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

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

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.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency, Chronic
• Intervention / Treatment: Drug: Ramipril; Drug: Ramipril; Drug: placebo to ramipril

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Goettingen, Germany, 37075
    • University Medical Center Goettingen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 months to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ramipril blinded; oral treatment with 1 to 6 mg per body surface area ramipril once daily for 3 years	Drug: Ramipril; 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.; Drug: Ramipril; Oral treatment with 1 to 6 mg per body surface area ramipril once daily for 3 years as per protocol.
Placebo Comparator: placebo to ramipril; 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; Oral application of placebo to ramipril, once daily with 1 to 6 mg per body surface area for 3 years or until disease progression.
Other: open label ramipril; Open label treatment with ramipril as per protocol, if randomization is refused.	Drug: Ramipril; 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.; Drug: Ramipril; Oral treatment with 1 to 6 mg per body surface area ramipril once daily for 3 years as per protocol.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH
• Collaborators: German Federal Ministry of Education and Research; University Medical Center Goettingen
• Investigators: Study Chair: Oliver Gross, Prof., University Medical Center Goettingen, Department Nephrology and Rheumatology

Publications and helpful links

General Publications

• Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021 Mar;36(3):711-719. doi: 10.1007/s00467-020-04819-6. Epub 2020 Nov 6. Erratum In: Pediatr Nephrol. 2021 Jan 12;:
• Gross O, Tonshoff B, Weber LT, Pape L, Latta K, Fehrenbach H, Lange-Sperandio B, Zappel H, Hoyer P, Staude H, Konig S, John U, Gellermann J, Hoppe B, Galiano M, Hoecker B, Ehren R, Lerch C, Kashtan CE, Harden M, Boeckhaus J, Friede T; German Pediatric Nephrology (GPN) Study Group and EARLY PRO-TECT Alport Investigators. A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. Kidney Int. 2020 Jun;97(6):1275-1286. doi: 10.1016/j.kint.2019.12.015. Epub 2020 Jan 17.
• Boeckhaus J, Hoefele J, Riedhammer KM, Tonshoff B, Ehren R, Pape L, Latta K, Fehrenbach H, Lange-Sperandio B, Kettwig M, Hoyer P, Staude H, Konrad M, John U, Gellermann J, Hoppe B, Galiano M, Gessner M, Pohl M, Bergmann C, Friede T, Gross O; GPN Study Group and EARLY PRO-TECT Alport Investigators. Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial. Clin Genet. 2021 Jan;99(1):143-156. doi: 10.1111/cge.13861. Epub 2020 Oct 25.
• Ahmed R, Duerr U, Gavenis K, Hilgers R, Gross O. Challenges for academic investigator-initiated pediatric trials for rare diseases. Clin Ther. 2014 Feb 1;36(2):184-90. doi: 10.1016/j.clinthera.2014.01.013.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: December 2, 2011
• First Submitted That Met QC Criteria: December 5, 2011
• First Posted (Estimate): December 6, 2011

Study Record Updates

• Last Update Posted (Actual): June 17, 2020
• Last Update Submitted That Met QC Criteria: June 15, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: chronic kidney disease; Alport Syndrome; renal fibrosis; nephroprotection; pediatric study
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Urogenital Abnormalities; Congenital Abnormalities; Connective Tissue Diseases; Nephritis; Collagen Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Nephritis, Hereditary; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Ramipril
• Other Study ID Numbers: EARLY_PRO-TECT_ALPORT