Determination of CRIM Status and Longitudinal Follow-up of Individuals With Pompe Disease

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ClinicalTrials.gov Identifier: NCT01665326

Recruitment Status : Recruiting

First Posted : August 15, 2012

Last Update Posted : July 14, 2017

See Contacts and Locations

Sponsor:

Collaborators:

Rare Diseases Clinical Research Network

National Center for Advancing Translational Science (NCATS)

National Institute of Neurological Disorders and Stroke (NINDS)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Information provided by (Responsible Party):

Duke University

Study Description

Brief Summary:

This is a longitudinal natural history study of Infantile Pompe disease. The investigators will regularly collect and review medical information for up to 10 years regarding the diagnosis of Pompe disease, response to enzyme replacement (ERT) using alglucosidase alfa (Myozyme) and response to immunosuppressive therapy in cases at risk for developing or those who have developed high and sustained antibodies to ERT. A subset of de-identified information about the natural history of Pompe disease and the response to treatment will be incorporated into the Lysosomal Disease Network (LDN) disease registry. The LDN is a nonprofit organization of scientists located around the world whose research focuses on Lysosomal disease.

The specific aims of this study are:

To determine and correlate Cross-Reactive Immunological Material (CRIM) status with the GAA gene mutations found on these patients
To validate an approach for determining CRIM status from whole blood sample, with the gold standard determination of CRIM status by skin fibroblasts and mutation analysis
To explore the clinical treatment response and natural history of CRIM-positive and CRIM-negative Pompe disease patients with and without immune modulation
To investigate the role of immune response to treatment

Condition or disease	Intervention/treatment
Pompe Disease	Other: Observational

Detailed Description:

Infantile-onset Pompe disease is an inherited disorder caused by lack of or defect in the enzyme acid alpha-glucosidase (GAA). GAA enzyme deficiency causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles, which is normally diagnosed within the first months of life. Current treatment for Pompe disease involves enzyme replacement therapy (ERT) using the drug alglucosidase alfa (Myozyme), which provides a form of the GAA enzyme to replace the enzyme that is missing or not working properly in the patient's blood.

In this study, the investigators will learn about the patient's ability to tolerate ERT. Cross-Reactive Immunological Material (CRIM) is a measurement of natural GAA production and an important factor that affects how patients respond to ERT with Myozyme. Children who produce some natural GAA are classified as CRIM positive (+), while children who do not produce any natural GAA are classified as CRIM negative (-). Children who are CRIM+ generally tolerate ERT well. But, children who are CRIM-, and some children classified as CRIM+, have a poor response to ERT due to complications from an immune response against the drug. Treatments are currently being developed to stop this immune response and prevent complications from ERT.

The specific aims of this study are:

To determine and correlate Cross-Reactive Immunological Material (CRIM) status with the GAA gene mutations found on these patients
To validate an approach for determining CRIM status from whole blood sample, with the gold standard determination of CRIM status by skin fibroblasts and mutation analysis
To explore the clinical treatment response and natural history of CRIM-positive and CRIM-negative Pompe disease patients with and without immune modulation
To investigate the role of immune response to treatment

Study Design


Study Type :	Observational
Estimated Enrollment :	300 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Official Title:	Determination of Cross-Reactive Immunological Material (CRIM) Status and Longitudinal Follow-up of Individuals With Pompe Disease
Study Start Date :	September 2009
Estimated Primary Completion Date :	August 2019
Estimated Study Completion Date :	August 2019

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Pompe disease Glycogen storage disease type IX

Genetic and Rare Diseases Information Center resources: Glycogen Storage Disease Type 2

U.S. FDA Resources

Groups and Cohorts

Group/Cohort	Intervention/treatment
Infantile Pompe disease Individuals with a confirmed diagnosis of Infantile Pompe disease	Other: Observational This is a longitudinal study focused on the emerging natural history of Infantile Pompe disease, response to ERT using alglucosidase alfa (Myozyme) and response to Immune Tolerance Induction (ITI).

Outcome Measures

Primary Outcome Measures :

Clinical response to enzyme replacement therapy (ERT) using alglucosidase alfa (Myozyme) [ Time Frame: Up to 10 years ]
Medical records will be tracked for up to 10 years to follow clinical response to ERT. This will allow us to gain an understanding of CRIM status in relation to clinical outcome and development for these subjects.

Secondary Outcome Measures :

Response to Immune Tolerance Induction (ITI) [ Time Frame: Up to 10 years ]
Medical records will be tracked for up to 10 years to follow clinical response to Immune Tolerance Induction (ITI) for patients who are CRIM- or CRIM+ with high antibody titers. This will allow us to increase our understanding of the history of Pompe disease in relation to treatment interventions and the role of high antibody titers in terms of patient outcome in order to develop strategies to ameliorate the immune response and other factors that may affect response to ERT.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	up to 18 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Study subjects will be babies/children with a confirmed diagnosis of infantile-onset Pompe disease who are:

seen by the clinical staff of Duke Division of Medical Genetics, or
whose physician or parent contacts the Duke Division of Medical Genetics with the wish to participate in this CRIM research study.

