A Prospective, double-blind, randomized, single centre trial to evaluate the rate of RAAS inhibitor withdrawal or down-titration in non-dialysis patients with CKD stage IIIB to Vrandomized to Patiromer or placebo

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Mario Negri Institute For Pharmacological Research IRCCS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

2 Aug 2023 → 16 Oct 2024

Decision date (initial)

2023-06-27

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Vifor Pharma Italia srl

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To compare the effects of patiromer and placebo on the rate of withdrawal or down-titration of RAAS inhibition therapy because of refractory hyperkalemia (serum K+ levels ≥ 5.5 mEq/L at two consecutive visits one-week apart) in non-dialysis patients with CKD stage IIIB to V receiving best available conservative therapy, including RAAS inhibition with ACE inhibitors and/or ARBs and/or aldosterone antagonists

Secondary objectives 4

1. To compare metabolic laboratory parameters between the two treatment groups
2. To compare renal function parameters between the two treatment groups
3. To compare clinical parameters between the two treatment groups
4. To assess the safety between the two study groups

Conditions and MedDRA coding

Hyyperkalemia in CKD stage IIIB to V patients

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Provision of informed consent prior to any study specific procedures
2. Age >18 years
3. GFR <45 ml/min/1.73m2, as per CKD-EPI equation (CKD Stage 3b to 5) not requiring dialysis therapy
4. Serum potassium >5.0 mEq/L (in at least two consecutive evaluations, one week apart) despite dietary counseling, optimized metabolic acidosis control, diuretic therapy as needed for blood pressure control and fluid balance, and effective blood glucose control in diabetics
5. Serum magnesium levels in normal range
6. Concomitant therapy with RAAS inhibitors (ACE inhibitors, ARBs and aldosterone antagonists, such as spironolactone and finerenone)

Exclusion criteria 21

1. Serum potassium >6.0 mEq/L and/or any clinical signs or symptoms of hyperkalemia (in at least two consecutive evaluations, one week apart) despite dietary counseling, optimized metabolic acidosis control, diuretic therapy as needed for blood pressure control and fluid balance, and effective blood glucose control in diabetics
2. Ongoing treatment with SPS before randomization* *Patient eligibility could be reassessed during the screening period after at least one week from SPS therapy withdrawal
3. Uncontrolled metabolic acidosis* or respiratory acidosis *Patient eligibility could be reassessed during the screening period after appropriate correction of metabolic acidosis by sodium bicarbonate supplementation and other other interventions as deemed clinically appropriate as per clinical practice
4. History of bowel obstruction or major gastrointestinal surgery, severe gastrointestinal disorders, or swallowing disorders
5. Marginal kidney function and/or marginal urine output or any other condition requiring urgent potassium lowering
6. Rapidly progressive kidney disease (eGFR reduction ≥ 30% over the last three months as per CKD-EPI equation) and expected risk of progression to ESKD and need of renal replacement therapy by dialysis or transplantation within six months
7. Active systemic autoimmune diseases
8. Concomitant treatment with steroids or any other immunosuppressive agent
9. Hypersensitivity to the active ingredient or any of the excipients. Patients with Hereditary Fructose Intolerance
10. Patients with or at risk of hypercalcaemia and/or hypomagnesaemia
11. Severe/unstable heart failure with or without decreased systolic function requiring hospitalization or changes in pharmacological therapy over the last three months
12. Refractory severe hypertension (BP >180/100 mmHg despite optimized pharmacological treatment with at least three blood pressure-lowering medications and a diuretic)
13. Positive hepatitis C antibodies, hepatitis B virus surface antigens at screening
14. Known to have tested positive for human immunodeficiency virus
15. Drug or alcohol abuse
16. Female subjects who are pregnant, lactating or who intend to become pregnant before or during the study period, or within 90 days of the last dose of study treatment. Female subjects who intend to donate ova over the same time period
17. Male subjects who intend to donate sperm during the study period or for the 90 days following the last dose of study treatment
18. Male and female subjects in childbearing age not using a highly effective contraception method according to the 2020 CTFG Recommendations related to contraception and pregnancy testing in clinical trials
19. Inability to fully understand the potential risks and benefits related to study participation
20. Involvement in the study planning and/or conduct
21. Participation in another clinical study with an investigational product during the last month

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Number of patients who withdraw or reduce RAAS inhibition therapy because of refractory hyperkalemia (serum K+ levels ≥ 5.5 mEq/L at two consecutive visits one-week apart) during the follow-up period

Secondary endpoints 17

1. To compare between the two treatment groups serum potassium normalization (serum K+<5.0 mEq/L considered as a dichotomous endpoint) for at least two consecutive visits one week apart
2. To compare between the two treatment groups serum potassium levels considered as a continuous variable
3. To compare between the two treatment groups Markers of mineral metabolism (serum calcium, phosphate, magnesium, intact parathyroid hormone, 1,25-dihydroxyvitamin D serum levels, 24-hour urinary calcium, phosphate, magnesium excretion)
4. To compare between the two treatment groups plasma renin activity and serum aldosterone levels and 24-hour urinary aldosterone excretion
5. To compare between the two treatment groups pH and Base Excess
6. To compare between the two treatment groups GFR decline (iohexol plasma clearance technique)
7. To compare between the two treatment groups 24-hour albuminuria and proteinuria and 24-hour urinary albumin/creatinine (A/C) ratio and 24-hour urinary protein/creatinine (P/C) ratio
8. To compare between the two treatment groups urinary spot morning albumin/creatinine (A/C) ratio and protein/creatinine (P/C) ratio
9. To compare between the two treatment groups albumin, total protein, calcium, phosphate, magnesium, sodium and potassium fractional clearances
10. To compare between the two treatment groups need of renal replacement therapy because of ESRD
11. To compare between the two treatment groups need of SPS therapy
12. To compare between the two treatment groups fatal and non-fatal cardiovascular events
13. To compare between the two treatment groups treatment costs for the study drugs, dialysis therapy and treatment-related complications
14. To compare between the two treatment groups quality of life as assessed using the Italian versions of validated questionnaires such as the SF-12 questionnaire
15. To assess the safety between the two study groups occurrence of hypokalemia (K+<3.5 mEq/L) and/or hypomagnesemia (<1.41 mg/dL)
16. To assess the safety between the two study groups study treatment withdrawal because of side effects or poor tolerability
17. To assess the safety between the two study groups serious and non-serious adverse events and treatment-related adverse events and any clinically relevant abnormality in routine laboratory tests

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Mario Negri Institute For Pharmacological Research IRCCS

Sponsor organisation

Mario Negri Institute For Pharmacological Research IRCCS

Address

Via Mario Negri 2

City

Milan

Postcode

20156

Country

Italy

Scientific contact point

Organisation

Mario Negri Institute For Pharmacological Research IRCCS

Contact name

Clinical trial regulatory office

Public contact point

Organisation

Mario Negri Institute For Pharmacological Research IRCCS

Contact name

Clinical trial regulatory office

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications