An Exploratory Study of the Safety and Efficacy of Prophylactic Immunomodulatory Treatment in Myozyme-naive Cross-Reacting Immunologic Material (CRIM[-]) Patients With Infantile-Onset Pompe Disease

• ClinicalTrials.gov Identifier: NCT00701129
• Recruitment Status: Completed
• First Posted: June 19, 2008
• Results First Posted: May 13, 2014
• Last Update Posted: May 13, 2014
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Study Description

Brief Summary:

The purpose of this study was to evaluate the efficacy, clinical benefits and safety of a prophylactic immunomodulatory regimen given prior to first treatment with alglucosidase alfa (Myozyme®) in patients with infantile-onset Pompe disease.

The objectives were to assess the efficacy of a prophylactic immunomodulatory regimen given prior to first treatment with alglucosidase alfa, as assessed by anti-recombinant human acid alpha-glucosidase (anti-rhGAA) antibody titers, and antibodies that inhibit the activity and/or uptake of alglucosidase alfa; to evaluate the clinical benefit as measured by overall survival, ventilator-free survival, left ventricular mass index (LVMI), gross motor function and development, disability index and the incidence of adverse events (AEs), serious adverse events (SAEs), and clinical laboratory abnormalities.

Condition or disease	Intervention/treatment	Phase
Pompe Disease; Glycogen Storage Disease Type II	Biological: Alglucosidase Alfa; Drug: Methotrexate; Drug: Rituximab	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Exploratory Study of the Safety and Efficacy of Prophylactic Immunomodulatory Treatment in Myozyme®-Naive, CRIM(-) Patients With Infantile-onset Pompe Disease
• Study Start Date: October 2009
• Actual Primary Completion Date: March 2013
• Actual Study Completion Date: March 2013

Arms and Interventions

Arm

Intervention/treatment

Experimental: Alglucosidase Alfa; Alglucosidase alfa (Myozyme®) 20 milligrams per kilogram (mg/kg) intravenous (IV) infusion every other week (qow) (or optionally 20 mg/kg IV infusion every week [qw]) beginning from Day 0 to a minimum of 18 months or if the patient was less than (<) 6 months of age at the time of enrollment, until the patient was 2 years of age, along with methotrexate 0.4 mg/kg subcutaneously for 3 consecutive days qow beginning from Day 0 to Week 6 (9 doses) and rituximab 375 milligrams per square meter (mg/m^2) (or 12.5 mg/kg for patients with body surface area less than or equal to 0.5 m^2) IV infusion qw beginning from Day -1 to Week 4 (4 doses) as per local prescribing information. An additional 4-week cycle of rituximab (up to 4 additional doses) and 6-week cycle of methotrexate (up to 9 additional doses) may have been administered within the first 6 months of the study as per local prescribing information.

