Evaluation of Aliskiren Versus Enalapril in the Management of C3 Glomerulopathy in Pediatric and Adult Populations
- Trial ID
- 2024-515892-36-00
- Sponsor
- Region Skane
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy and safety of **aliskiren**, a direct renin inhibitor, as a novel therapeutic approach for patients with C3 glomerulopathy. The study aims to determine the ability of aliskiren to block complement activation in the kidneys, thereby potentially attenuating renal disease and stabilizing or improving kidney function. This will be compared to the current standard treatment with the angiotensin-converting enzyme inhibitor (ACEi) **enalapril**. The clinical relevance of this objective lies in the potential for aliskiren to offer a more effective treatment option for managing complement-mediated renal disease, which could lead to improved patient outcomes.
Secondary objectives include assessing the effect of aliskiren compared to enalapril on various clinical parameters: - Complement activation markers such as serum C3a, C3d, C5a, and related assays - Proteinuria levels - Kidney function and biopsy findings - Blood pressure regulation - Activation of the renin-angiotensin system
Participants
The clinical trial involves participants diagnosed with **C3 glomerulopathy**, specifically Dense Deposit Disease and C3 glomerulonephritis, confirmed by kidney biopsy within two years prior to the study. The study population includes both male and female subjects, ranging from children aged 6 years to adults. Participants may either be treatment-naïve or currently undergoing treatment with aliskiren, ACE inhibitors, ARBs, or immunosuppressive medications. The trial does not focus on a vulnerable population. Female participants of childbearing potential are required to adhere to strict contraceptive measures due to the teratogenic risk of the study medication. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is a **Phase 2**, multicenter, randomized, open-label, controlled, 2-arm cross-over study designed to evaluate the clinical efficacy and safety of a renin inhibitor, **aliskiren**, compared to an angiotensin-converting enzyme inhibitor, **enalapril**, in children and adults with **C3 glomerulopathy**. The trial aims to assess the effect of aliskiren on reducing systemic and local complement activation, as indicated by a reduction of serum C3 levels and complement deposition in renal biopsies, compared to enalapril. The study is expected to run until December 31, 2030, with recruitment having started on October 7, 2020.
Participants will be involved in the study for a maximum treatment period of 30 days, with the trial consisting of several key visits. The initial visit will be a screening visit to confirm eligibility based on criteria such as age (children ≥ 6 years and adults), diagnosis of Dense Deposit Disease or C3 glomerulonephritis confirmed by kidney biopsy, and informed consent. Following the screening, participants will be randomized to receive either aliskiren or enalapril, with the possibility of cross-over to the alternate treatment arm. Follow-up visits will be scheduled to monitor serum C3 levels, kidney function, and other secondary endpoints such as proteinuria and blood pressure. The end-of-study visit will conclude the participant's involvement, with a final assessment of the primary and secondary endpoints.
Participants may be withdrawn from the study early if they experience adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety. Female participants of childbearing potential must adhere to strict contraceptive measures and undergo regular pregnancy testing throughout the study. The trial's primary endpoints include serum C3 levels during the cross-over study and complement deposition in renal biopsies during the extension study. Secondary endpoints encompass various measures of complement activation, kidney function, and the activation of the renin-angiotensin system.
Treatment
The clinical trial involves the administration of **Enalapril Viatris 5 mg tablets**, which contain the active substance **enalapril maleate**. This medication is presented in tablet form and is administered orally. The maximum daily dose for enalapril is 20 mg, with a total maximum dose of 18,250 mg over a treatment period of 30 days. Enalapril is an angiotensin-converting enzyme inhibitor (ACEi) used to manage conditions such as hypertension and heart failure. In this study, enalapril serves as a comparator treatment to evaluate its efficacy and safety against the experimental medication, aliskiren, in patients with C3 glomerulopathy.
