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

A Unicentric, Randomized, Open-label, Cross-over Clinical Trial to Assess the Effect of Dapagliflozin, Spironolactone and Their Combination, When Added to Renin-Angiotensin System Blockade, On Lowering Urine Albumin-to-Creatinine Ratio in Adult Patients With Alport Syndrome

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).

Study Overview

• Status: Completed
• Conditions: Alport Syndrome; Thin Basement Membrane Disease; Alport Nephropathy
• Intervention / Treatment: Drug: Treatment with Spironolactone followed by Dapagliflozin followed by their combination; Drug: Treatment with Dapagliflozin followed by Spironolactone followed by their combination

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• Romania
  • Sector 2
    • Bucharest, Sector 2, Romania, 020021
      • Fundeni Clinical Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	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.; Other Names: Treatment succession no. 1; Spironolactone-Dapagliflozin-Combination; SDC succession; Spironolactone first
Experimental: 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.	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.; Other Names: Treatment succession no. 2; Dapagliflozin-Spironolactone-Combination; DSC succession; Dapagliflozin first

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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)

Collaborators and Investigators

• Sponsor: Stefan Lujinschi
• Collaborators: Carol Davila University of Medicine and Pharmacy; Institutul Clinic Fundeni

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2024
• Primary Completion (Actual): November 21, 2025
• Study Completion (Actual): April 30, 2026

Study Registration Dates

• First Submitted: July 7, 2024
• First Submitted That Met QC Criteria: July 7, 2024
• First Posted (Actual): July 15, 2024

Study Record Updates

• Last Update Posted (Actual): June 25, 2026
• Last Update Submitted That Met QC Criteria: June 24, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Chronic kidney disease; Albuminuria; Alport syndrome; Glomerulopathy; Type IV collagen; Monogenic kidney disorders
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Connective Tissue Diseases; Urination Disorders; Urological Manifestations; Renal Insufficiency; Congenital Abnormalities; Urogenital Abnormalities; Proteinuria; Nephritis; Collagen Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Signs and Symptoms; Renal Insufficiency, Chronic; Nephritis, Hereditary; Albuminuria; Hematuria, Benign Familial; Therapeutics
• Other Study ID Numbers: 66035

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No