Efficacy and Safety of KBP-5074 in Uncontrolled Hypertension and Moderate or Severe CKD

Study Overview
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Brief Summary
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This Phase 3, randomized, Double-blind, placebo-controlled, 2-arm, parallel-group, multicenter study with randomized withdrawal will evaluate the efficacy, safety, and durability of KBP-5074 in adult participants who have stage 3b/4 chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula [eGFR {EPI}] ≥15 to ≤44 mL/min/1.73 m^2) and uncontrolled hypertension (systolic blood pressure (SBP) ≥140 and <180 mm Hg and taking 2 or more antihypertensive medications.

Detailed Description
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Participants in this study will be recruited, screened, and enrolled at approximately 140 study sites globally. The study will consist of the following periods: Pretreatment Phase: This will include prescreening assessment and screening period of up to 4 weeks and 2-week Open-label placebo Run-In period. A 24-week Double-blind Treatment Period (Randomization to Week 24) will include: An initial 12-week (Randomization to Week 12) and second 12-week (Week 12 to Week 24) treatment period and a second 12-week treatment period (Week 12 to Week 24), during both the periods study drug will be titrated. A 24-week Open-label Treatment Period (Week 24 to Week 48) during which eligible participants will receive Open-label KBP-5074. A 4-week Randomized Double-blind Withdrawal Period (Week 48 to Week 52) during which eligible participants will be randomized to continue their current KBP-5074 dose at the end of Open-label treatment or receive matching placebo for 4 weeks. A 4-week post-treatment Follow-Up Period (Week 52 to Week 56). During, 24-week Double-blind Treatment Period, 24-week Open-label Treatment Period, and at 4-week Randomized Double-blind Withdrawal Period, the background antihypertensive medications change may or may not be allowed. At Double-blind Treatment Period, eligible participants will be randomly assigned in a 1:1 ratio to KBP-5074 0.25 mg or matching placebo once daily (QD). At the Randomized Double-blind Withdrawal Period, participants who meet the randomized withdrawal criteria will be randomly assigned in a 1:1 ratio to continue their current KBP-5074 dose at the end of the Open-label Treatment Period or matching placebo QD.

Official Title
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A Phase 3 Randomized Double-Blind Placebo-Controlled Multicenter Study to Assess the Efficacy and Safety of KBP-5074 Mineralocorticoid Receptor Antagonist in Subjects With Uncontrolled Hypertension and Moderate or Severe (Stage 3b/4) CKD

Conditions
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Chronic Kidney Diseases

Intervention / Treatment
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* Drug: Placebo
* Drug: KBP-5074


