Efficacy and Safety Study to Delay Renal Failure in Children With Alport Syndrome

Study Overview
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Brief Summary
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This is a phase III, multi-centre, randomised, placebo-controlled, patient and investigator-blind study in paediatric patients with early stages of Alport syndrome to assess the safety and efficacy of the ACEi ramipril in slowing disease progression. Alport syndrome stages that describe the extent of renal damage and loss of function are defined as: 0 Microhaematuria without microalbuminuria (usually at birth) I Microalbuminuria (30-300 mg albumin/gCrea) II Proteinuria >300 mg albumin/gCrea III > 25% decline of normal renal function (creatinine clearance) IV End stage renal failure (ESRF) Eligible patients with Alport stages 0 and I will be randomly assigned at a 2:1 ratio to receive once daily ramipril or placebo. In addition, Alport stage II patients may be treated open Label. Eligible patients who, or whose parents/legal guardian refuse randomisation after eligibility is confirmed, and patients who have been treated with ramipril prior to the study, may be treated open-label with ramipril as per protocol. The total number of patients will not exceed 120, with the number of randomised patients not exceeding 60, and the number of patients treated open label from Day 1 of the study aimed to be approximately 60. Randomised patients whose disease progresses to the next disease level during the 3 year treatment period will be unblinded, and open label ramipril treatment will be initiated and continued, respectively, depending on prior treatment randomisation.

Official Title
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Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome

Conditions
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Renal Insufficiency, Chronic

Intervention / Treatment
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* Drug: Ramipril
* Drug: placebo to ramipril
* Drug: Ramipril


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Definitive diagnosis of Alport syndrome: Kidney biopsy (patient or affected relative/s), and/or mutation analysis (hemizygous X-chromosomal or homozygous autosomal-recessive) and assessment of criteria for clinical diagnosis (haematuria, positive family history regarding kidney diseases, ocular changes, labyrinthine hearing loss) Alport syndrome levels 0, I or II at screening (microhaematuria without microalbuminuria or microalbuminuria [30-300 mg albumin/gCrea]) or proteinuria >300 mg albumin/gCrea with GFR>80ml/min). Patients with Alport stage II are not subject to randomization but are treated opel label. Aged between ≥24 months and <18 years at screening Assent from patient and informed consent from parents/legal guardian Exclusion Criteria: Uncertain diagnosis or variants of Alport syndrome such as a heterozygous carrier Alport syndrome levels III, or IV (albuminuria >300 mg/g Crea, creatinine clearance <60 mL/min, or end stage renal failure [ESRF]) Known allergies or intolerances to ramipril or related compounds Known contraindication for ACEi-therapy Additional chronic renal, pulmonary or cardiac diseases Pregnancy and lactation

Ages Eligible for Study
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Minimum Age: 24 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ramipril blinded<br>oral treatment with 1 to 6 mg per body surface area ramipril once daily for 3 years | Drug: Ramipril<br>* Ramipril (Delix) tablets containing 2.5 mg ramipril, oral application with 1 to 6 mg per body surface area ramipril once daily for 3 years.<br>|
| Placebo Comparator: placebo to ramipril<br>Oral placebo treatment to ramipril once daily for 3 years or until progress to next disease level. After progression to next disease level, patients will be unblinded, and ramipril treatment will be initiated. | Drug: placebo to ramipril<br>* Oral application of placebo to ramipril, once daily with 1 to 6 mg per body surface area for 3 years or until disease progression.<br>|
| Other: open label ramipril<br>Open label treatment with ramipril as per protocol, if randomization is refused. | Drug: Ramipril<br>* Oral treatment with 1 to 6 mg per body surface area ramipril once daily for 3 years as per protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to next disease level | Time to progression of Alport Syndrome to the next disease level within 3 years under ramipril treatment compared to placebo, for all randomised patients. | within 3 years | 
| Incidence of Adverse Drug Events before progression | Incidence of adverse drug events (ADEs, e.g., angioedema, acute renal failure, hyperkalaemia) under ramipril treatment before disease progression compared to placebo before disease progression, for all randomised patients. | within 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Albuminuria after three years | Albuminuria after 3 years corrected for baseline albuminuria for patients randomised to receive ramipril compared to placebo. | after 3 years | 
| Adverse Drug Events over three years | Incidence of ADEs (e.g., angioedema, acute renal failure, hyperkalaemia) during 3 years of treatment for patients randomised to receive ramipril compared to placebo. | after 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alport Syndrome, chronic kidney disease, renal fibrosis, nephroprotection, pediatric study