E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hyperkalemia in Patients with Hypertension and Diabetic Nephropathy |
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E.1.1.1 | Medical condition in easily understood language |
Patients with high blood pressure and kidney disease due to diabetes |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020772 |
E.1.2 | Term | Hypertension |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020647 |
E.1.2 | Term | Hyperkalemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061835 |
E.1.2 | Term | Diabetic nephropathy |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 |
The primary objective of this study is to determine the optimal starting dose of RLY5016 in treating hyperkalemia in patients with hypertension and diabetic nephropathy receiving ACEI and/or ARB drugs, with or without spironolactone |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are: •To determine the efficacy of RLY5016 in treating hyperkalemia in patients with hypertension and diabetic nephropathy receiving ACEI and/or ARB drugs, with or without spironolactone •To determine the safety of RLY5016 in treating hyperkalemia in patients with hypertension and diabetic nephropathy receiving ACEI and/or ARB drugs, with or without spironolactone •To evaluate the chronic use of RLY5016 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet ALL of the following inclusion criteria:
1. Age 30 – 80 years old at screening
2. Type 2 diabetes mellitus (T2DM) diagnosed after age 30 which has been treated with oral medications or insulin for at least one year prior to screening
3. Chronic kidney disease: estimated GFR 15 – < 60 mL/min/1.73m2 at screening based on central laboratory serum creatinine measurement (except for patients with hyperkalemia at S1, whose eligibility will be assessed based on local lab eGFR value)
4.Urine ACR: a)Cohorts 1 and 2: urine ACR ≥ 30 mg/g at screening (S1) AND average urine ACR ≥ 30 mg/g at the beginning of Run-In Period (R0) based on up to 3 ACR values obtained starting at S1 and ending at the R0 Visit b)Cohort 3: not applicable
5.Local laboratory serum K+ values of: a) Cohorts 1 and 2: 4.3 – 5.0 mEq/L at S1; AND 4.5 – 5.0 mEq/L at R0; AND > 5.0 – < 6.0 mEq/L at randomization to RLY5016 (Baseline, T0 Visit) b) Cohort 3: > 5.0 – < 6.0 mEq/L at S1 OR at R0 after same day confirmation
6. Must be receiving an ACEI and/or ARB for at least 28 days prior to screening
7. Average SBP ≥ 140 – < 180 mmHg OR average DBP ≥ 90 – < 110 mmHg (sitting) at screening
8. Females of child-bearing potential must be non-lactating, must have a negative serum pregnancy test at screening, and must have used a highly effective form of contraception for at least 3 months before RLY5016 administration, during the study, and for one month after study completion
9. Provide their written informed consent prior to participation in the study |
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E.4 | Principal exclusion criteria |
Patients must NOT meet ANY of the following exclusion criteria:
1. Type 1 diabetes mellitus
2. Central lab hemoglobin A1c > 12% at S1 (except for Cohort 3 patients who are hyperkalemic at S1)
3. Emergency treatment for T2DM within the last 3 months
4. Diabetic gastroparesis
5. Non-diabetic chronic kidney disease
6. History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery (e.g., cholectomy)
7. Current diagnosis of NYHA Class III or IV heart failure
8. Body mass index (BMI) ≥ 40 kg/m2
9. Any of the following events having occurred within 2 months prior to screening: unstable angina as judged by the Investigator, unresolved acute coronary syndrome, cardiac arrest or clinically significant ventricular arrhythmias, transient ischemic attack or stroke, use of any intravenous cardiac medication 9. 10. Prior kidney transplant, or anticipated need for transplant during study participation
11. Active cancer, currently on cancer treatment or history of cancer in the past two years except for non-melanocytic skin cancer which is considered cured
12. History of alcoholism or drug/chemical abuse within 1 year
13. Central lab liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] > 3 times upper limit of normal (except for Cohort 3 patients with hyperkalemia at S1, who will have local lab ALT and AST)
14. Loop and thiazide diuretics or other antihypertensive medications (calcium channel blocker, beta-blocker, alpha-blocker, or centrally acting agent) that have not been stable for at least 28 days prior to screening or not anticipated to remain stable during study participation
15. Current use of polymer-based drugs (e.g., sevelamer, sodium polystyrene sulfonate, colesevelam, colestipol, cholestyramine), phosphate binders (e.g., lanthanum carbonate), or other potassium binders, or their anticipated need during study participation
16. Current use of lithium
17. Use of potassium sparing medications, including aldosterone antagonists (e.g., spironolactone), drospirenone, potassium supplements, bicarbonate or baking soda in the last 7 days prior to screening 18. Use of any investigational product within 30 days or 5 half-lives, whichever is longer, prior to screening
19. Inability to consume the investigational product, or, in the opinion of the Investigator, inability to comply with the protocol
20. In the opinion of the Investigator, any medical condition, uncontrolled systemic disease, or serious intercurrent illness that would significantly decrease study compliance or jeopardize the safety of the patient or affect the validity of the trial results |
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E.5 End points |
E.5.1 | Primary end point(s) |
•Mean change in serum potassium from baseline (T0) to week 4 or prior to the initiation of RLY5016 dose titration (if occurs before week 4) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 4 or earlier if RLY5016 dose titration is initiated before Week 4 |
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E.5.2 | Secondary end point(s) |
•Mean change in serum potassium from baseline (T0) to week 8 or prior to the initiation of RLY5016 dose titration
•Proportion of patients maintaining the starting RLY5016 dose at weeks 4 and 8
•Mean change in serum potassium from baseline (T0) to post-baseline visits
•Mean change in serum potassium from end of RLY5016 treatment to follow-up visits
•Proportion of patients requiring RLY5016 titration
•Proportion of patients achieving a stable RLY5016 dose (defined as same RLY5016 dose for 3 consecutive visits) by end of week 8
•Mean time to first serum K+ in the range of 4.0 – 5.0 mEq/L
•Mean time to first RLY5016 titration
•Mean number of RLY5016 titrations
•Proportion of patients who maintain serum potassium in the range of
3.5 – 5.5 mEq/L by visit and during the entire Treatment Initiation Period
•Proportion of patients who maintain serum K+ in the range of
4.0 – 5.0 mEq/L by visit and during the entire Treatment Initiation Period
•Proportion of patients who discontinue from the study due to high serum potassium withdrawal criteria
•Mean change in blood pressure from Run-In Visit (R0) to weeks 4 and 8
•Mean change in urine albumin to creatinine ratio (ACR) from R0 to weeks 4 and 8
•Proportion of patients with ≥ 35% reduction in urine ACR from R0 to weeks 4 and 8
•Proportion of patients with urine ACR ≥ 500 mg/g at R0 who achieve ACR < 500 mg/g at weeks 4 and 8
•Proportion of patients with urine ACR ≥ 300 mg/g at R0 who achieve ACR < 300 mg/g at weeks 4 and 8
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 8 or earlier if RLY5016 titration is initiated before Week 8
2. Weeks 4 and 8
3. Weeks 1-8 and 7 days following final treatment visit
4. Through Week 8
5. Through Week 8
6. Week 8
7. Weeks 1-8
8. Weeks 1-8
9. Through Week 8
10. Weeks 4 and 8
11. Weeks 4 and 8
12. Weeks 4 and 8
13. Weeks 4 and 8 |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
All Patients randomised to starting dose of RLY5016 |
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 |
European Union |
Croatia |
Serbia |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 12 |
E.8.9.2 | In all countries concerned by the trial days | 0 |