The experimental medication in this trial is **Rasilez 300 mg film-coated tablets**, containing the active substance **aliskiren**. Aliskiren is a direct renin inhibitor, and the tablets are administered orally. The maximum daily dose of aliskiren is 300 mg, with a total maximum dose of 273,750 mg over a 30-day treatment period. The study aims to assess the potential of aliskiren to block complement activation in the kidneys, thereby reducing systemic and local complement activation, as indicated by a reduction in serum C3 levels and complement deposition in renal biopsies. This trial seeks to compare the effects of aliskiren with the standard treatment using enalapril in patients with C3 glomerulopathy.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the measurement of **serum C3** levels during the cross-over study and the evaluation of serum C3 and complement deposition in renal biopsies during the extension study. These endpoints are critical for determining the effect of the treatment on complement activation in patients with C3 glomerulopathy.
Secondary endpoints will provide additional insights into the treatment's efficacy. These include assessments of complement activation markers such as serum C3a, C3d, and C5a, as well as other complement assays. Additional parameters include proteinuria, kidney function, kidney biopsy findings, blood pressure, and the activation of the renin-angiotensin system. These measurements will help to further elucidate the impact of the treatment on renal health and systemic physiological responses.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Children ≥ 6 years and adults.
- Initial diagnosis of Dense Deposit Disease and C3 glomerulonephritis confirmed by kidney biopsy obtained not more than 2 years before the first dose of the study drug.
- Either absence of treatment at the study start or ongoing treatment with aliskiren, ACEi, ARBs or immune suppressive medications (such as mycophenolate mofetil/MMF or corticosteroids)
- Written informed consent has been given by: A. the patient’s legal guardians if the patient is less than 15 years old B. the patient and his/her legal guardians if the patient is ≥ 15 but < 18 years old C. the patient, if the patient is ≥ 18 years old
- Female subjects of childbearing potential must: a. Understand that the study medication is expected to have a teratogenic risk b. Agree to use a highly effective contraceptive during study drug therapy. This applies unless the subject is less than 18 years of age, has not had sexual debut and commits to sexual abstinence confirmed by a pregnancy test on every study visit. Either of the following methods of contraception may be used: • Combined (estrogen and progesterone) hormonal contraception associated with inhibition of ovulation: oral, intravaginal or transdermal • Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable or implantable • Intrauterine device • Intrauterine hormone-releasing system • Bilateral tubal occlusion • Vasectomized partner • Sexual abstinence • Male or female condom with or without spermicide • Cap, diaphragm or sponge with spermicide c. Agree to have a pregnancy test before the start of study medication. This requirement also applies to women of childbearing age who practice complete and continued abstinence and adolescent girls after menarche. d. Agree to have a pregnancy test every 3rd month including at the end of study treatment, except in the case of confirmed tubal sterilization. This requirement also applies to women of childbearing age who practice complete and continued abstinence and adolescent girls after menarche.
Exclusion Criteria
- Known allergy to aliskiren, ACEi or substances contained in these preparations.
- Angioedema caused by aliskiren or enalapril
- Weight < 25 kg
- Glomerular filtration rate ≤ 50 ml/min/1.73 m2 (measured by iohexol clearance) in children and ≤ 30 ml/min/1.73 m2 in adults.
- Rapid deterioration of kidney function during the latest year of the disease
- Patients with a renal transplant
- Immune complex-mediated membranoproliferative glomerulonephritis (such as in HIV infection, hepatitis, SLE)
- Females who breastfeed, are pregnant or planning to become pregnant during the study.
- Co-morbidity such as malignancy, congestive heart failure, recent myocardial infarction.
- Mental incapacity or language barriers to understand the contents of the study design.
- Simultaneous use of another complement-antagonist (such as eculizumab). Eculizumab must be discontinued and complement activity normalized before the start of study drug.
- Simultaneous use of aliskiren or enalapril with cyclosporine or nonsteroidal antiinflammatory drugs (NSAID).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Sweden | Not Recruiting | 07 Oct 2020 | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Enalapril Viatris 5 mg comprimidos EFG | Test | COMPRIMIDOS | ORAL USE | 20 | 30 | PRD10112968 |
Rasilez 300 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 300 | 30 | PRD5307222 |