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

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

Interventions

DRUG

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.

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.

Sponsors & Collaborators

• Carol Davila University of Medicine and Pharmacy

  collaborator OTHER

• Institutul Clinic Fundeni

  collaborator OTHER

• Stefan Lujinschi

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2024-02-26

Primary Completion

2025-11-21

Completion

2026-04-30

Countries

• Romania

Study Locations