NCT04183101

Evaluation of a Renin Inhibitor, Aliskiren, Compared to Enalapril, in C3 Glomerulopathy

Phase 2, Multicenter, Randomized, Open-label, Controlled, 2-arm Cross-over Study to Evaluate the Clinical Efficacy of a Renin Inhibitor, Aliskiren, Compared to an Angiotensin Converting Enzyme Inhibitor, Enalapril, in C3 Glomerulopathy

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Sponsor: Region Skane · Academic / Other
• Sex: All
• Age: 6 Years
• Healthy volunteers: Not accepted

Summary

The aim of this cross-over trial is to assess aliskiren, a direct renin inhibitor, as a novel treatment to block complement activation in the kidneys and thereby attenuate renal disease and stabilize or improve kidney function and compare it to the currently used treatment with the angiotensin converting enzyme inhibitor, enalapril, in patients with the complement-mediated renal disease C3 glomerulopathy. Patients will be randomized to one or the other treatment for the first 6 months and then switch to the other treament for the following 2.5 years. Treatment will continue for altogether 3 years for each patient.

Detailed description

The primary objective is to assess the effect and safety of aliskiren on reducing systemic and local complement activation as indicated by a reduction of serum C3 during the cross-over study and serum C3 and complement deposition in renal biopsies during the extension study in patients with C3 glomerulopathy as compared to the currently used treatment with the angiotensin converting enzyme inhibitor (ACEi) enalapril. Secondary objectives are to assess the effect of aliskiren as compared to the currently used treatment with the ACEi enalapril on: complement activation (such as serum C3a, C3dg, C5a and related complement assays), proteinuria, kidney function, kidney biopsy findings, blood pressure, activation of the renin angiotensin system. Aliskiren will be administered orally in tablet form at 150 -300 mg/daily (maximal dose 300 mg). Enalapril 2.5-20 mg/daily (maximal dose 20 mg). These drugs may be administered once or twice. The investigators estimate an inclusion of maximum 15 patients for start of treatment with aliskiren and maximum 15 patients for start of treatment with enalapril. Suitable patients will be chosen from those patients who: 1. Do not have severe renal failure. Pediatric patients will be included if they have a glomerular filtration rate ≥ 50 ml/min/1.73m2, adults ≥ 30 ml/min/1.73m2. 2. Children, above the age of 6 years of age and adults. 3. Patients treated with aliskiren will be compared to patients treated with the ACE inhibitor enalapril as monotherapy. Use of ACE inhibitor as a nephroprotective therapy will increase renin levels without blocking its effect. Thus, the investigators will compare patients on aliskiren with those on enalapril to investigate if ACE inhibition as monotherapy has a negative effect on complement activation in comparison to direct renin inhibition. 4. Patients treated with immune suppressive medications at the start (such as mycophenolate mofetil (MMF) or corticosteroids) will be compared to patients treated with MMF or steroids plus aliskiren or enalapril. All suitable patients who fulfill inclusion criteria and who submitted written informed consent (patient or patient's legal guardians) will have undergone a renal biopsy at the most 2 years before inclusion or at inclusion and will be randomized for treatment with aliskiren or enalapril. After 6 months patients on aliskiren will switch to enalapril and vice versa, patients on enalapril will switch to aliskiren treatment. Patients will be followed routinely, every 3rd month, regarding renal function (creatinine, urea, estimated glomerular filtration rate), albumin (blood and urine), renin levels and complement activation assays in blood samples (C3, C3dg, C5, properdin, soluble terminal complement complex, C3a, C5a, C3 nephritic factor and other complement assays). The follow-up period, a total of 3 years from the start, will be carried out by the patient's own nephrologist and will not differ from the clinical follow-up offered patients not participating in the study. After 1-3 years (when medically indicated but at the most 3 years after start), a repeat renal biopsy will be performed to validate the effect of treatment on renal morphology. Renal biopsies, both the initial and the repeat biopsy, will be evaluated for complement deposition and glomerular basement membrane thickness.

Conditions

• C3 Glomerulopathy
• Membranoproliferative Glomerulonephritis
• Complement Abnormality
• Dense Deposit Disease
• C3 Glomerulonephritis

Interventions

Type	Name	Description
DRUG	Aliskiren	Patients will be randomized to start treatment with aliskiren tablet 150 mg every other day up to 300 mg daily depending on weight. After 6 months switch to enalapril 2.5-20 mg daily and continue with that 2.5 years.
DRUG	Enalapril	Patients will be randomized to start with enalapril 2.5-20 mg daily depending on weight. After 6 months switch to aliskiren tablet 150 mg every other day up to 300 mg daily depending on weight and continue with this treatment for 2.5 years.

Timeline

• Start date: 2020-10-01
• Primary completion: 2029-12-01
• Completion: 2029-12-01
• First posted: 2019-12-03
• Last updated: 2025-06-22

Locations

4 sites across 1 country: Sweden