A Multicenter, Randomized, Double-Blind Phase 3 Trial of KDF1901 in Patients With Essential Hypertension

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.

Inclusion criteria

• 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.

Exclusion criteria

• 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