Clinical trial NCT01485978: Efficacy and Safety Study to Delay Renal Failure in Children With Alport Syndrome
Official title: Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Renal Insufficiency, Chronic
Keywords: Alport Syndrome
chronic kidney disease
renal fibrosis
nephroprotection
pediatric study
Lead sponsor: Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH
Sponsor class: OTHER
Collaborators: name: University Medical Center Goettingen
name: German Federal Ministry of Education and Research
First posted: 2011-12-06
Enrollment: 66
Sex: ALL
Minimum age (years): 24
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Time to next disease level
timeFrame: within 3 years
measure: Incidence of Adverse Drug Events before progression
timeFrame: within 3 years
Secondary outcomes:
measure: Albuminuria after three years
timeFrame: after 3 years
measure: Adverse Drug Events over three years
timeFrame: after 3 years
Other outcomes:
Locations:
city: Goettingen
country: Germany
facility: University Medical Center Goettingen
Study officials:
affiliation: University Medical Center Goettingen, Department Nephrology and Rheumatology
name: Oliver Gross, Prof.
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.