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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


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.


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 HealthcareResearch and Quality (US); 2010 Sep.


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.


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.


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.


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


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


Sustaining a Registry

• CostsDatabase set-up and maintenanceInterviews and data entryStatistical supportPersonnel: coordinators, programmer,

biostatistician• Sources of financing

Individual donorsFoundationsFederal governmentIndustry -- pharmaceutical, diagnostic services


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 Enrollment



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


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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


Stages of Alport Kidney Disease


TIME

O I II III IV

hematuria microalbuminuriaproteinuria

reducedfunction

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



Biomarker Studies and Alport Syndrome


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


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



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)



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


Rationale for Targeting Microalbuminuria and Proteinuria


TIME


No intervention

Intervention?


reducedfunction

ESRD


Protect Alport Kidneys (PAK) Trial (proposed)


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)


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


ARC: Population Resources

Families (approx.)

ASTOR 500

European Alport Registry 400

MARHEA 196

The Hospital for Sick Children 42

Peking University First Hospital 216


Early Pro-Tect Trial



Early Pro-Tect Trial


Eligibility:Hematuria onlyorHematuria + Microalbuminuria

Endpoints:Time to progression to next disease levelAlbuminuria


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

astorastor alport syndrome treatments and outcomes registry alport syndrome family conference alport...

Documents

alport syndrome foundation

human alport syndrome

alport kidney disease

mn slide

clinical trials

low cost slide

patient registry

new trials