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

NCT ID: NCT02378805

Last Updated: 2025-03-06

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

800 participants

Study Classification

OBSERVATIONAL

Study Start Date

1995-07-31

Study Completion Date

2036-03-01

Brief Summary

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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.

Detailed Description

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Early diagnosis in children with Alport syndrome (AS) with isolated hematuria opens a "window of opportunity" for early intervention. In the Alport mouse-model, this early intervention with the ACE-inhibitor Ramipril let to a delay of kidney failure by 111%. In order to observe treatment approaches for AS in humans, this registry has been established in 2006 to collect data over several generations of Alport families across Europe. In the meantime, this registry has been expanded to "Alport XXL" via the International Alport Alliance as a global effort across all continents.

Small children with AS first develop microscopic hematuria (stage 0), proceeding to microalbuminuria (stage I), overt proteinuria (stage II), impaired kidney function (stage III) and finally can end up with kidney failure (stage IV), leading to impaired quality of life and premature death (stage V). This registry uses these stages to assess if earlier initiation of medications such as ACE-inhibition at earlier stages of disease is more effective than later therapy in delaying the time to disease progression (doubeling or tripeling of albuminuria), delaying loss of estimated glomerular filtration rate (eGFR), and if therapy improves life-expectancy.

Untreated children with autosomal-recessive AS, digenic AS, and boys with X-linked AS typically all develop kidney failure early in life. Untreated girls with X-linked AS have a 30-40% risk of kidney failure, typically later in life (40 years or older). Untreated heterozygous patients with COL4A3/COL4A4 variants typically have a less severe phenotype (in former times also called "familial benign hematuria" or "thin basement membrane nephropathy" (TBMN)) and a 1-2% risk of kidney failure.

Several interim results of this registry have been published since 2012.

Alport XXL is designed and conducted as strictly observational, non-interventional data acquisition with prospective (and in parts retrospective) data analysis. Young patients with AS in disease stages 0,I,II from all over the world are included. The renewed version from 2021 has been re-approved by the Ethics Committee of the University Medical Center Göttingen as "Alport XXL", a further development of the former European Alport Therapy Registry (AZ 10/11/06). "Alport XXL" registry and data storage are in conformity with Good Clinical Practice guidelines.

ICH-GCP-conform patient information and data exchange is secured by data transfer and cooperation agreements between all international trial centers and the coordinating principal investigator at University Medical Center Goettingen. At baseline, data collection including retrospective data is performed using a standardized, ICH-GCP-conform and pseudonymized questionnaire assessing age, sex, weight, height, mode of inheritance (X-linked, autosomal, compound heterozygous/homozygous, number of missense variants), family history, albumin in 24-hour or spontaneous urine, serum-creatinine, RAS-blockade with preparation and dose. Follow-up visits include same data than baseline plus blood-pressure, smoking-status, serum-potassium, eGFR, hearing loss and eye involvement, other symptoms such as leiomyomatosis, comorbidities and adverse events (adverse events of special interest defined as hyperkalemia, cough, hypotension, acute renal failure, malignancy, death).

Conditions

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

Study Design

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Observational Model Type

COHORT

Study Time Perspective

CROSS_SECTIONAL

Study Groups

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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)

No interventions assigned to this group

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).

ACE-inhibitor

Intervention Type DRUG

observational study

Angiotensin-receptor blocker (ARB)

Intervention Type DRUG

observational study

HMG-Coenzyme inhibitor (statin)

Intervention Type DRUG

observational study

Spironolactone or Finerenone

Intervention Type DRUG

observational study

Paricalcitol

Intervention Type DRUG

observational study!

SGLT2 inhibitor

Intervention Type DRUG

observational study

T-II: early therapy in patients

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

ACE-inhibitor

Intervention Type DRUG

observational study

Angiotensin-receptor blocker (ARB)

Intervention Type DRUG

observational study

HMG-Coenzyme inhibitor (statin)

Intervention Type DRUG

observational study

Spironolactone or Finerenone

Intervention Type DRUG

observational study

Paricalcitol

Intervention Type DRUG

observational study!

SGLT2 inhibitor

Intervention Type DRUG

observational study

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).

ACE-inhibitor

Intervention Type DRUG

observational study

Angiotensin-receptor blocker (ARB)

Intervention Type DRUG

observational study

HMG-Coenzyme inhibitor (statin)

Intervention Type DRUG

observational study

Spironolactone or Finerenone

Intervention Type DRUG

observational study

Paricalcitol

Intervention Type DRUG

observational study!

SGLT2 inhibitor

Intervention Type DRUG

observational study

no therapy in heterozygous patients

heterozygous patients without therapy

No interventions assigned to this group

therapy in heterozygous patients

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

ACE-inhibitor

Intervention Type DRUG

observational study

Angiotensin-receptor blocker (ARB)

Intervention Type DRUG

observational study

HMG-Coenzyme inhibitor (statin)

Intervention Type DRUG

observational study

Spironolactone or Finerenone

Intervention Type DRUG

observational study

Paricalcitol

Intervention Type DRUG

observational study!

SGLT2 inhibitor

Intervention Type DRUG

observational study

Interventions

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ACE-inhibitor

observational study

Intervention Type DRUG

Angiotensin-receptor blocker (ARB)

observational study

Intervention Type DRUG

HMG-Coenzyme inhibitor (statin)

observational study

Intervention Type DRUG

Spironolactone or Finerenone

observational study

Intervention Type DRUG

Paricalcitol

observational study!

Intervention Type DRUG

SGLT2 inhibitor

observational study

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

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).

Exclusion Criteria

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

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Society for Pediatric Nephrology (Germany)

OTHER

Sponsor Role collaborator

University Hospital Goettingen

OTHER

Sponsor Role lead

Responsible Party

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Prof. Dr. O. Gross

Prof. Dr. Oliver Gross

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Oliver Gross, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital Goettingen

Locations

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University Medical Center Göttingen

Göttingen, Lower Saxony, Germany

Site Status RECRUITING

Countries

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Germany

Central Contacts

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Oliver Gross, MD

Role: CONTACT

+49-551-39- ext. 60488

Facility Contacts

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Oliver Gross, MD

Role: primary

+49-551-39- ext. 60488

References

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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.

Reference Type BACKGROUND
PMID: 33159213 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 32386680 (View on PubMed)

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.

Reference Type RESULT
PMID: 22997344 (View on PubMed)

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.

Reference Type RESULT
PMID: 22237748 (View on PubMed)

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.

Reference Type RESULT
PMID: 22166847 (View on PubMed)

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.

Reference Type RESULT
PMID: 27402170 (View on PubMed)

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.

Reference Type RESULT
PMID: 30691124 (View on PubMed)

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.

Reference Type RESULT
PMID: 35022790 (View on PubMed)

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.

Reference Type RESULT
PMID: 33772369 (View on PubMed)

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.

Reference Type RESULT
PMID: 34359984 (View on PubMed)

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.

Reference Type RESULT
PMID: 39698346 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

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Alport-UMG2010

Identifier Type: -

Identifier Source: org_study_id

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