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

NCT01485978 | Completed Phase 3 DMC

• 1 other identifier: EARLY_PRO-TECT_ALPORT
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Renal Insufficiency, Chronic

Keywords

Alport Syndrome; chronic kidney disease; renal fibrosis; nephroprotection; pediatric study

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Albuminuria after three years

  after 3 years

• Adverse Drug Events over three years

  after 3 years

Study Arms (3)

Ramipril blinded

ACTIVE COMPARATOR

oral treatment with 1 to 6 mg per body surface area ramipril once daily for 3 years

Drug: Ramipril

placebo to ramipril

PLACEBO COMPARATOR

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

open label ramipril

OTHER

Open label treatment with ramipril as per protocol, if randomization is refused.

Drug: Ramipril

Interventions

Ramipril DRUG

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.

Ramipril blinded

placebo to ramipril DRUG

Oral application of placebo to ramipril, once daily with 1 to 6 mg per body surface area for 3 years or until disease progression.

placebo to ramipril

Eligibility Criteria

• Age: 24 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH: lead
• University Medical Center Goettingen: collaborator
• German Federal Ministry of Education and Research: collaborator

Study Sites (1)

University Medical Center Goettingen

Göttingen, 37075, Germany

Location

Related Publications (4)

• 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.

  PMID: 32299679 RESULT

• 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.

  PMID: 33159213 DERIVED

• 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.

  PMID: 33040356 DERIVED

• 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.

  PMID: 24529291 DERIVED

Related Links

• Related Information

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Nephritis, Hereditary

Interventions

Ramipril

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Urogenital Abnormalities; Nephritis; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Collagen Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Oliver Gross, Prof.

  University Medical Center Goettingen, Department Nephrology and Rheumatology

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2011
• First Posted: December 6, 2011
• Study Start: March 1, 2012
• Primary Completion: September 1, 2018
• Study Completion: March 1, 2019
• Last Updated: June 17, 2020

Record last verified: 2020-06

Locations

DE (1)