A Study of Intrathecal Enzyme Therapy for Cognitive Decline in MPS I

NCT00852358 | Completed DMC

• 4 other identifiers: MIRC-002IRB Project No. 13270-01IND 104,354U54NS065768
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 3

Brief Summary

This is a 24-month study of the use of laronidase administered into the spinal fluid to treat cognitive decline in mucopolysaccharidosis I (MPS I). MPS I is a rare genetic condition due to deficiency of the enzyme alpha-l-iduronidase. Laronidase is the manufactured form of the enzyme alpha-l-iduronidase. MPS I is a heterogeneous disease with several clinical phenotypes ranging from the most severe, Hurler syndrome, to the attenuated forms, Hurler-Scheie and Scheie. Although patients with milder forms of MPS I may not have grossly observable problems with cognition, these patients do have learning difficulties that are apparent in school and with neuropsychological testing. The goal of this study is to evaluate whether intrathecal recombinant human alpha-l-iduronidase (rhIDU) injections can stabilize or improve cognitive decline in individuals with MPS I.

Conditions

Cognitive Decline; Mucopolysaccharidosis I; Hurler-Scheie Syndrome; Scheie Syndrome; Lysosomal Storage Disease

Keywords

mucopolysaccharidosis; Hurler-Scheie; Scheie; laronidase; cognitive decline; central nervous system; enzyme replacement therapy; intrathecal; LA Biomed

Outcome Measures

Primary Outcomes (1)

• The objective of this study is to assess the ability of intrathecal α-L-iduronidase to be administered safely

  24 months

Secondary Outcomes (1)

• The objective of this study is to assess the ability of intrathecal α-L-iduronidase to stabilize or reverse cognitive decline.

  24 months

Study Arms (2)

intrathecal laronidase

EXPERIMENTAL

The Experimental treatment group will receive study assessments and intrathecal laronidase (1.74 mg laronidase) treatments every 1-3 months beginning at start of study.

Drug: laronidase

Control Group

OTHER

During the first 11 months, the control group will receive study assessments but will be unblinded with no intrathecal treatment or placebo administered. Beginning at month 12, the control group will receive intrathecal laronidase (1.74 mg) treatment every 3 months (months 12, 15, 18, and 21).

Drug: laronidase

Interventions

laronidase DRUG

For the treatment group, intrathecal rhIDU injections will consist of 3 cc of Aldurazyme® (laronidase) (approximately 1.74 mg) diluted with 6 cc of Elliotts B® solution for a total injection of 9 cc. The diluted enzyme will be administered via a lumbar puncture (IT) on day 0 after baseline assessments. IT injections will be repeated on days 30, 60, and 90. The subsequent doses will be administered at 3-month intervals for a total of 10 doses during the two-year period. Control patients will not receive treatment, lumbar puncture, or placebo, but will undergo all other study procedures and assessments during year one. Control patients will then enter a treatment phase consisting of four IT doses at 3-month intervals.

Also known as: Aldurazyme, recombinant human alpha-l-iduronidase

Control Group; intrathecal laronidase

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• The presence of MPS I disease as documented by low α-L-iduronidase activity
• Age six years or older.
• The presence of acquired cognitive deficits as demonstrated by:
• A score of one standard deviation below mean on IQ testing or in one domain of neuropsychological function (language, memory, or non-verbal ability), OR
• Documented historical evidence of a decline of greater than one standard deviation on sequential testing, OR
• A score between 0.75 and 1 standard deviation below the mean, AND the cognitive deficit affects daily performance.
• The decline in function is not explainable by other neurological or psychiatric factors.
• Subject and/or guardian willing and able to provide written informed consent.
• Negative urine pregnancy test at screening (non-sterile females of child-bearing potential only)
• Currently using two acceptable methods of birth control as determined by the investigator and willing to continue to use acceptable birth control during their participation in the study (non-sterile females of child-bearing potential who are sexually active only)
• Willing and able to comply with study procedures. For example, the subjects must be able to complete written and computer-based testing. The subjects must be able to lie still in the MRI scanner for at least 40 minutes without sedation.

You may not qualify if:

• The subject has undergone hematopoietic stem cell transplantation
• Recent initiation of intravenous Aldurazyme® therapy with less than 6 months of therapy. Subjects who have been receiving Aldurazyme® therapy for more than 6 months, and those who have never received Aldurazyme® therapy, will be allowed to enroll
• Pregnant or lactating, or considering pregnancy
• Receipt of an investigational drug or procedure within 30 days of enrollment
• A condition, medical or other, that prevents participation in the study, including severe auditory or visual impairment, significant lumbar pathology, lumbar catheter, or recent major surgery within 6 weeks that would preclude their ability to participate.
• Infusion reactions to intravenous Aldurazyme® therapy that require ongoing medical intervention, special prophylaxis or altered rate or dose of enzyme administration
• The subject has a programmable VP shunt that is incompatible with the 3 Tesla MRI magnet and is unable or unwilling to undergo shunt revision to a MRI compatible device.
• The subject has another contraindication for MRI, such as nonremovable metal in the body.
• The subject has severely impaired spinal CSF flow, demonstrated by failure of appearance of 99mTechnetium-DTPA in the basal cisterns by 4 hours after intra-lumbar administration.

Sponsors & Collaborators

• Patricia I. Dickson, M.D.: lead
• The Ryan Foundation: collaborator
• BioMarin Pharmaceutical: collaborator
• Rare Diseases Clinical Research Network: collaborator
• National Center for Advancing Translational Sciences (NCATS): collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• University of Minnesota: collaborator
• University of California, Los Angeles: collaborator

Study Sites (3)

Children's Hospital & Research Center Oakland

Oakland, California, 94609-1809, United States

Location

Los Angeles Biomedical Institute at Harbor-UCLA

Torrance, California, 90502, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

Cognitive Dysfunction; Mucopolysaccharidosis I; Lysosomal Storage Diseases; Mucopolysaccharidoses

Interventions

Iduronidase

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Glycoside Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes

Study Officials

• Agnes Chen, MD

  Los Angeles Biomedical Institute at Harbor-UCLA

  PRINCIPAL INVESTIGATOR

• Patricia I Dickson, MD

  Los Angeles Biomedical Institute at Harbor-UCLA

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDIV
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: February 25, 2009
• First Posted: February 27, 2009
• Study Start: June 1, 2009
• Primary Completion: April 1, 2015
• Study Completion: April 1, 2015
• Last Updated: January 26, 2016

Record last verified: 2016-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)