European Alport Therapy Registry - European Initiative Towards Delaying Renal Failure in Alport Syndrome: Current and Novel Therapies
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Sponsor
- Enrollment
- 800
- Locations
- 1
- Primary Endpoint
- age at onset of end stage kidney failure (need for renal replacement therapy)
Study Overview
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.
Detailed Description
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.
Study Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Cross Sectional
Eligibility Criteria
- Sex
- All
- Accepts Healthy Volunteers
- Yes
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.
Exclusion Criteria
- Not provided
Arms & Interventions
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).
Intervention: SGLT2 inhibitor (Drug)
T-II: early therapy in patients
therapy starts in patients with albuminuria >300mg/gCreatinine and eGFR higher than 60 ml/min.
Intervention: ACE-inhibitor (Drug)
T-II: early therapy in patients
therapy starts in patients with albuminuria >300mg/gCreatinine and eGFR higher than 60 ml/min.
Intervention: Angiotensin-receptor blocker (ARB) (Drug)
T-II: early therapy in patients
therapy starts in patients with albuminuria >300mg/gCreatinine and eGFR higher than 60 ml/min.
Intervention: HMG-Coenzyme inhibitor (statin) (Drug)
T-II: early therapy in patients
therapy starts in patients with albuminuria >300mg/gCreatinine and eGFR higher than 60 ml/min.
Intervention: Spironolactone or Finerenone (Drug)
T-II: early therapy in patients
therapy starts in patients with albuminuria >300mg/gCreatinine and eGFR higher than 60 ml/min.
Intervention: Paricalcitol (Drug)
T-II: early therapy in patients
therapy starts in patients with albuminuria >300mg/gCreatinine and eGFR higher than 60 ml/min.
Intervention: SGLT2 inhibitor (Drug)
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).
Intervention: ACE-inhibitor (Drug)
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).
Intervention: Angiotensin-receptor blocker (ARB) (Drug)
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).
Intervention: ACE-inhibitor (Drug)
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).
Intervention: Angiotensin-receptor blocker (ARB) (Drug)
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).
Intervention: HMG-Coenzyme inhibitor (statin) (Drug)
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).
Intervention: Spironolactone or Finerenone (Drug)
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).
Intervention: Paricalcitol (Drug)
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).
Intervention: HMG-Coenzyme inhibitor (statin) (Drug)
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).
Intervention: Spironolactone or Finerenone (Drug)
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).
Intervention: Paricalcitol (Drug)
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).
Intervention: SGLT2 inhibitor (Drug)
therapy in heterozygous patients
heterozygous patients with therapy (which also can be divided into subgroups stage T-0, I, II, III)
Intervention: ACE-inhibitor (Drug)
therapy in heterozygous patients
heterozygous patients with therapy (which also can be divided into subgroups stage T-0, I, II, III)
Intervention: Angiotensin-receptor blocker (ARB) (Drug)
therapy in heterozygous patients
heterozygous patients with therapy (which also can be divided into subgroups stage T-0, I, II, III)
Intervention: HMG-Coenzyme inhibitor (statin) (Drug)
therapy in heterozygous patients
heterozygous patients with therapy (which also can be divided into subgroups stage T-0, I, II, III)
Intervention: Spironolactone or Finerenone (Drug)
therapy in heterozygous patients
heterozygous patients with therapy (which also can be divided into subgroups stage T-0, I, II, III)
Intervention: Paricalcitol (Drug)
therapy in heterozygous patients
heterozygous patients with therapy (which also can be divided into subgroups stage T-0, I, II, III)
Intervention: SGLT2 inhibitor (Drug)
Outcomes
Primary Outcomes
age at onset of end stage kidney failure (need for renal replacement therapy)
Time Frame: until end of observation in 2037
kidney disease in Alport syndrome starts at birth, age at onset of end stage kidney failure in years
life-expectancy in years (age at death)
Time Frame: until end of observation in 2037
Alport syndrome starts at birth, age at death of patients in years
yearly loss of estimated glomerular filtration rate (eGFR)
Time Frame: until end of observation in 2037
kidney disease in Alport syndrome starts at birth, eGFR-loss per year in ml/min/1.73m2
time in years until doubling or tripling of urinary albumin to creatinine ratio (UACR)
Time Frame: until end of observation in 2037
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.
Secondary Outcomes
- 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)
- number of patients with eye involvement(until end of observation in 2037)
- number of patients with positive family history of end stage kidney failure(until end of observation in 2037)
- age of relatives at end stage kidney failure(until end of observation in 2037)
Investigators
Prof. Dr. O. Gross
Prof. Dr. Oliver Gross
University Hospital Goettingen