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

Phase

Condition

Nephropathy

Kidney Failure (Pediatric)

Proteinuria

Treatment

N/A

Clinical Study ID

NCT06499948

66035

Ages 18-70
All Genders

Study 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).

Eligibility Criteria

Inclusion

Inclusion Criteria:

Genetically proven Alport syndrome (AS) - defined as following:
gt;Men having hemizygous pathogenic/likely pathogenic variants involving COL4A5gene - classified as X-linked AS involving men
gt;Women having heterozygous pathogenic/likely pathogenic variants involvingCOL4A5 gene - classified as X-linked AS involving women
gt;Both men and women with heterozygous pathogenic/likely pathogenic variantsinvolving COL4A3 or COL4A4 genes - classified as autosomal dominant AS
gt;Both men and women with homozygous pathogenic/likely pathogenic variantsinvolving COL4A3 or COL4A4 genes - classified as autosomal recessive AS
gt;Patients having variants of uncertain significance will be included if thefulfill at least 2 of the following criteria: (1) clinical features suggestiveof AS, (2) positive family history suggestive of AS (i.e., at least one grade Irelative having the same variant and presenting clinical features suggestive ofAS) and (3) kidney biopsy showing the characteristic lesion of AS (i.e.,structural defect of the glomerular basement membrane, "basket-wave" appearanceof the basement membrane, lamination of the basement membrane) or for thinbasement 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 thetime of enrolment
Stable kidney function: variation of eGFR under 25% from baseline in the last 6weeks before randomization
24-hours urine albumin-to-creatinine ratio greater than 30 mg/g after adjusting thedose of renin-angiotensin-system inhibitor
Stable renin-angiotensin-system inhibitor dose for at least 2 weeks beforerandomization

Exclusion

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 28days 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 ofconcomitant IgA nephropathy on kidney biopsy)
Pregnancy and breastfeeding
History of solid organ transplant
Immunosuppressive treatment in the last 12 weeks prior to enrollment

Study Design

February 26, 2024

March 31, 2026