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European Alport Therapy Registry - European Initiative Towards Delaying Renal Failure in Alport Syndrome

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ClinicalTrials.gov Identifier: NCT02378805
Recruitment Status : Recruiting
First Posted : March 4, 2015
Last Update Posted : April 28, 2021
Sponsor:
Collaborators:
Society for Pediatric Nephrology (Germany)
Deutsche Gesellschaft für Nephrologie
Alport Selbsthilfe e.V.
Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques (AIRG)
KfH Foundation Preventive Medicine
Information provided by (Responsible Party):
Prof. Dr. O. Gross, University Hospital Goettingen

Tracking Information
First Submitted Date February 26, 2015
First Posted Date March 4, 2015
Last Update Posted Date April 28, 2021
Study Start Date July 1995
Actual Primary Completion Date July 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: February 26, 2015)
  • end stage renal disease [ Time Frame: unlimited ]
    Age at onset of end stage renal failure
  • life-expectancy [ Time Frame: unlimited ]
    life-expectancy of patients and carriers
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: February 26, 2015)
  • proteinuria after initiation of ACE-inhibitor-therapy [ Time Frame: unlimited ]
  • proportion of patients with a clinical diagnosis of hypertension [ Time Frame: unlimited ]
  • proportion of patients experiencing side effects from ACE-inhibitors [ Time Frame: unlimited ]
    defined as acute renal failure (doubling of serum-creatinine), angioedema, hyperkalemia >5.0 mmol/l, dry cough, symptomatic hypotension (orthostatic collapse) and others, and death from all causes.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title European Alport Therapy Registry - European Initiative Towards Delaying Renal Failure in Alport Syndrome
Official Title European Alport Therapy Registry - European Initiative Towards Delaying Renal Failure in Alport Syndrome: Current and Novel Therapies
Brief Summary The hereditary type IV collagen disease Alport syndrome inevitably leads to end-stage renal disease. Currently there are no therapies known to improve outcome. Our non-interventional, observational study investigates, if medications such as ACE-inhibitors can (1) delay time to dialysis and (2) improve life-expectancy within three generations of Alport-families in Europe.
Detailed Description

Early diagnosis in children with Alport syndrome (AS) with isolated hematuria opens a "window of opportunity" for early intervention. Currently there are no causal therapeutic options which are proven to delay renal failure in AS. ACE-inhibition (ACEi) has been shown to reduce proteinuria in Alport patients and to delay renal failure in Alport-mice suggesting it may be of value as an effective treatment to delay renal failure in humans. To test this we established the European Alport Registry to collect data over several generations of Alport families across Europe. Small children with AS first develop microscopic hematuria, proceeding to microalbuminuria, overt proteinuria, impaired renal function and end up with end stage renal disease. These different steps of disease enabled us to assess if earlier introduction of ACE-inhibition at earlier degrees of disease is more effective than later therapy in delaying the time to dialysis and improving life-expectancy.

Heterozygous COL4A3/COL4A4 mutations result in the phenotype "familial benign hematuria" or "thin basement membrane nephropathy" (TBMN). Affected subjects typically present with hematuria. Having longtime been regarded as "benign" familial hematuria, those patients might have an increased risk to develop severe renal impairment - comparable to the findings in female XLAS carriers (see above). TBMN is not a rare disease, as at least 1% of the population is affected.

For the first time, the present study compares the risk of renal impairment, end stage renal disease and premature death in between heterozygous carriers of XLAS and of ARAS mutations. Additionally, the nephroprotective effect of RAAS-blockade in patients with heterozygous Alport-mutations is evaluated.

Study Type Observational [Patient Registry]
Study Design Observational Model: Cohort
Time Perspective: Cross-Sectional
Target Follow-Up Duration 10 Years
Biospecimen Retention:   Samples Without DNA
Description:
Urine and serum-samples.
Sampling Method Non-Probability Sample
Study Population

Currently there are no causal therapeutic options which are proven to delay renal failure in AS. We established the European Alport Registry to collect data over several generations of Alport families across Europe. The different steps of disease enabled us to assess if earlier introduction of ACE-inhibition at earlier degrees of disease is more effective than later therapy in delaying the time to dialysis and improving life-expectancy.

Heterozygous COL4A3/COL4A4 mutations result in the phenotype "familial benign hematuria" or "thin basement membrane nephropathy" (TBMN).

