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

Alport Syndrome Clinical Trial

Official title:

European Alport Therapy Registry - European Initiative Towards Delaying Renal Failure in Alport Syndrome: Current and Novel Therapies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02378805
• Other study ID #: Alport-UMG2010
• Status: Recruiting
• Start date: July 1995
• Est. completion date: January 2035

Study information

• Verified date: May 2022
• Source: University Hospital Goettingen
• Contact: Oliver Gross, MD
• Phone: +49-551-39-
• Email: gross.oliver[@]med.uni-goettingen.de
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: January 2035
• Est. primary completion date: July 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

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).

Related Conditions & MeSH terms

• Alport Syndrome
• Familial Benign Hematuria
• Hematuria
• Hereditary Kidney Disease
• Kidney Diseases
• Nephritis, Hereditary
• Pediatric Kidney Disease
• Renal Insufficiency
• Syndrome
• Thin Basement Membrane Disease

Intervention

Drug:
• ACE-inhibitor
observational study!
• AT1-inhibitor
observational study!
• HMG-Coenzyme inhibitor (statin)
observational study!
• Spironolactone
observational study!
• Paricalcitol
observational study!
• SGLT2 inhibitor
observational study!

Locations

Country	Name	City	State
Germany	University Hospital Goettingen	Goettingen

Sponsors (6)

Lead Sponsor	Collaborator
University Hospital Goettingen	Alport Selbsthilfe e.V., Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques (AIRG), Deutsche Gesellschaft für Nephrologie, KfH Foundation Preventive Medicine, Society for Pediatric Nephrology (Germany)

Country where clinical trial is conducted

Germany, 

References & Publications (9)

Boeckhaus J, Hoefele J, Riedhammer KM, Nagel M, Beck B, Choi M, Gollasch M, Bergmann C, Sonntag JE, Troesch V, Stock J, Gross O. Lifelong Effect of Therapy in Young Patients with the COL4A5 Alport Missense Variant p.(Gly624Asp): a Prospective Cohort Study — View Citation

Frese J, Kettwig M, Zappel H, Hofer J, Gröne HJ, Nagel M, Sunder-Plassmann G, Kain R, Neuweiler J, Gross O. Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis. Int J M — View Citation

Gross O, Licht C, Anders HJ, Hoppe B, Beck B, Tönshoff B, Höcker B, Wygoda S, Ehrich JH, Pape L, Konrad M, Rascher W, Dötsch J, Müller-Wiefel DE, Hoyer P; Study Group Members of the Gesellschaft für Pädiatrische Nephrologie, Knebelmann B, Pirson Y, Grunfe — View 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. Review. Erratum in: Pediatr Nephrol. 2021 Jan 12;:. — View Citation

Stock J, Kuenanz J, Glonke N, Sonntag J, Frese J, Tönshoff B, Höcker B, Hoppe B, Feldkötter M, Pape L, Lerch C, Wygoda S, Weber M, Müller GA, Gross O. Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients wi — View Citation

Temme J, Kramer A, Jager KJ, Lange K, Peters F, Müller GA, Kramar R, Heaf JG, Finne P, Palsson R, Reisæter AV, Hoitsma AJ, Metcalfe W, Postorino M, Zurriaga O, Santos JP, Ravani P, Jarraya F, Verrina E, Dekker FW, Gross O. Outcomes of male patients with A — View Citation

Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Müller GA, Gross O. Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutatio — View Citation

Weinstock BA, Feldman DL, Fornoni A, Gross O, Kashtan CE, Lagas S, Lennon R, Miner JH, Rheault MN, Simon JF; Workshop Participants. Clinical trial recommendations for potential Alport syndrome therapies. Kidney Int. 2020 Jun;97(6):1109-1116. doi: 10.1016/j.kint.2020.02.029. Epub 2020 Apr 6. — View Citation

Zhang Y, Böckhaus J, Wang F, Wang S, Rubel D, Gross O, Ding J. Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome. Pediatr Nephrol. 2021 Sep;36(9):2719-2730. doi: 10.1007/s0 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	end stage renal disease	Age at onset of end stage renal failure	unlimited
Primary	life-expectancy	life-expectancy of patients and carriers	unlimited
Secondary	proteinuria after initiation of ACE-inhibitor-therapy		unlimited
Secondary	proportion of patients with a clinical diagnosis of hypertension		unlimited
Secondary	proportion of patients experiencing side effects from ACE-inhibitors	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.	unlimited