KDF1901-L (Drug)
KDF1901 group
Run-in Period (4 weeks): KDF1901-R0, a fixed-dose combination tablet containing valsartan 80 mg and amlodipine 5 mg, administered once daily
Treatment Period 1 (2 weeks): KDF1901-L, containing valsartan 80 mg, amlodipine 5 mg, and chlorthalidone 12.5 mg, administered once daily
Treatment Period 2 (6 weeks): KDF1901, containing valsartan 160 mg, amlodipine 10 mg, and chlorthalidone 25 mg, administered once daily
干预措施: KDF1901 (Drug)
Dual Therapy group
Run-in Period (4 weeks): KDF1901-R0, a fixed-dose combination tablet containing valsartan 80 mg and amlodipine 5 mg, administered once daily
Treatment Period 1 (2 weeks): KDF1901-R0, same as above, administered once daily
Treatment Period 2 (6 weeks): KDF1901-R1, containing valsartan 160 mg and amlodipine 10 mg, administered once daily
干预措施: KDF1901-R0 (Drug)
Dual Therapy group
Run-in Period (4 weeks): KDF1901-R0, a fixed-dose combination tablet containing valsartan 80 mg and amlodipine 5 mg, administered once daily
Treatment Period 1 (2 weeks): KDF1901-R0, same as above, administered once daily
Treatment Period 2 (6 weeks): KDF1901-R1, containing valsartan 160 mg and amlodipine 10 mg, administered once daily
干预措施: KDF1901-R1 (Drug)
结局指标
主要结局
Change in Mean Sitting Systolic Blood Pressure (MSSBP) from baseline to Week 8
时间窗: Baseline to Week 8
Mean change in sitting systolic blood pressure (MSSBP) after 8 weeks of treatment, measured at trough using a validated automated device.
次要结局
- Change in Mean Sitting Systolic Blood Pressure (MSSBP) from baseline to Week 8(Baseline to Week 2 and Week 4)
- Change in Mean Sitting Diastolic Blood Pressure (MSDBP) from baseline to Week 2, Week 4, and Week 8(Baseline to Week 2, Week 4, and Week 8)
- Response rate at Weeks 2, 4, and 8(Week 2, Week 4, and Week)
- Proportion of subjects achieving target blood pressure at Weeks 2, 4, and 8(Week 2, Week 4, and Week 8)