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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.
Full description
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.
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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):
If currently receiving antihypertensive medication:
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.
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:
Severe pulmonary, cardiac, or vascular conditions, such as:
History of serious cardiovascular events or interventions within 24 weeks prior to screening:
History of cerebrovascular disorders within 24 weeks prior to screening:
History of ocular conditions within 24 weeks prior to screening:
History of malignancy within 5 years prior to screening, except:
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
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286 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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