Albuminuria Lowering Effect of Dapagliflozin, Spironolactone and Their Combination in Adult Patients with Alport Syndrome (COMBINE-ALPORT)

NCT ID: NCT06499948

Last Updated: 2024-07-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-02-26
• Study Completion Date: 2026-03-31

Brief Summary

Alport syndrome (AS) is one of the most common monogenic kidney disorders, oftentimes leading to end-stage kidney disease (ESKD). As AS is caused by variants involving type IV collagen genes (COL4), there is no specific treatment aimed at stopping the disease progression. Large studies have validated the use of renin-angiotensin-system inhibitors (RASis) in AS, as these drugs can slow the progression to chronic kidney disease (CKD). These studies included mainly pediatric patients with X-linked AS (XLAS). There is a lack of data regarding the therapeutic approach in patients having autosomal dominant AS (ADAS).

Recent data from murine studies suggest that the combined therapy using a sodium-glucose-cotransporter 2 inhibitor (SGLT2i) and a mineralocorticoid receptor blocker (MRB) can reduce proteinuria in COL4A3 knock-out mice. The albuminuria lowering effect of this combination was demonstrated in other non-diabetic nephropathies. Used in monotherapy, both drugs have showed protective and antifibrotic effects in murine models of AS.

The COMBINE-ALPORT trial aims to evaluate the albuminuria lowering effect of Dapagliflozin, Spironolactone and their combination in adult patients with genetically proven AS when added to maximum tolerated RASi dose. As proteinuria is the primary driver of CKD progression, and the change in albuminuria is widely used as a surrogate endpoint for kidney disease progression, lowering albuminuria will delay the onset of ESKD in patients with AS.

The main hypothesis of COMBINE-ALPORT trial is that the association of Dapagliflozin and Spironolactone will significantly reduce albuminuria in adult patient with AS.

The patients will be randomized to receive either Spironolactone or Dapagliflozin on top of standard therapy (maximum RASi dose) in a cross-over trial design (4 weeks of treatment followed by 4 weeks of wash-out). Finally, the whole cohort will receive both Spironolactone and Dapagliflozin for another 4 weeks.

The patients will visit the clinic every 4 weeks for checkups and tests.

The primary outcome is the effect on albuminuria by each treatment regimen (Spironolactone, Dapagliflozin or their combination).

Conditions

Alport Syndrome; Thin Basement Membrane Disease; Alport Nephropathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Succession no.1: Spironolactone followed by Dapagliflozin followed by the combined therapy arm

The patients will be randomized to receive either Spironolactone or Dapagliflozin on top of standard therapy (stable doses of renin-angiotensin-system inhibitors) in a crossover trial design (4 weeks of treatment followed by 4 weeks of wash-out). Finally, the whole cohort will receive both Spironolactone and Dapagliflozin for another 4 weeks.

Treatment succession no.1 description: (1)1st treatment period - patients will receive Spironolactone 25 mg od on top of standard for 4 weeks; (2) 1st washout-period - treatment with Spironolactone will be stopped for 4 weeks; (3) 2nd treatment period - patients will receive Dapagliflozin 10 mg od for 4 weeks; (4) 2nd washout-period - treatment with Dapagliflozin will be stopped for 4 weeks; (5) 3rd treatment period - patients will receive Spironolactone 25 mg od plus Dapagliflozin 10 mg od for 4 weeks; (6) 3rd washout-period - treatment with Spironolactone and Dapagliflozin will be stopped for 4 weeks.

Group Type: EXPERIMENTAL

Treatment with Spironolactone followed by Dapagliflozin followed by their combination

Intervention Type: DRUG

After titrating the renin-angiotensin-system inhibitor dose, patients will receive 25 mg of Spironolactone once daily for 4 weeks. Spironolactone will be stopped after 4 weeks. The first treatment period will be followed by 4 weeks of wash-out. After the first wash-out period, treatment with Dapagliflozin will be started. Patients will receive 10 mg of Dapagliflozin once daily for 4 weeks. Dapagliflozin will be stopped after 4 weeks. The second treatment period will be followed by 4 weeks of wash-out. After the second wash-out period, treatment with both Spironolactone 25 mg and Dapagliflozin will be started. Patients will receive 25 mg of Spironolactone once daily in combination with 10 mg of Dapagliflozin daily for a duration of 4 weeks. Spironolactone and Dapagliflozin will be stopped after 4 weeks. The third treatment period will be followed by 4 weeks of wash-out, after which the study will be finalized.

Succession no.2: Dapagliflozin followed by Spironolactone followed by the combined therapy arm

The patients will be randomized to receive either Spironolactone or Dapagliflozin on top of standard therapy (stable doses of renin-angiotensin-system inhibitors) in a crossover trial design (4 weeks of treatment followed by 4 weeks of wash-out). Finally, the whole cohort will receive both Spironolactone and Dapagliflozin for another 4 weeks.

Treatment succession no.2 description: (1) 1st treatment period - patients will receive Dapagliflozin 10 mg od on top of standard for 4 weeks; (2) 1st washout-period - treatment with Dapagliflozin will be stopped for 4 weeks; (3) 2nd treatment period - patients will receive Spironolactone 25 mg od for 4 weeks; (4) 2nd washout-period - treatment with Spironolactone will be stopped for 4 weeks; (5) 3rd treatment period - patients will receive Spironolactone 25 mg od plus Dapagliflozin 10 mg od for 4 weeks; (6) 3rd washout-period - treatment with Spironolactone and Dapagliflozin will be stopped for 4 weeks.

Group Type: EXPERIMENTAL

Treatment with Dapagliflozin followed by Spironolactone followed by their combination

Intervention Type: DRUG

After titrating the renin-angiotensin-system inhibitor dose, patients will receive 10 mg of Dapagliflozin once daily for 4 weeks. Dapagliflozin will be stopped after 4 weeks. The first treatment period will be followed by 4 weeks of wash-out. After the first wash-out period, treatment with Spironolactone will be started. Patients will receive 25 mg of Spironolactone once daily for 4 weeks. Spironolactone will be stopped after 4 weeks. The second treatment period will be followed by 4 weeks of wash-out. After the second wash-out period, treatment with both Spironolactone and Dapagliflozin will be started. Patients will receive 25 mg of Spironolactone once daily in combination with 10 mg of Dapagliflozin daily for a duration of 4 weeks. Spironolactone and Dapagliflozin will be stopped after 4 weeks. The third treatment period will be followed by 4 weeks of wash-out, after which the study will be finalized.

Interventions

Treatment with Spironolactone followed by Dapagliflozin followed by their combination

After titrating the renin-angiotensin-system inhibitor dose, patients will receive 25 mg of Spironolactone once daily for 4 weeks. Spironolactone will be stopped after 4 weeks. The first treatment period will be followed by 4 weeks of wash-out. After the first wash-out period, treatment with Dapagliflozin will be started. Patients will receive 10 mg of Dapagliflozin once daily for 4 weeks. Dapagliflozin will be stopped after 4 weeks. The second treatment period will be followed by 4 weeks of wash-out. After the second wash-out period, treatment with both Spironolactone 25 mg and Dapagliflozin will be started. Patients will receive 25 mg of Spironolactone once daily in combination with 10 mg of Dapagliflozin daily for a duration of 4 weeks. Spironolactone and Dapagliflozin will be stopped after 4 weeks. The third treatment period will be followed by 4 weeks of wash-out, after which the study will be finalized.

Intervention Type: DRUG

Treatment with Dapagliflozin followed by Spironolactone followed by their combination

After titrating the renin-angiotensin-system inhibitor dose, patients will receive 10 mg of Dapagliflozin once daily for 4 weeks. Dapagliflozin will be stopped after 4 weeks. The first treatment period will be followed by 4 weeks of wash-out. After the first wash-out period, treatment with Spironolactone will be started. Patients will receive 25 mg of Spironolactone once daily for 4 weeks. Spironolactone will be stopped after 4 weeks. The second treatment period will be followed by 4 weeks of wash-out. After the second wash-out period, treatment with both Spironolactone and Dapagliflozin will be started. Patients will receive 25 mg of Spironolactone once daily in combination with 10 mg of Dapagliflozin daily for a duration of 4 weeks. Spironolactone and Dapagliflozin will be stopped after 4 weeks. The third treatment period will be followed by 4 weeks of wash-out, after which the study will be finalized.