For the first time, the present study compares the risk of renal impairment, end stage renal disease and premature death in between heterozygous carriers of XLAS and of ARAS mutations. Additionally, the nephroprotective effect of RAAS-blockade in patients with heterozygous Alport-mutations is evaluated.

Condition
  • Alport Syndrome
  • Hereditary Kidney Disease
  • Pediatric Kidney Disease
  • Thin Basement Membrane Disease
  • Familial Benign Hematuria
Intervention
  • Drug: ACE-inhibitor
    observational study!
    Other Name: Ramipril
  • Drug: AT1-inhibitor
    observational study!
  • Drug: HMG-Coenzyme inhibitor (statin)
    observational study!
  • Drug: Spironolactone
    observational study!
  • Drug: Paricalcitol
    observational study!
Study Groups/Cohorts
  • no-T: untreated patients
    untreated patients, typically uncles or grandfathers of present patients. No Intervention (means no therapy until CKD stage V, on renal replacement therapy)
  • T-III: late therapy in patients
    patients treated with RAAS-Blockade after onset of renal failure (GFR below 60 ml/min) (starts at patients with CKD stages III and IV).
    Interventions:
    • Drug: ACE-inhibitor
    • Drug: AT1-inhibitor
    • Drug: HMG-Coenzyme inhibitor (statin)
    • Drug: Spironolactone
    • Drug: Paricalcitol
  • T-II: early therapy in patients
    therapy starts at patients with proteinuria >0.3 g/day or per gCreatinine
    Interventions:
    • Drug: ACE-inhibitor
    • Drug: AT1-inhibitor
    • Drug: HMG-Coenzyme inhibitor (statin)
    • Drug: Spironolactone
    • Drug: Paricalcitol
  • T-I: very early tharpy in patients
    starts at patients with microhematuria only (usually at birth) or microalbuminuria (30-300 mg protein per day or per gCreatinine in children).
    Interventions:
    • Drug: ACE-inhibitor
    • Drug: AT1-inhibitor
    • Drug: HMG-Coenzyme inhibitor (statin)
    • Drug: Spironolactone
    • Drug: Paricalcitol
  • no therapy in heterozygous carriers
    heterozygous carriers without therapy
  • therapy in heterozygous carriers
    heterozygous carriers with RAAS-blockade
    Interventions:
    • Drug: ACE-inhibitor
    • Drug: AT1-inhibitor
    • Drug: HMG-Coenzyme inhibitor (statin)
    • Drug: Spironolactone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: February 26, 2015)
500
Original Estimated Enrollment Same as current
Estimated Study Completion Date January 2035
Actual Primary Completion Date July 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria/ Exclusion Criteria:

The diagnosis of Alport syndrome (AS) was proven by kidney biopsy or mutation analysis (or both). Patients were included if they were affected males with X-linked AS or patients with genetically proven homozygous autosomal AS. Patients were excluded if they did not give informed consent or the diagnosis was suspected but not confirmed.

The diagnosis of the heterozygous status was proven by (1) mutation analysis or (2) kidney biopsy plus genetic consultation for decision in between XLAS or ARAS inheritance (including a conclusive genealogic tree and/or linkage analysis). Patients were excluded if they were affected males with XLAS or patients with genetically proven homozygous ARAS. Patients were excluded if they did not give informed consent or the diagnosis was suspected but not confirmed or if they donated a kidney (living donor to affected family member).

Sex/Gender
Sexes Eligible for Study: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers Yes
Contacts
Contact: Oliver Gross, MD +49-551-39- ext 6331 gross.oliver@med.uni-goettingen.de
Listed Location Countries Germany
Removed Location Countries  
 
Administrative Information
NCT Number NCT02378805
Other Study ID Numbers Alport-UMG2010
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Prof. Dr. O. Gross, University Hospital Goettingen
Study Sponsor University Hospital Goettingen
Collaborators
  • Society for Pediatric Nephrology (Germany)
  • Deutsche Gesellschaft für Nephrologie
  • Alport Selbsthilfe e.V.
  • Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques (AIRG)
  • KfH Foundation Preventive Medicine
Investigators
Principal Investigator: Oliver Gross, MD University Hospital Goettingen
PRS Account University Hospital Goettingen
Verification Date April 2021