Alport Syndrome Family Conference
Alport Syndrome Registries
Clifford E. Kashtan, M.D.
University of Minnesota
July 22 , 2012
Minneapolis, MN
ASTOR
Alport Syndrome Treatments and Outcomes Registry
Disclosures
•
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.
ASTOR
What is a Patient Registry?
• “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 Healthcare
Research and Quality (US); 2010 Sep.
ASTOR
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.
ASTOR
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.
ASTOR
What are the major barriers to clinical trials
in Alport syndrome?
• Alport syndrome is a rare disorder that causes gradual
loss 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.
ASTOR
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
ASTOR
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
ASTOR
Sustaining a Registry
• Costs
Database set-up and maintenance
Interviews and data entry
Statistical support
Personnel: coordinators, programmer,
biostatistician
• Sources of financing
Individual donors
Foundations
Federal government
Industry -- pharmaceutical, diagnostic services
ASTOR
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
ASTOR
ASTOR Enrollment
ASTOR
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
ASTOR
ASTOR Microalbuminuria Study, 2008 - 2012
Affected males (120)
Eligible (58)
(< 18, no meds, no h/o proteinuria)
Urine kits returned (47)
(3 heme-negative)
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)
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
Stages of Alport Kidney Disease
O
hematuria
I
microalbuminuria
II
proteinuria
TIME
ASTOR
III
reduced
function
IV
ESRD
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
ASTOR
Biomarker Studies and Alport Syndrome
ASTOR
Urine Proteins in Dogs with Alport Syndrome
Alport
Normal
Alport
Normal
Vinge, L. et al. Nephrol. Dial. Transplant. 2010 25:2458-2467; doi:10.1093/ndt/gfq044
ASTOR
Copyright restrictions may apply.
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
ASTOR
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)
ASTOR
Can Early Intervention Delay ESRD in Alport Syndrome?
No intervention
100
Intervention at onset of
proteinuria
Intervention at onset of
microalbuminuria
% ESRD
75
Intervention before onset of
microalbuminuria
50
25
0
10
20
30
40
50
AGE (years)
ASTOR
60
70
Rationale for Targeting Microalbuminuria and
Proteinuria
No intervention
hematuria
microalbuminuria
proteinuria
reduced
function
Intervention?
hematuria
microalbuminuria
TIME
ASTOR
proteinuria
ESRD
Protect Alport Kidneys (PAK) Trial (proposed)
Male > 12 mos of age
Confirmed diagnosis of Alport syndrome
Estimated GFR > 60 ml/min/1.73m2
No past or current treatment with ACEi or ARB
Alb/Cr < 30 mg/g
Normalbuminuria
ramipril
(2.5
Alb/Cr 30 - 200 mg/g
Microalbuminuria
placebo
Prot/Cr > 0.2 mg/mg
Proteinuria
ramipril
mg/m2/day)
(2.5 - 5
mg/m2/day)
spironolactone
(25 mg/day)
ramipril
(2.5 - 5 mg/m2/day)
ASTOR
placebo
ramipril
(2.5 - 5 mg/m2/day)
placebo
Alport Research Collaborative (ARC)
Alport Syndrome Treatments and Outcomes Registry (ASTOR)
U. of Minnesota
Clifford Kashtan
U. of Utah
Martin Gregory
European Alport Registry
U. 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 Heidet
Bertrand Knebelmann
The Hospital for Sick Children
U. of Toronto
Christoph Licht
Peking University First Hospital
Beijing, China
Jie Ding
ASTOR
ARC: Population Resources
Families (approx.)
ASTOR
ASTOR
500
European Alport Registry
400
MARHEA
196
The Hospital for Sick Children
42
Peking University First Hospital
216
Early Pro-Tect Trial
ASTOR
Early Pro-Tect Trial
Eligibility:
Hematuria only
or
Hematuria +
Microalbuminuria
Endpoints:
Time to progression to next disease level
Albuminuria
ASTOR
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
ASTOR