Criteria

Inclusion Criteria:

Confirmed diagnosis of infantile, atypical or juvenile onset Pompe disease
Must have a parent or guardian provide written informed consent

Exclusion Criteria:

Age 18 or older

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01665326

Contacts


Contact: Ankit K Desai, MBBS	919-613-6310	ankit.desai@duke.edu
Contact: Stephanie DeArmey, MHS, PA-C	919-681-1946	Stephanie.Dearmey@duke.edu

Locations


United States, North Carolina
Duke University Medical Center	Recruiting
Durham, North Carolina, United States, 27710
Contact: Ankit K Desai, MBBS 919-613-6310 ankit.desai@duke.edu
Contact: Stephanie DeArmey, MHS, PA-C 919-681-1946 Stephanie.Dearmey@duke.edu
Principal Investigator: Priya S Kishnani, MD

Sponsors and Collaborators

Duke University

Rare Diseases Clinical Research Network

National Center for Advancing Translational Science (NCATS)

National Institute of Neurological Disorders and Stroke (NINDS)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators


Principal Investigator:	Priya S Kishnani, MD	Duke University

More Information

Publications of Results:

Banugaria SG, Prater SN, Ng YK, Kobori JA, Finkel RS, Ladda RL, Chen YT, Rosenberg AS, Kishnani PS. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med. 2011 Aug;13(8):729-36. doi: 10.1097/GIM.0b013e3182174703.

Messinger YH, Mendelsohn NJ, Rhead W, Dimmock D, Hershkovitz E, Champion M, Jones SA, Olson R, White A, Wells C, Bali D, Case LE, Young SP, Rosenberg AS, Kishnani PS. Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease. Genet Med. 2012 Jan;14(1):135-42. doi: 10.1038/gim.2011.4.

Mendelsohn NJ, Messinger YH, Rosenberg AS, Kishnani PS. Elimination of antibodies to recombinant enzyme in Pompe's disease. N Engl J Med. 2009 Jan 8;360(2):194-5. doi: 10.1056/NEJMc0806809.

Berrier KL, Kazi ZB, Prater SN, Bali DS, Goldstein J, Stefanescu MC, Rehder CW, Botha EG, Ellaway C, Bhattacharya K, Tylki-Szymanska A, Karabul N, Rosenberg AS, Kishnani PS. CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. Genet Med. 2015 Nov;17(11):912-8. doi: 10.1038/gim.2015.6. Epub 2015 Mar 5. Erratum in: Genet Med. 2015 Jul;17(7):596. Rosenburg, Amy S [corrected to Rosenberg, Amy S].

Banugaria SG, Prater SN, Patel TT, Dearmey SM, Milleson C, Sheets KB, Bali DS, Rehder CW, Raiman JA, Wang RA, Labarthe F, Charrow J, Harmatz P, Chakraborty P, Rosenberg AS, Kishnani PS. Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT. PLoS One. 2013 Jun 25;8(6):e67052. doi: 10.1371/journal.pone.0067052. Print 2013.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kazi ZB, Desai AK, Berrier KL, Troxler RB, Wang RY, Abdul-Rahman OA, Tanpaiboon P, Mendelsohn NJ, Herskovitz E, Kronn D, Inbar-Feigenberg M, Ward-Melver C, Polan M, Gupta P, Rosenberg AS, Kishnani PS. Sustained immune tolerance induction in enzyme replacement therapy-treated CRIM-negative patients with infantile Pompe disease. JCI Insight. 2017 Aug 17;2(16). pii: 94328. doi: 10.1172/jci.insight.94328. [Epub ahead of print]


Responsible Party:	Duke University
ClinicalTrials.gov Identifier:	NCT01665326 History of Changes
Other Study ID Numbers:	Pro00001562 U54NS065768 ( U.S. NIH Grant/Contract )
First Posted:	August 15, 2012 Key Record Dates
Last Update Posted:	July 14, 2017
Last Verified:	July 2017

Keywords provided by Duke University:


Pompe disease Glycogen Storage Disease Type II Acid Maltase Deficiency CRIM Status Acid Alpha-Glucosidase Deficiency	Alglucosidase alfa Myozyme Enzyme replacement therapy Immune Tolerance Induction

Additional relevant MeSH terms:


Glycogen Storage Disease Type II Lysosomal Storage Diseases, Nervous System Brain Diseases, Metabolic, Inborn Brain Diseases, Metabolic Brain Diseases Central Nervous System Diseases Nervous System Diseases	Metabolism, Inborn Errors Genetic Diseases, Inborn Glycogen Storage Disease Carbohydrate Metabolism, Inborn Errors Lysosomal Storage Diseases Metabolic Diseases

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