ASTORASTOR Alport Syndrome Treatments and Outcomes Registry Alport Syndrome Family Conference Alport...
-
Upload
augustus-mcdonald -
Category
Documents
-
view
227 -
download
2
Transcript of ASTORASTOR Alport Syndrome Treatments and Outcomes Registry Alport Syndrome Family Conference Alport...
ASTORASTORASTORASTOR
Alport Syndrome Treatments and Outcomes Registry
Alport Syndrome Family Conference
Alport Syndrome Registries
Clifford E. Kashtan, M.D.University of Minnesota
July 22 , 2012
Minneapolis, MN
ASTORASTORASTORASTOR
Disclosures
ASTORASTORASTORASTOR
• I have received reimbursement of travel expenses and honoraria from Athena Diagnostics, one of several commercial laboratories offering molecular genetic testing for Alport syndrome. I am not a paid consultant for Athena and neither my family nor I has any financial interest in the company.
• The Alport Syndrome Treatments and Outcomes Registry (ASTOR) is supported by private philanthropy, the Alport Syndrome Foundation, federal funding and is engaged in research supported by the Novartis Institute for Biomedical Research.
ASTORASTORASTORASTOR
What is a Patient Registry?
ASTORASTORASTORASTOR
• “an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition or exposure”
• “The registry is designed to fulfill specific purposes, and these purposes are defined before collecting and analyzing the data.”
Registries for Evaluating Patient Outcomes: A User’s Guide. 2nd edition.Gliklich RE, Dreyer NA, editors. Rockville (MD): Agency for HealthcareResearch and Quality (US); 2010 Sep.
ASTORASTORASTORASTOR
The Purpose of Alport Syndrome Registries
The purpose of Alport syndrome registries is to enable the development of safe, affordable and effective therapies for Alport syndrome by testing treatments that have shown promise in animal studies.
ASTORASTORASTORASTOR
Why are clinical trials in Alport Syndrome needed?
• Alport syndrome leads to kidney failure in all affected males and many affected females. Besides kidney transplantation, there is no proven treatment for Alport kidney disease.
• Several therapies have shown promise in animal studies.
• These possible therapies are associated with very different potential adverse effects and costs.
• ACE inhibition has shown promise in studies of animals with Alport syndrome. This therapy is widely used in human Alport syndrome but its efficacy has not been tested in humans. Conventional timing of therapy may prevent maximal benefit.
ASTORASTORASTORASTOR
What are the major barriers to clinical trials in Alport syndrome?
• Alport syndrome is a rare disorder that causes gradualloss of kidney function, creating challenges for
- Recruitment of subjects- Funding to initiate and sustain trials
• Mechanisms of rapidly identifying potential trial participants have been lacking, until recently.
ASTORASTORASTORASTOR
How can registries support clinical trials?
• Feasibility• Is the pool of potential participants large enough?• Stored biological samples can be used to evaluate
a potential therapeutic pathway
• Recruitment – • Rapid identification of eligible individuals• Stored contact information• Information about new trials can be widely
distributed at low cost
ASTORASTORASTORASTOR
What else can registries do?
• Provide better data about a known aspect of the disease• Corneal erosions• Aortic disease
• Discover previously unknown problems
• Publicize new findings
ASTORASTORASTORASTOR
Sustaining a Registry
• CostsDatabase set-up and maintenanceInterviews and data entryStatistical supportPersonnel: coordinators, programmer,
biostatistician• Sources of financing
Individual donorsFoundationsFederal governmentIndustry -- pharmaceutical, diagnostic services
ASTORASTORASTORASTOR
Alport Syndrome Treatments and Outcomes Registry(ASTOR)
• ASTOR is a cooperative effort of the U. of Minnesota and the U. of Utah to create an electronic database of all Alport families in North America
• ASTOR’s goals are to perform studies of early markers of disease progression and to work with registries in Europe and elsewhere to test promising therapies for Alport syndrome– Study 1: A Prospective Study of Microalbuminuria in Untreated Boys
with Alport Syndrome (2008-12)– Study 2: Urinary Biomarkers of Alport Kidney Disease Progression
(2012-13)
• Over 400 families have enrolled since ASTOR went live in September, 2007
ASTORASTORASTORASTOR
ASTORASTORASTORASTOR
ASTOR Enrollment
ASTORASTORASTORASTOR
ASTORASTORASTORASTOR
A Prospective Study of Microalbuminuria in Untreated Boys with Alport Syndrome
• Objectives– To determine mean ages of onset of microalbuminuria and overt
proteinuria– To determine mean duration of microalbuminuria before
transition to overt proteinuria
• Inclusion criteria– Diagnosis of Alport syndrome– Male gender– Absence of overt proteinuria (urine protein:creatinine ratio < 0.2
mg/mg)– No past or current treatment with angiotensin antagonists
ASTORASTORASTORASTOR
ASTORASTORASTORASTORASTORASTORASTORASTOR
Affected males (120)
Eligible (58)(< 18, no meds, no h/o proteinuria)
Ineligible (62)> 18 (N = 14; mean age 35 yrs)on meds (N = 33; mean age 9.2 yrs)> 18 + meds (N = 15; mean age 32 yrs)Urine kits returned (47)
(3 heme-negative)
Normal urine albumin (24) Mean age 8 yrs
Microalbuminuria (13)Mean age 7 yrs
Proteinuria (7)Mean age 10 yrs
Normal urine albumin (20)Microalbuminuria (2)Proteinuria (2)
Microalbuminuria (10)Proteinuria (5)
Proteinuria (14)
ASTOR Microalbuminuria Study, 2008 - 2012
ASTORASTORASTORASTOR
Stages of Alport Kidney Disease
ASTORASTORASTORASTOR
TIME
O I II III IV
hematuria microalbuminuriaproteinuria
reducedfunction
ESRD
ASTORASTORASTORASTOR
Biomarker Studies and Alport Syndrome
• The ultimate goal of treatment of Alport syndrome is to prevent scarring of the kidneys (renal fibrosis)
• “Hard” markers of renal fibrosis:– Quantitative measurement of renal fibrosis– requires
kidney biopsies– Reduced kidney function – takes too long to
develop
• We need “surrogate” markers of renal fibrosis that are reliable and easily measured
ASTORASTORASTORASTOR
ASTORASTORASTORASTOR
Biomarker Studies and Alport Syndrome
ASTORASTORASTORASTOR
ASTORASTORASTORASTORCopyright restrictions may apply.
