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

NCT ID: NCT07116863

Last Updated: 2025-08-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 286 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-21
• Study Completion Date: 2024-09-13

Brief Summary

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.

Detailed 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.

Conditions

Essential Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

KDF1901-R0

Intervention Type: DRUG

Fixed-dose combination tablet containing valsartan 80 mg and amlodipine 5 mg. Orally administered once daily for 4 weeks during the run-in period, and for 2 weeks during Treatment Period 1(Dual Therapy group).

KDF1901-L

Intervention Type: DRUG

Fixed-dose combination tablet containing valsartan 80 mg, amlodipine 5 mg, and chlorthalidone 12.5 mg.

Orally administered once daily for 2 weeks during Treatment Period 1.

KDF1901

Intervention Type: DRUG

Fixed-dose combination tablet containing valsartan 160 mg, amlodipine 10 mg, and chlorthalidone 25 mg.

Orally administered once daily for 6 weeks during Treatment Period 2.

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

Group Type: ACTIVE_COMPARATOR

KDF1901-R0

Intervention Type: DRUG

Fixed-dose combination tablet containing valsartan 80 mg and amlodipine 5 mg. Orally administered once daily for 4 weeks during the run-in period, and for 2 weeks during Treatment Period 1(Dual Therapy group).

KDF1901-R1

Intervention Type: DRUG

Fixed-dose combination tablet containing valsartan 160 mg and amlodipine 10 mg. Orally administered once daily for 6 weeks during Treatment Period 2.

Interventions

KDF1901-R0

Fixed-dose combination tablet containing valsartan 80 mg and amlodipine 5 mg. Orally administered once daily for 4 weeks during the run-in period, and for 2 weeks during Treatment Period 1(Dual Therapy group).

Intervention Type: DRUG

KDF1901-L

Fixed-dose combination tablet containing valsartan 80 mg, amlodipine 5 mg, and chlorthalidone 12.5 mg.

Orally administered once daily for 2 weeks during Treatment Period 1.

Intervention Type: DRUG

KDF1901

Fixed-dose combination tablet containing valsartan 160 mg, amlodipine 10 mg, and chlorthalidone 25 mg.

Orally administered once daily for 6 weeks during Treatment Period 2.

Intervention Type: DRUG

KDF1901-R1

Fixed-dose combination tablet containing valsartan 160 mg and amlodipine 10 mg. Orally administered once daily for 6 weeks during Treatment Period 2.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Male or female participants aged ≥19 years at the time of screening.

2. Participants who meet one of the following blood pressure criteria at screening:

1. If not currently receiving antihypertensive medication for at least 4 weeks (treatment-naïve):

• Mean Sitting Systolic Blood Pressure (MSSBP) ≥160 mmHg and <200 mmHg

2. 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

3. Willing and able to provide written informed consent prior to participation in the study.

4. 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

5. At least 70% compliance with run-in period medication, as assessed by tablet count.

Exclusion Criteria

1. Mean sitting diastolic blood pressure (MSDBP) ≥110 mmHg at screening (Visit 1) or baseline (Visit 3)

2. Difference in blood pressure between arms: MSSBP ≥20 mmHg and MSDBP ≥10 mmHg at screening

3. History or presence of secondary hypertension or suspected secondary hypertension, including:

• Aortic coarctation, pheochromocytoma, Cushing's syndrome, hyperaldosteronism, polycystic kidney disease

4. Severe pulmonary, cardiac, or vascular conditions, such as:

• Pulmonary hypertension, severe heart failure (NYHA class III or IV), hypertrophic cardiomyopathy, aortic aneurysm, thrombocytopathy

5. History of serious cardiovascular events or interventions within 24 weeks prior to screening:

• Myocardial infarction, unstable angina, coronary revascularization (PCI/CABG)

6. History of cerebrovascular disorders within 24 weeks prior to screening:

• Stroke, TIA, cerebral hemorrhage

7. History of ocular conditions within 24 weeks prior to screening:

• Retinal hemorrhage, optic neuropathy, severe visual impairment

8. 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

9. Hereditary blood disorders or history of angioedema related to ACE inhibitors or ARBs

10. History of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

11. Diagnosis of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) within 48 weeks prior to screening

12. Clinically significant conditions affecting drug absorption, distribution, metabolism, or excretion

13. Symptoms of orthostatic hypotension or risk of falls or syncope

14. Severe anemia, leukopenia, or thrombocytopenia at screening

15. Heart failure NYHA class III or IV

16. Known serious arrhythmias, including ventricular tachycardia or fibrillation

17. Known autoimmune disease or connective tissue disorder

18. Clinically significant renal, hepatic, or cardiovascular disease

19. eGFR <30 mL/min/1.73 m² or serum creatinine ≥2.0 mg/dL

20. ALT or AST >3× upper limit of normal (ULN)

21. Serum K+ <3.5 or >5.5 mmol/L, Na+ <135 mmol/L, Ca2+ >10.5 or <2.63 mmol/L

22. Requiring long-term immunosuppressive therapy or systemic corticosteroids

23. Clinically significant chronic inflammatory conditions

24. History of major surgery or active GI disorders

25. Type 2 diabetes mellitus with HbA1c ≥9.0%

26. Known edematous disorders (e.g., untreated nephrotic syndrome)

27. Requirement for prohibited medications (emergency drugs) during study period (Visit 1-6)

28. Use of lithium therapy

29. Use of terfenadine or astemizole

30. Hypersensitivity to study drugs, dihydropyridine-class CCBs, thiazide diuretics, or sulfonamides

31. History or suspicion of drug or alcohol abuse

32. Pregnancy or lactation

33. Women of childbearing potential or male participants not agreeing to use reliable contraception during study

34. Participation in other clinical trials or use of investigational products within 4 weeks prior to screening

35. Judged by the investigator to be otherwise unsuitable for study participation

• Minimum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kyungdong Pharmaceutical Co., Ltd.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

CHA Gangnam Medical Center, CHA University

Seoul, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Countries

South Korea

Other Identifiers

KDF1901-3H

Identifier Type: -

Identifier Source: org_study_id