| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Chronic Kidney Disease and uncontrolled hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Kidney Disease and uncontrolled high blood pressure |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066860 |
| E.1.2 | Term | Uncontrolled hypertension |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of KBP-5074 in patients with moderate-to-severe Chronic kidney disease (CKD) on uncontrolled hypertension (eg, Grade 1 to 2 systolic hypertension – ESC/ESH) as determined by change in trough cuff seated systolic blood pressure (SBP) from baseline to Day 84. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the change in trough cuff seated diastolic blood pressure from baseline to Day 84;
To evaluate the change in 24-hour mean, daytime mean, nighttime mean, morning mean, last 6 hours of the dosing interval mean, SBP, DBP, mean arterial pressure and heart rate from baseline to Day 84 in a subset of patients as measured by 24-hour ambulatory blood pressure monitoring;
To evaluate the change and percent change in urine albumin-to-creatinine ratio from baseline to Day 84 or microalbuminuria;
To evaluate the change in serum aldosterone and plasma renin levels from baseline to Day 84;
To evaluate the incidence of hyperkalemia, incidence of severe hyperkalemia and incidence of patients with serum potassium > 5.0 mmol/L;
To evaluate the change in serum potassium levels from baseline to Day 84;
To evaluate the changes in estimated glomerular filtration rate and creatinine levels > 30% throughout the study period;
To evaluate population pharmacokinetics of KBP-5074. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female, between 18 and 85 years of age, inclusive. The lower age limit may be higher if it is legally required in the participating country;
2.Body mass index between 19 and 45 kg/m2, inclusive;
3.Stage 3B/4 CKD (defined as eGFR ≥ 15 and ≤ 44 mL/min/1.73 m2, based on the isotope dilution mass spectrometry traceable MDRD equation version 4, according to central laboratory results at Screening;
4. Uncontrolled hypertension (Grade 1 to 2 systolic hypertension – ESC/ESH), defined as:
- Resting trough cuff seated SBP ≥ 140 and ≤ 179 mmHg based on the mean of at least 2 current consecutive clinic blood pressure readings at Screening and at the end of the placebo run-in period (Visit 3); AND
- Currently on 2 or more antihypertensive medications, which have been titrated upward as tolerated to recommended hypertension target doses (such as diuretics [except for potassium-sparing diuretics], renin angiotensin system blockers, and/or calcium channel blockers. One of the antihypertensive medications must be high ceiling diuretic (loop or thiazide like), unless there is a documented intolerance or contraindication to diuretic therapy. The doses of the antihypertensive medications should be stable without any dose adjustment during the 30 days prior to randomization; OR
- Patients with uncontrolled hypertension and moderate-to-severe CKD with documented history of intolerance to multiple antihypertensive medications on fewer than 2 antihypertensive medications;
5. Serum potassium ≤ 4.8 mmol/L at both Screening and the end of the placebo run-in period. A single retest is allowed to exclude laboratory error or hemolyzed samples;
6.Women of childbearing potential (WOCBP) must agree to use 2 medically accepted, effective methods of birth control during the study and for 90 days after the end of the study. Adequate methods of contraception are defined as those that result in a low failure rate (< 1% per year) when used consistently and correctly.
- WOCBP are defined as women who are not surgically or chemically sterilized, including hysterectomy or bilateral oophorectomy (tubal ligation is not acceptable), and who are between menarche and 1-year post-menopause; and
- Post-menopausal is defined as amenorrheic for at least 1 year, AND if aged under 60 years, have a serum follicle-stimulating hormone (FSH) level > 20 mIU/L. Women who are taking hormone replacement therapy (HRT) do not have to have FSH assessments, but the amenorrhea (before starting HRT) must have been naturally (spontaneously) occurring and have been accompanied by an appropriate clinical profile (eg, age appropriate and history of vasomotor symptoms);
7.Males with partners who are WOCBP must agree to use condoms plus spermicide and their female partner must also be using contraception (eg, hormonal or intra-uterine device). This double contraception must be used from the first dose of study drug until at least 90 days after the last dose of study drug;
8. Males must also refrain from donating sperm during the study and for 90 days after the last dose;
9.Capable of understanding the written informed consent, provide signed and witnessed written informed consent before any study-specific procedure, and agree to comply with protocol requirements. |
|
| E.4 | Principal exclusion criteria |
1. Resting trough cuff seated SBP ≥ 180 or < 140 mmHg, based on the mean of at least 2 current consecutive clinic blood pressure readings at Screening and the end of the placebo run-in period;
2. Serum potassium > 4.8 mmol/L;
3. Compliance with medications < 80% or > 120% during the run-in period;
4. Currently on an MRA other than KBP-5074 or received any MRAs during the last 3 months prior to Screening or currently on any potassium supplements;