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) must be ≥19 to <45 kg/m^2 at the Screening Visit Participant must have uncontrolled hypertension defined as meeting both of the following criteria: The participant has a resting seated trough cuff SBP ≥140 mm Hg at the Screening Visit (Visit 1), and at the start (Visit 2) and end (Visit 3) of the Run-In Period The participant is taking 2 or more antihypertensive medications that have been titrated upward as tolerated to hypertension target doses per local SoC and have been stable (i.e., without any dose adjustments) from 4 weeks before the Screening Visit (Visit 1) through the end of the Run-In Period (Visit 3) The participant must have Stage 3b (eGFR [EPI] ≥30 and ≤44 mL/min/1.73 m^2) or Stage 4 (eGFR [EPI] ≥15 and <30 mL/min/1.73 m^2) CKD. Exclusion Criteria: Participant has a resting seated trough cuff SBP ≥180 mm Hg at the Screening Visit (Visit 1) or at the start (Visit 2) or end (Visit 3) of the Run-In Period Participant has a serum potassium level >4.8 mmol/L during the Screening or Run-In Periods Participant has had a serum potassium level >5.6 mmol/L within 2 weeks before the Screening Visit (Visit 1) Participant has been hospitalized for hyperkalemia within the 3 months before the Randomization Visit (Visit 3) Participant was not compliant with taking placebo during the Run-in Period or participant was not compliant with background antihypertensive medications during the Run-in Period as assessed at the Randomization Visit (Visit 3) Participant has taken an mineralocorticoid receptor antagonist (MRA), a potassium-sparing diuretic, or chronic potassium supplements during the 4 weeks before the Screening Visit (Visit 1) Participant has taken potassium binders for the treatment of hyperkalemia during the 3 months before the Screening Visit (Visit 1) Participant has taken a strong cytochrome P450 (CYP) CYP3A4 inducer or strong CYP3A4 inhibitor during the 7 days before the Randomization Visit (Visit 3) Participant has taken a prohibited traditional Chinese medication during the 28 days prior to Screening Visit (Visit 1). Participant was administered any other investigational product within 4 weeks or 5 half-lives (whichever is longer) prior to the Screening Visit (Visit 1).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>All eligible participants will receive KBP-5074 matching placebo, for approximately 2 weeks, during the Open-label placebo Run-In period, then up to 24 weeks during the Double-blind treatment Period and during the Open-label treatment period, and thereafter for 4 weeks, during the randomized Double-blind withdrawal period. | Drug: Placebo<br>* Participants will orally receive placebo matching to KBP-5074 tablets QD.<br>|
| Experimental: KBP-5074<br>All eligible participants will receive KBP-5074, for up to 24 weeks during the Double-blind treatment Period and during the Open-label treatment period. Thereafter, eligible participants will continue current dose of KBP-5074 at the end of the Open-label treatment period. | Drug: KBP-5074<br>* Participants will orally receive KBP-5074 tablets, from 0.25 mg to a maximum dose of 0.5-mg QD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in seated trough cuff SBP from baseline to Week 12 | Efficacy of KBP-5074 in reducing SBP by assessing change in seated trough cuff SBP for KBP-5074 dose regimen compared to placebo, will be evaluated. | From baseline to Week 12 | 
| Change in seated trough cuff SBP from Week 48 to Week 52 | Durability of KBP-5074 in reducing SBP by assessing change in seated trough cuff SBP for the KBP-5074 dose regimen compared to placebo, will be evaluated. | Week 48 to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in seated trough cuff SBP from baseline to Week 24 | Efficacy and durability of KBP-5074 in reducing SBP by assessing change in seated trough cuff SBP, will be evaluated. | From baseline to Week 24 | 
| Changes in seated trough cuff diastolic blood pressure (DBP) from baseline to Week 12 and Week 24 | Effect of KBP-5074 on DBP by assessing change in seated trough cuff DBP, will be evaluated. | From baseline to Week 12 and Week 24 | 
| Changes in seated trough cuff SBP and DBP from baseline to Week 48 | Effect of KBP-5074 on SBP and DBP by assessing change in seated trough cuff SBP and DBP, will be evaluated. | From baseline to Week 48 | 
| Changes in urinary albumin: creatinine ratio (UACR) from baseline to Week 12 and Week 24 for participants with UACR ≥30 mg/g at baseline | Effect of KBP-5074 on UACR by assessing changes in UACR for participants with UACR ≥30 mg/g at baseline, will be evaluated. | From baseline to Week 12 and Week 24 | 
| Percentage changes in UACR from baseline to Week 12 and Week 24 for participants with UACR ≥30 mg/g at baseline | Effect of KBP-5074 on UACR by assessing percentage changes in UACR for participants with UACR ≥30 mg/g at baseline, will be evaluated. | From baseline to Week 12 and Week 24 | 
| Changes in UACR from baseline to Week 12, Week 24, and Week 48 | Effect of KBP-5074 on UACR by assessing changes in UACR for participants with macroalbuminuria (defined as UACR ≥300 mg/g) and microalbuminuria (defined as UACR ≥30 and <300 mg/g) at baseline, will be evaluated. | From baseline to Week 12, Week 24, and Week 48 | 
| Percentage changes in UACR from baseline to Week 12, Week 24, and Week 48 | Effect of KBP-5074 on UACR by assessing percentage changes in UACR for participants with macroalbuminuria (defined as UACR ≥300 mg/g) and microalbuminuria (defined as UACR ≥30 and <300 mg/g) at baseline, will be evaluated. | From baseline to Week 12, Week 24, and Week 48 | 
| Change in seated trough cuff DBP from Week 48 to Week 52 | Effect of KBP-5074 on DBP by assessing change in seated trough cuff DBP, will be evaluated. | Week 48 to Week 52 | 
| Change in UACR from Week 48 to Week 52 | Effect of KBP-5074 on UACR by assessing changes in UACR for participants with UACR ≥30 mg/g, macroalbuminuria (defined as UACR ≥300 mg/g) and microalbuminuria (defined as UACR ≥30 and <300 mg/g) at baseline, will be evaluated. | Week 48 to Week 52 | 
| Percentage change in UACR from Week 48 to Week 52 | Effect of KBP-5074 on UACR by assessing percentage changes in UACR for participants with UACR ≥30 mg/g, macroalbuminuria (defined as UACR ≥300 mg/g) and microalbuminuria (defined as UACR ≥30 and <300 mg/g) at baseline, will be evaluated. | Week 48 to Week 52 | 
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) | The safety and tolerability of KBP-5074,will be evaluated. | Screening (Week -6 to -2) until EOS (Week 56) or Unscheduled visit or end of treatment or early termination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage 3b/4 chronic kidney disease, Hypertension, Uncontrolled Hypertension, Blood pressure, Mineralocorticoid Receptor Antagonist, Randomized withdrawal