Intervention Type: DRUG

Other Intervention Names

Treatment succession no. 1; Spironolactone-Dapagliflozin-Combination; SDC succession; Spironolactone first; Treatment succession no. 2; Dapagliflozin-Spironolactone-Combination; DSC succession; Dapagliflozin first

Eligibility Criteria

Inclusion Criteria

• Genetically proven Alport syndrome (AS) - defined as following:

• gt;Men having hemizygous pathogenic/likely pathogenic variants involving COL4A5 gene - classified as X-linked AS involving men
• gt;Women having heterozygous pathogenic/likely pathogenic variants involving COL4A5 gene - classified as X-linked AS involving women
• gt;Both men and women with heterozygous pathogenic/likely pathogenic variants involving COL4A3 or COL4A4 genes - classified as autosomal dominant AS
• gt;Both men and women with homozygous pathogenic/likely pathogenic variants involving COL4A3 or COL4A4 genes - classified as autosomal recessive AS
• gt;Patients having variants of uncertain significance will be included if the fulfill at least 2 of the following criteria: (1) clinical features suggestive of AS, (2) positive family history suggestive of AS (i.e., at least one grade I relative having the same variant and presenting clinical features suggestive of AS) and (3) kidney biopsy showing the characteristic lesion of AS (i.e., structural defect of the glomerular basement membrane, "basket-wave" appearance of the basement membrane, lamination of the basement membrane) or for thin basement membrane disease (i.e., diffusely thin basement membrane)
• Age between 18 and 70 years-old at the time of enrolment
• Baseline estimated glomerular filtration rate (eGFR) over 10ml/min/1.73m2 at the time of enrolment
• Stable kidney function: variation of eGFR under 25% from baseline in the last 6 weeks before randomization
• 24-hours urine albumin-to-creatinine ratio greater than 30 mg/g after adjusting the dose of renin-angiotensin-system inhibitor
• Stable renin-angiotensin-system inhibitor dose for at least 2 weeks before randomization

Exclusion Criteria

• The need for kidney replacement therapy (i.e., hemodialysis, peritoneal dialysis, and kidney transplant) for more than 4 weeks in the last 12 months before enrollment
• Treatment with Spironolactone or Dapagliflozin for more than 14 days in the last 28 days prior to enrollment
• History of prior serious adverse event due to Spironolactone or Dapagliflozin
• Active neoplasia
• Autosomal dominant or recessive polycystic kidney disease
• Type I diabetes
• Patients with type II diabetes and diabetic nephropathy
• Diagnosis of another concomitant distinct glomerulopathy (with the exception of concomitant IgA nephropathy on kidney biopsy)
• Pregnancy and breastfeeding
• History of solid organ transplant
• Immunosuppressive treatment in the last 12 weeks prior to enrollment

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Carol Davila University of Medicine and Pharmacy

OTHER

Sponsor Role: collaborator

Institutul Clinic Fundeni

OTHER

Sponsor Role: collaborator

Stefan Lujinschi

OTHER

Sponsor Role: lead

Responsible Party

Stefan Lujinschi

MD, PhD candidate

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Fundeni Clinical Institute

Bucharest, Sector 2, Romania

Site Status: RECRUITING

Countries

Romania

Central Contacts

Ștefan N Lujinschi, MD, PhD candidate

Role: CONTACT

stefanlujinschi@gmail.com

+40728102643

Facility Contacts

Ștefan N Lujinschi, MD, PhD candidate

Role: primary

stefanlujinschi@gmail.com

0728102643

Ștefan N Lujinschi, MD, PhD candidate

Role: backup

Gener Ismail, Professor, MD, PhD

Role: backup

Bogdan Obrișcă, Lecturer, MD, PhD

Role: backup

Other Identifiers

66035

Identifier Type: -

Identifier Source: org_study_id