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

NCT02378805 | Recruiting

• 1 other identifier: Alport-UMG2010
• Study Type: observational
• Target: 800
• Locations: 1 country
• Sites: 1

Brief Summary

The hereditary type IV collagen disease Alport syndrome leads to kidney failure early in life. Currently there are no specific medications approved for treatment, however, several therapies have been evaluated preclinically and could improve outcome. For that reason, this non-interventional, observational study investigates, if medications (1) delay disease progression; (2) delay time to kidney failure; (3) improve life-expectancy compared to untreated patients (relatives). This observational study started in 2006 as an European registry. Since 2019, this registry has been expanded to "Alport XXL" via the International Alport Alliance as a global effort across all continents. From 2020 on to present, "Alport XXL" has a special focus on the outcomes of early therapy in young patients on ACE-inhibitors vs. Angiotensin-receptor blockers vs. their combination.

Conditions

Alport Syndrome; Hereditary Kidney Disease; Pediatric Kidney Disease; Thin Basement Membrane Disease; Familial Benign Hematuria

Keywords

Alport syndrome; thin basement membrane disease; familial benign hematuria

Outcome Measures

Primary Outcomes (4)

• age at onset of end stage kidney failure (need for renal replacement therapy)

  kidney disease in Alport syndrome starts at birth, age at onset of end stage kidney failure in years

  until end of observation in 2037

• life-expectancy in years (age at death)

  Alport syndrome starts at birth, age at death of patients in years

  until end of observation in 2037

• yearly loss of estimated glomerular filtration rate (eGFR)

  kidney disease in Alport syndrome starts at birth, eGFR-loss per year in ml/min/1.73m2

  until end of observation in 2037

• time in years until doubling or tripling of urinary albumin to creatinine ratio (UACR)

  kidney disease in Alport syndrome starts at birth; time since birth to doubling (AS stages I or II) or tripling (AS stage 0) of UACR in years.

  until end of observation in 2037

Secondary Outcomes (8)

• amount of albuminuria over time

  until end of observation in 2037

• amount of proteinuria over time

  until end of observation in 2037

• number of patients with X-chromosomal or autosomal inheritance

  until end of observation in 2037

• number of patients experiencing side effects (AEs)

  until end of observation in 2037

• number of patients with hearing loss

  until end of observation in 2037

Study Arms (6)

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 medications with low eGFR (below 60 ml/min) (starts at patients with CKD stages III and IV).

Drug: ACE-inhibitor; Drug: Angiotensin-receptor blocker (ARB); Drug: HMG-Coenzyme inhibitor (statin); Drug: Spironolactone or Finerenone; Drug: Paricalcitol; Drug: SGLT2 inhibitor

T-II: early therapy in patients

therapy starts in patients with albuminuria \>300mg/gCreatinine and eGFR higher than 60 ml/min.

Drug: ACE-inhibitor; Drug: Angiotensin-receptor blocker (ARB); Drug: HMG-Coenzyme inhibitor (statin); Drug: Spironolactone or Finerenone; Drug: Paricalcitol; Drug: SGLT2 inhibitor

T-I: very early therapy in patients

therapy starts in patients with microhematuria only (usually at birth) or microalbuminuria (30-300 mg albumin per gCreatinine).

Drug: ACE-inhibitor; Drug: Angiotensin-receptor blocker (ARB); Drug: HMG-Coenzyme inhibitor (statin); Drug: Spironolactone or Finerenone; Drug: Paricalcitol; Drug: SGLT2 inhibitor

no therapy in heterozygous patients

heterozygous patients without therapy

therapy in heterozygous patients

heterozygous patients with therapy (which also can be divided into subgroups stage T-0, I, II, III)

Drug: ACE-inhibitor; Drug: Angiotensin-receptor blocker (ARB); Drug: HMG-Coenzyme inhibitor (statin); Drug: Spironolactone or Finerenone; Drug: Paricalcitol; Drug: SGLT2 inhibitor

Interventions

ACE-inhibitor DRUG

observational study

T-I: very early therapy in patients; T-II: early therapy in patients; T-III: late therapy in patients; therapy in heterozygous patients

Angiotensin-receptor blocker (ARB) DRUG

observational study

T-I: very early therapy in patients; T-II: early therapy in patients; T-III: late therapy in patients; therapy in heterozygous patients

HMG-Coenzyme inhibitor (statin) DRUG

observational study

T-I: very early therapy in patients; T-II: early therapy in patients; T-III: late therapy in patients; therapy in heterozygous patients

Spironolactone or Finerenone DRUG

observational study

T-I: very early therapy in patients; T-II: early therapy in patients; T-III: late therapy in patients; therapy in heterozygous patients

Paricalcitol DRUG

observational study!

T-I: very early therapy in patients; T-II: early therapy in patients; T-III: late therapy in patients; therapy in heterozygous patients

SGLT2 inhibitor DRUG

observational study

T-I: very early therapy in patients; T-II: early therapy in patients; T-III: late therapy in patients; therapy in heterozygous patients

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

For Alport XXL, eligible patients were children or young adults with a definitive diagnosis of AS by genetic analysis or kidney biopsy and at early stages of AS (stages 0, I or II) at baseline. AS stages were defined as: Stage 0 Microhematuria without microalbuminuria Stage I Microalbuminuria: UACR 30-300 mg/gCreatinine Stage II Proteinuria: UACR \>300 with eGFR\>60 ml/min/1.73m2 Stage III eGFR\<60 ml/min/1.73m2 Stage IV end stage kidney failure Stage V death (from all causes)

You may qualify if:

• Diagnosis of Alport syndrome (AS) by kidney biopsy or mutation analysis (or both).
• Any type of genetic variant is accepted for X-linked, autosomal or digenic Alport syndrome (COL4A3, 4 or 5 genes).

You may not qualify if:

• Patients not willing to give informed consent. Patient with suspected diagnosis, whcih cannot be confirmed.

Sponsors & Collaborators

• University Hospital Goettingen: lead
• Society for Pediatric Nephrology (Germany): collaborator

Study Sites (1)

University Medical Center Göttingen

Göttingen, Lower Saxony, 37075, Germany

RECRUITING

Related Publications (11)

• 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 BACKGROUND

• 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.

  PMID: 32386680 BACKGROUND

• Temme J, Kramer A, Jager KJ, Lange K, Peters F, Muller GA, Kramar R, Heaf JG, Finne P, Palsson R, Reisaeter 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 Alport syndrome undergoing renal replacement therapy. Clin J Am Soc Nephrol. 2012 Dec;7(12):1969-76. doi: 10.2215/CJN.02190312. Epub 2012 Sep 20.

  PMID: 22997344 RESULT

• Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Muller GA, Gross O. Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Kidney Int. 2012 Apr;81(8):779-83. doi: 10.1038/ki.2011.452. Epub 2012 Jan 11.

  PMID: 22237748 RESULT

• Gross O, Licht C, Anders HJ, Hoppe B, Beck B, Tonshoff B, Hocker B, Wygoda S, Ehrich JH, Pape L, Konrad M, Rascher W, Dotsch J, Muller-Wiefel DE, Hoyer P; Study Group Members of the Gesellschaft fur Padiatrische Nephrologie; Knebelmann B, Pirson Y, Grunfeld JP, Niaudet P, Cochat P, Heidet L, Lebbah S, Torra R, Friede T, Lange K, Muller GA, Weber M. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012 Mar;81(5):494-501. doi: 10.1038/ki.2011.407. Epub 2011 Dec 14.

  PMID: 22166847 RESULT

• Stock J, Kuenanz J, Glonke N, Sonntag J, Frese J, Tonshoff B, Hocker B, Hoppe B, Feldkotter M, Pape L, Lerch C, Wygoda S, Weber M, Muller GA, Gross O. Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations. Pediatr Nephrol. 2017 Jan;32(1):131-137. doi: 10.1007/s00467-016-3452-z. Epub 2016 Jul 11.

  PMID: 27402170 RESULT

• Frese J, Kettwig M, Zappel H, Hofer J, Grone 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 Mol Sci. 2019 Jan 26;20(3):519. doi: 10.3390/ijms20030519.

  PMID: 30691124 RESULT

• Boeckhaus J, Hoefele J, Riedhammer KM, Nagel M, Beck BB, 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. Nephrol Dial Transplant. 2022 Nov 23;37(12):2496-2504. doi: 10.1093/ndt/gfac006.

  PMID: 35022790 RESULT

• Zhang Y, Bockhaus 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/s00467-021-05040-9. Epub 2021 Mar 27.

  PMID: 33772369 RESULT

• Boeckhaus J, Gross O. Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Hereditary Podocytopathies, Alport Syndrome, and FSGS: A Case Series to Better Plan a Large-Scale Study. Cells. 2021 Jul 18;10(7):1815. doi: 10.3390/cells10071815.

  PMID: 34359984 RESULT

• Boeckhaus J, Gale DP, Simon J, Ding J, Zhang Y, Bergmann C, Turner AN, Hall M, Sayer JA, Srivastava S, Kang HG, Cerkauskaite-Kerpauskiene A, Gillion V, Claes KJ, Krueger B, de Fallois J, Walden U, Choi M, Schueler M, Mueller RU, Todorova P, Hohenstein B, Zeisberg M, Friede T, Knebelmann B, Halbritter J, Gross O. SGLT2-Inhibition in Patients With Alport Syndrome. Kidney Int Rep. 2024 Sep 24;9(12):3490-3500. doi: 10.1016/j.ekir.2024.09.014. eCollection 2024 Dec.

  PMID: 39698346 RESULT

MeSH Terms

Conditions

Nephritis, Hereditary; Hematuria, Benign Familial

Interventions

Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Spironolactone; finerenone; paricalcitol; Sodium-Glucose Transporter 2 Inhibitors

Condition Hierarchy (Ancestors)

Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Nephritis; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Collagen Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Lipid Regulating Agents; Therapeutic Uses; Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hypoglycemic Agents; Physiological Effects of Drugs

Study Officials

• Oliver Gross, MD

  University Hospital Goettingen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Oliver Gross, MD

CONTACT

+49-551-39-; gross.oliver@med.uni-goettingen.de

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Target Duration: 30 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Oliver Gross

Study Record Dates

• First Submitted: February 26, 2015
• First Posted: March 4, 2015
• Study Start: July 1, 1995
• Primary Completion (Estimated): March 1, 2036
• Study Completion (Estimated): March 1, 2036
• Last Updated: March 6, 2025

Record last verified: 2025-03

Locations

DE (1)