Vinge, L. et al. Nephrol. Dial. Transplant. 2010 25:2458-2467; doi:10.1093/ndt/gfq044
Urine Proteins in Dogs with Alport Syndrome
Alport Normal Alport Normal
ASTORASTORASTORASTOR
Urinary Biomarkers of Alport Kidney Disease Progression
• Objective– To identify biomarkers of renal tubular injury and renal
fibrosis in urine of people with Alport syndrome
• Inclusion criteria– Diagnosis of Alport syndrome– Glomerular filtration rate above 60 ml/min/1.73m2
• Enrollment target: 100
ASTORASTORASTORASTOR
ASTORASTORASTORASTOR
Multicenter Controlled Clinical Trials in Alport Syndrome:A Feasibility Study
• Goal: to demonstrate that five Alport syndrome research centers have access to sufficient numbers of children and adolescents with Alport syndrome to populate a clinical trial aimed at delaying development of microalbuminuria and proteinuria by very early intervention
• Supported by the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK)
ASTORASTORASTORASTOR
ASTORASTORASTORASTOR
Can Early Intervention Delay ESRD in Alport Syndrome?
0 10 20 30 40 50 60 70
AGE (years)
% E
SR
D
25
50
75
100No intervention
Intervention at onset of proteinuria
Intervention at onset ofmicroalbuminuria
Intervention before onset of microalbuminuria
ASTORASTORASTORASTOR
Rationale for Targeting Microalbuminuria and Proteinuria
ASTORASTORASTORASTOR
TIME
hematuria microalbuminuriaproteinuria
No intervention
Intervention?
hematuria microalbuminuriaproteinuria
reducedfunction
ESRD
ASTORASTORASTORASTOR
Protect Alport Kidneys (PAK) Trial (proposed)
ASTORASTORASTORASTOR
Male > 12 mos of ageConfirmed diagnosis of Alport syndromeEstimated GFR > 60 ml/min/1.73m2
No past or current treatment with ACEi or ARB
Alb/Cr 30 - 200 mg/gMicroalbuminuria
Alb/Cr < 30 mg/gNormalbuminuria
Prot/Cr > 0.2 mg/mgProteinuria
ramipril(2.5 mg/m2/day)
placebo
ramipril(2.5 - 5 mg/m2/day)
placebo
ramipril(2.5 - 5 mg/m2/day)
placebo
ramipril(2.5 - 5 mg/m2/day) spironolactone
(25 mg/day)
ASTORASTORASTORASTOR
Alport Research Collaborative (ARC)Alport Syndrome Treatments and Outcomes Registry (ASTOR)
U. of Minnesota Clifford KashtanU. of Utah Martin Gregory
European Alport RegistryU. of Goettingen Oliver Gross
Centre de References des Malades Renales Hereditaires de l’Enfant et de l’Adult (MARHEA)
Hopital Necker - Enfants Malades (Paris) Laurence HeidetBertrand Knebelmann
The Hospital for Sick ChildrenU. of Toronto Christoph Licht
Peking University First HospitalBeijing, China Jie Ding
ASTORASTORASTORASTOR
ARC: Population Resources
Families (approx.)
ASTOR 500
European Alport Registry 400
MARHEA 196
The Hospital for Sick Children 42
Peking University First Hospital 216
ASTORASTORASTORASTOR
Early Pro-Tect Trial
ASTORASTORASTORASTOR
ASTORASTORASTORASTOR
Early Pro-Tect Trial
ASTORASTORASTORASTOR
Eligibility:Hematuria onlyorHematuria + Microalbuminuria
Endpoints:Time to progression to next disease levelAlbuminuria
ASTORASTORASTORASTOR
Optimal treatment for Alport kidney disease
• Effective -- treatment would delay ESRD by years
• Safe -- low incidence of side effects that are predictable, mild and reversible
• Inexpensive and available• beyond patent protection• market is larger than Alport population• easy to manufacture• easy to ship
• May involve combination therapy – angiotensin antagonist + anti-fibrotic agent