5. Chronic or intermittent use of a potassium binder for the treatment of hyperkalemia from 3 months prior to Screening until the end of study assessments;
6. Have routinely or chronically used or required potassium-sparing diuretics within 3 months prior to Screening until the end of study assessments;
7. History of known/suspected contraindications, allergy, or intolerance to MRAs or has a known hypersensitivity to KBP-5074, other MRAs or related compounds;
8. Clinically significant hyperkalemia while on an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, direct renin inhibitor and/or MRA, requiring down titration or discontinuation of above medication, or hospitalization for hyperkalemia within 3 months prior to Screening, or hyperkalemia > 5.6 mmol/L during the 2 weeks prior to Screening;
9. History/diagnosis of renal artery stenosis or history/diagnosis of renovascular hypertension;
10. Currently receiving HD, or peritoneal dialysis within 3 months prior to Screening, and those patients with an episode of acute kidney injury within 3 months of Screening;
11. History of a renal transplant, or impending renal transplant;
12. Acute decompensated heart failure including exacerbation of chronic heart failure manifested by signs and symptoms that may require hospitalization and/or intravenous diuretic therapy within 3 months prior to Screening, or presence of hemodynamically significant valve diseases and/or other hemodynamically significant obstructive lesions of left ventricular outflow tract;
13. Major cardiac, cerebral, and/or carotid artery diseases within 6 months prior to Screening; OR Cardiovascular conditions likely to require surgical or percutaneous intervention within 6 months from Screening;
14. History of clinically significant arrhythmia, including but not limited to any of the following:
-Symptomatic bradycardia and/or symptomatic ventricular arrhythmia within 3 months prior to Screening
- Second- or third-degree heart block or New onset or untreated atrial fibrillation
15. QT interval corrected using Fridericia’s formula (QTcF) > 450 ms for males or > 470 ms for females at Screening or Day 1; QTcF should be the average of the required triplicate set of ECGs at each timepoint
16. History of prolonged QT interval;
17. History or family history of sudden cardiac death or long QT syndrome;
18. History of cardiac transplant, on a heart transplant list, or has a left ventricular assistance device;
19. History of clinically significant acute or chronic hepatitis, hepatocirrhosis, or hepatic tumors;
20. History of gastrointestinal surgery that might affect absorption/oral bioavailability of oral antihypertensive therapies including KBP-5074;
21. Clinically significant abnormal liver function test at Screening or the end of the run-in period;
22. Positive blood screen for HIV, hepatitis B surface antigen, or hepatitis C virus antibody;
23. History of malignancy in the past 5 years, with the exception of basal or resected cutaneous squamous cell carcinoma of the skin or carcinoma in situ, prostate cancer in situ with a normal prostate-specific antigen post treatment, cervical carcinoma in situ, gastric cancer in situ, colon cancer in situ adequately treated with no progression over the past 2 years;
24. History of prescription drug abuse, illicit drug use, or alcohol abuse according to medical history within 6 months prior to Screening;
25. A positive drug screen test at Screening or the end of the run-in period;
26. Female patients who are known to be pregnant or breastfeeding;
27. Previously enrolled in any KBP-5074 study;
28. Receipt of any other investigational product within 30 days or 5 half-lives prior to Screening;
29. Use of any nutrients known to modulate cytochrome P450 (CYP)3A activity or any strong or moderate inhibitors or inducers of CYP3A4, starting from 14 days prior to the first dose of study drug at Day 1 until the end of study assessments;
30. Has donated or lost a significant volume (> 500 mL) of blood or plasma within 30 days prior to Screening
31. An employee or family member of the Investigator or study site personnel;
32. Unlikely to comply with the protocol requirements, instructions, and/or study-related restrictions ;
33. History of any other prior or concomitant clinical condition or acute and/or unstable systemic disease not listed above that, in the opinion of the Investigator, compromises patient inclusion. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable is the change in trough-cuff resting seated SBP from baseline to Day 84.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy variables include the following:
• Change in trough-cuff seated DBP from baseline to Day 84;
• Change in 24-hour mean, daytime mean, nighttime mean, morning mean, last 6 hours of the dosing interval mean, SBP, DBP, MAP, and HR from baseline to Day 84 as measured by 24-hour ABPM in a subset of up to 40 patients per treatment group; and
• Change and percent change in UACR from baseline to Day 84 (for patients with albuminuria [defined as UACR > 300 mg/g] or microalbuminuria [defined as UACR in the range of 30 mg/g to 300 mg/g]). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Chile |
| Georgia |
| Hungary |
| Israel |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
Print
