Albuminuria Lowering Effect of Dapagliflozin, Spironolactone and Their Combination in Adult Patients with Alport Syndrome (COMBINE-ALPORT)
NCT Number: NCT06499948
Acronym: COMBINE-ALPORT
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE4
Conditions: Alport Syndrome|Thin Basement Membrane Disease|Alport Nephropathy
Sponsor: Stefan Lujinschi
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 34
Study Design: Allocation: RANDOMIZED|Intervention Model: CROSSOVER|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-02-26
Completion Date: 2026-03

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).

Primary Outcome Measures: Change in 24-hours urine albumin-to-creatinine ratio (UACR) compared to baseline after treatment with Dapagliflozin, Spironolactone and with their combination, 24-hours UACR will be measured at 0, 2, 6, 10, 14, 18, 22, 26 and 30 weeks after eligibility assessment
Secondary Outcome Measures: Change in estimated glomerular filtration ratio (eGFR) compared to baseline after treatment with Dapagliflozin, Spironolactone and with their combination, eGFR will be measured at 0, 2, 6, 10, 14, 18, 22, 26 and 30 weeks after eligibility assessment|Change in serum potassium compared to baseline after treatment with Dapagliflozin, Spironolactone and with their combination, Serum K will be measured at 0, 2, 6, 10, 14, 18, 22, 26 and 30 weeks after eligibility assessment|The occurrence of adverse events, including serious adverse events, During and after each period of treatment, up to 24 weeks after randomization (30 weeks after assessing eligibility)|Change in urinary electrolytes excretion (sodium and potassium) compared to baseline after treatment with Dapagliflozin, Spironolactone and with their combination, Urinary sodium and potassium will me measured each 4 weeks up to 24 weeks after randomization: before and after each period of treatment and wash-out
Other Outcome Measures: Reduction of 24-hours UACR with more than 30% from baseline after treatment with Dapagliflozin, Spironolactone and with their combination, Change of UACR will be asses after each period of treatment (at 4, 12 and 20 weeks after randomization)|Reduction of 24-hours UACR with more than 50% from after treatment with Dapagliflozin, Spironolactone and with their combination, Change of UACR will be asses after each period of treatment (at 4, 12 and 20 weeks after randomization)|Reduction of eGFR with more than 30% from baseline after treatment with Dapagliflozin, Spironolactone and with their combination, Change in eGFR will be asses after each period of treatment (at 4, 12 and 20 weeks after randomization)|Reduction of eGFR with more than 50% from baseline and/or doubling serum creatinine and/or initiation of kidney replacement therapy after treatment with Dapagliflozin, Spironolactone and with their combination, Change in eGFR will be asses after each period of treatment (at 4, 12 and 20 weeks after randomization)|Increase in serum potassium over 5.5 mmol/l and with more than 15% compared to baseline after treatment with Dapagliflozin, Spironolactone and with their combination, Changes in serum K will be assessed after each period of treatment (4, 12 and 20 weeks after randomization)