Biological: Alglucosidase Alfa; Administered as IV infusion.; Other Name: Myozyme®; Drug: Methotrexate; Administered subcutaneously.; Drug: Rituximab; Administered as IV infusion.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Number of Patients With Anti-Recombinant Human Acid Alfa-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibody at End of Study [ Time Frame: Baseline, End of Study (up to Week 79 or early termination) ]
   Serum samples from patients were analyzed for the presence of anti-rhGAA IgG antibodies. End of study (EOS) refers to the last post baseline observation during study period (up to Week 79).
2. Number of Patients With Recombinant Human Acid Alfa-glucosidase (rhGAA) Inhibitory Antibody at End of Study [ Time Frame: End of study (up to Week 79) ]
   Patients with positive anti-rhGAA IgG antibody were assessed for the presence of inhibitory antibodies (inhibition of enzyme activity and inhibition of enzyme uptake). Enzyme-linked immunosorbent assay (ELISA) was used to measure inhibition of rhGAA enzymatic activity in vitro and a cell-based assay was used to measure the inhibition of the uptake of rhGAA in normal fibroblast cells by flow cytometry.
3. Number of Patients Who Survived at End of Study [ Time Frame: Baseline up to End of study (Week 79) ]
4. Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index at End of Study [ Time Frame: End of study (up to Week 79 or early termination) ]
   LVM Z-score and LVM index were assessed by ECHO. LVM Z-Score provides an indicator of degree of standard deviations from the mean in a normal distribution. Negative values indicate a smaller LVM than mean and values higher than 0 indicate a larger LVM than the mean. The normal range for LVM Z-Score is -2 to 2. Values <-2 or >2 indicate abnormal LVM Z-Score. LVM index is an index value derived by normalizing LVM by body surface area. LVM index provides evidence of cardiomyopathy. LVM index values <65 gram per meter^2 (g/m^2) were considered as normal and LVM index values >=65 g/m^2 were considered as abnormal. End of study refers to the last post baseline observation during study period (up to Week 79).
5. Number of Patients With Ventilator Use at End of Study [ Time Frame: End of study (up to Week 79 or early termination) ]
   Number of patients who had ventilator support at end of study was reported. End of study refers to the last post baseline observation during study period (up to Week 79).
6. Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) at End of Study [ Time Frame: End of study (up to Week 79 or early termination) ]
   GMFM-88 is an 88-item measure to detect gross motor function. It consists of 5 categories: lying and rolling; sitting; crawling and kneeling; standing; walking, running and jumping. Each item is scored on a 4-point Likert scale (0 = cannot do; 1 = initiates [<10% of the task]; 2 = partially completes [10% to <100% of the task]; 3 = task completion). The score for each dimension is expressed as a percentage of the maximum score for that dimension. Total score is obtained by adding the percentage scores for each dimension and dividing the sum by the total number of dimensions. Total score ranges from 0% to 100%, where higher scores indicate better motor functions. A total score of <7.5% demonstrates gross motor disability. End of study refers to the last post baseline observation during study period (up to Week 79).
7. Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) at End of Study [ Time Frame: End of study (up to Week 79 or early termination) ]
   AIMS is a 58-item reliable and valid measure of motor development for infants at risk for motor delay. It assesses infant movement in 4 positions (subscales): prone (reciprocal crawling); supine (moving hands to feet); sitting (sitting with arm support); and standing (pulls to stand). For each subscale, items were scored as "observed" or "not observed". Item in the observed range create a motor window. When scoring, subscale scores are calculated by giving the child credit (1 point) for observed items within the motor window in addition to being given credit (1 point) for all of the less mature items before motor window. AIMS total score was calculated by summing the scores for 58 items and ranged from 0 to 58, with higher score indicating more mature motor development. Score was then compared with age-equivalent peers from normative sample and equivalence level age (in months) is reported. End of study refers to the last post baseline observation during study period (up to Week 79).
8. Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study [ Time Frame: End of study (up to Week 79 or early termination) ]
   The Pompe PEDI is a disease specific version of the PEDI that was developed to assess functional capabilities and performance in children with Pompe disease from 2 months through adolescence. It consists of all items of the original PEDI (197 functional skill items in 3 domains: self-care; mobility; and social function) and additional items in the functional skills, mobility, and self-care domains to reflect clinically relevant functional skills for children with Pompe disease. Each domain consisted of 2 subdomains: functional skill performance and caregiver assistance scale. Norm-based scoring was developed for these additional items, and scoring algorithms for the PEDI have been adjusted to reflect additional normative data collected for the Pompe PEDI. Total score range for each domain (mean of subdomains) and subdomain ranges from 0 to 100, where higher score indicates high capability. End of study refers to the last post baseline observation during study period (up to Week 79).

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• The patient's legal guardian(s) must have provided written informed consent prior to any study-related procedures being performed
• The patient must have had a clinical diagnosis of Pompe disease as defined by documented acid alpha-glucosidase (GAA) deficiency (deficient endogenous GAA activity) in skin fibroblasts, muscle, or blood, or 2 GAA mutations. Consent was also sought from the biological parent(s) for parental GAA mutational analysis, but was not a requirement for study eligibility
• The patient must have not received Myozyme® or any rhGAA therapies prior to enrollment in the study
• The patient must be CRIM negative via Western Blot analysis performed on skin fibroblasts or via 2 known CRIM negative mutations (in which case CRIM status was to be confirmed by Western Blot analysis after enrollment)
• The patient's legal guardian(s) must have the ability to comply with the clinical protocol

Exclusion Criteria:

• The patient had any medical condition that, in the opinion of the Investigator, could be exacerbated/precipitated by or interfere with the study regimen or assessments; such conditions may include but were not limited to human immunodeficiency virus, cancer, Hepatitis B, Hepatitis C, Cytomegalovirus, Herpes Simplex, John Cunningham (JC) virus, Parvovirus, or Epstein Barr virus or tuberculosis
• The patient had used any investigational product within 30 days prior to study enrollment
• The patient had or was required to have any live vaccination within 1 month prior to enrollment

Contacts and Locations

Locations

United States, Kentucky

Kosair Children's Hospital

Louisville, Kentucky, United States, 40202

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Genzyme, a Sanofi Company

Investigators

• Study Director: Medical Monitor; Genzyme Coorporation

More Information

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00701129
• Other Study ID Numbers: AGLU03807; MSC12862 ( Other Identifier: Sanofi )
• First Posted: June 19, 2008
• Results First Posted: May 13, 2014
• Last Update Posted: May 13, 2014
• Last Verified: April 2014

Keywords provided by Sanofi ( Genzyme, a Sanofi Company ):

Glycogenesis 2; Acid; Maltase; Deficiency

Additional relevant MeSH terms:

Glycogen Storage Disease Type II; Glycogen Storage Disease; 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; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Rituximab; Methotrexate; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents