Immune Tolerance Induction Study

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00701701
• Collaborator: (none)
• Enrollment: 4
• Locations: 5
• Arms: 2
• Actual Duration (Months): 134.1
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

An exploratory, open-labeled study of participants with Pompe disease, who had previously received Myozyme® (alglucosidase alfa) treatment, to evaluate the efficacy, safety and clinical benefit of 2 Immune Tolerance Induction (ITI) regimens in combination with Myozyme®. Eligible participants who were then receiving Myozyme® therapy were enrolled into the study, and were followed for a minimum of 18 months on-study (a 6-month ITI treatment module and a 12-month follow-up module on Myozyme® alone). Eligible participants were followed for a minimum of 18 months on treatment or, if a participant was <6 months of age at the time of enrollment, until the participant was 2 years of age. Both cross-reacting immunologic material (CRIM)-negative and CRIM-positive participants were eligible for Regimen A depending if they met the required criteria. Regimen B, however, was limited to CRIM-negative participants.

Condition or Disease	Intervention/Treatment	Phase
Pompe Disease; Glycogen Storage Disease Type II (GSD-II); Glycogenesis 2 Acid Maltase Deficiency	Biological: Myozyme® (alglucosidase alfa); Biological: Myozyme® (alglucosidase alfa)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Exploratory Study of the Safety and Efficacy of Immune Tolerance Induction (ITI) in Patients With Pompe Disease Who Have Previously Received Myozyme
• Actual Study Start Date: Dec 14, 2008
• Actual Primary Completion Date: Feb 18, 2020
• Actual Study Completion Date: Feb 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen A: Alglucosidase alfa and Cyclophosphamide Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high recombinant human acid alpha-glucosidase (rhGAA) antibody titer (defined as at least 2 titers greater than or equal to [>=] 25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) Intravenous (IV) infusion of 20 milligram per kilogram (mg/kg) every other week (qow) for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was less than [<6] months of age at the time of enrollment). In addition, cyclophosphamide 250 milligram per square meter (mg/m^2) IV infusion was administered every 4 weeks (q4w) after Myozyme® infusion for 6 months.	Biological: Myozyme® (alglucosidase alfa); Myozyme®: IV infusion of 20 mg/kg qow; Cyclophosphamide: 250 mg/m^2 IV q4w after Myozyme infusion for 6 months.; Other Names: Myozyme®
Experimental: Regimen B: Alglucosidase alfa, Rituximab and Methotrexate CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.	Biological: Myozyme® (alglucosidase alfa); Myozyme®: IV infusion of 20 mg/kg qow; Rituximab: 375 mg/m^2 IV weekly beginning the day after Myozyme infusion for 4 weeks (an optional additional 2nd cycle could be administered at the discretion of the investigator); Methotrexate: 15 mg/m^2 subcutaneous qow on the day after Myozyme infusion for 6 months.; Other Names: Myozyme®

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [From Baseline up to 18 months]

   An Adverse event (AE) was defined as any undesirable physical, psychological, or behavioral effect experienced by participant during his/her participation in an investigational study, in conjunction with the use of the drug or biologic, whether or not product-related. TEAEs were defined as AEs that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product [IMP] administration up to 18 months). Serious AE (SAE) was any AE that resulted in any of the following outcomes: death, was life-threatening, required or prolonged inpatient hospitalization, persistent or significant disability/incapacity; congenital anomaly; or important medical events that may jeopardize the patient or participant and may require medical or surgical intervention to prevent one of the outcomes listed above; and/or new invasive ventilator use.

Other Outcome Measures

1. Number of Participants With Anti-Recombinant Human Acid Alpha-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibodies at Month 18 [Month 18]

2. Number of Participants With Recombinant Human Acid Alpha-glucosidase (rhGAA) Inhibitory Antibody at Month 18 [Month 18]

   Participants with positive anti-rhGAA IgG antibody were planned to be 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. Overall Survival (OS) [From randomization until death or study cut-off whichever comes earlier (up to 18 months)]

   OS was defined as the time interval from the date of first IMP administration to the date of death due to any cause.

4. Number of Participants With Ventilator Use [From Baseline up to 18 months]

5. Left Ventricular Mass (LVM) Z-Score and LVM Index [From Baseline up to 18 months]

   LVM Z-score and LVM index were assessed by echocardiograms (ECHOs). LVM Z-Score is an indicator of degree of standard deviations from the mean in a normal distribution. The normal range for LVM Z-Score is -2 to 2. Values <-2 or >2 indicate abnormal LVM Z-Score. Values less than 0 (negative values) indicate a smaller LVM than mean and values higher than 0 indicate a larger LVM than the mean. 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 square meter (g/m^2) were considered as normal and LVM index values >=65 g/m^2 were considered as abnormal.

6. Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) Score [From Baseline up to 18 months]

   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; and walking, running and jumping. Each item is scored on a 4-point Likert scale (0=cannot do; 1=initiates [<10 percent (%) 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.

7. Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) Score [From Baseline up to 18 months]

   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 are scored as "observed" or "not observed". Items in observed range create a motor window. When scoring, subscale scores are calculated by giving child credit (1 point) for observed items within motor window in addition to being given credit (1 point) for all of the less mature items before motor window. AIMS total score is calculated by summing scores for 58 items and ranges from 0-58, with lower score indicating less mature motor development and higher score indicating more mature motor development.

8. Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Score [From Baseline up to 18 months]

   Pompe PEDI is a disease specific version of PEDI which assesses functional capabilities and performance in children with Pompe disease from 2 months through adolescence.It consists of all items of original PEDI (197 functional skill items in 3 domains: self-care; mobility; and social function) and additional items in functional skills, mobility, and self-care domains to reflect clinically relevant functional skills. Each domain consists of 2 subdomains: functional skill performance and caregiver assistance scale. Norm-based scoring was developed for these additional items, and scoring algorithms for PEDI have been adjusted to reflect additional normative data collected for Pompe PEDI. Total score range for each domain (mean of subdomains) and subdomains ranges from 0-100, higher score indicates higher capability.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Month and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The participant (and/or participant's legal guardian if participant was < 18 years) provided written informed consent prior to any study-related procedures that were performed.

• The participants had a confirmed diagnosis of Pompe disease defined as a documented acid α-glucosidase (GAA) enzyme deficiency from any tissue source or 2 GAA gene mutations.

• The participant (and/or legal guardian) had ability to comply with clinical protocol.

• If the participant was CRIM-positive, he/she had received at least 6 consecutive months of Myozyme® infusions (20 mg/kg qow).

• If the participant was CRIM-negative, he/she had received at least 1 Myozyme® infusion prior to enrollment.

• Regimen A only: The participants exhibits clinical decline; The participant had persistent high anti-recombinant human acid α-glucosidase (anti-rhGAA) antibody titers and/or tested positive for antibodies that inhibit enzymatic activity and/or uptake of Myozyme®;

• Regimen B only: The participant was CRIM-negative AND The participant did not exhibit clinical decline; OR all of the following: The participant was CRIM-negative AND The participant exhibited clinical decline AND The participant did not exhibit high anti-rhGAA antibody titers and had not tested positive for antibodies that inhibit enzymatic activity and/or uptake of Myozyme®.

Exclusion Criteria:

• The participant had a clinical condition unrelated to Pompe disease that would interfere with program assessments.

• The participant was at risk of reactivation or was a carrier of Hepatitis B or Hepatitis C.

• The participant was at risk of reactivation or had positive serology suggestive of active infection for cytomegalovirus, Herpes simplex, JC virus, Parvovirus or Epstein Barr virus.

• The participant was at risk of reactivation of tuberculosis or had regular contact with individuals who were being actively treated for tuberculosis.

• The participant had low serum albumin.

• The participant had a major congenital abnormality.

• The participant had used any investigational product (other than alglucosidase alfa) within 30 days prior to study enrollment.

• The participant was pregnant or lactating.

• The participant has had or was required to have any live vaccination within one month prior to enrollment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Louisville	Kentucky	United States
2		Durham	North Carolina	United States
3		Salt Lake City	Utah	United States
4		Norfolk	Virginia	United States
5		Haifa		Israel

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Medical Monitor, Genzyme, a Sanofi Company

Study Documents (Full-Text)

• Study Protocol - Oct 1, 2009
• Statistical Analysis Plan - Jan 23, 2012

More Information

Publications

None provided.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00701701
• Other Study ID Numbers: MSC12817; AGLU03707; 2015-000583-34
• First Posted: Jun 19, 2008
• Last Update Posted: Apr 7, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Glycogen Storage Disease Type II; Glycogen Storage Disease

Study Results

Participant Flow

Recruitment Details	The study was conducted in 2 countries. A total of 5 participants were screened between 14 December 2008 and 17 August 2010 (dates when first participant and last participant signed informed consent), of which one participant died before enrollment.
Pre-assignment Detail	A total of 4 participants were included and treated in this study. Participants were assigned to either Regimen A or Regimen B.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high recombinant human acid alpha-glucosidase (rhGAA) antibody titer (defined as at least 2 titers greater than or equal to [>=] 25,600 obtained at least 1 month apart), regardless of their cross-reacting immunologic material (CRIM) status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) Intravenous (IV) infusion of 20 milligram per kilogram (mg/kg) every other week (qow) for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was less than [<6] months of age at the time of enrollment). In addition, cyclophosphamide 250 milligram per square meter (mg/m^2) IV infusion was administered every 4 weeks (q4w) after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Period Title: Overall Study
STARTED	1	3
COMPLETED	1	1
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate	Total
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.	Total of all reporting groups
Overall Participants	1	3	4
Age, Customized (Count of Participants)
Infants and toddlers (28 days-23 months)	0 0%	2 66.7%	2 50%
Children (2-11 years)	1 100%	1 33.3%	2 50%
Sex: Female, Male (Count of Participants)
Female	0 0%	2 66.7%	2 50%
Male	1 100%	1 33.3%	2 50%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	An Adverse event (AE) was defined as any undesirable physical, psychological, or behavioral effect experienced by participant during his/her participation in an investigational study, in conjunction with the use of the drug or biologic, whether or not product-related. TEAEs were defined as AEs that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product [IMP] administration up to 18 months). Serious AE (SAE) was any AE that resulted in any of the following outcomes: death, was life-threatening, required or prolonged inpatient hospitalization, persistent or significant disability/incapacity; congenital anomaly; or important medical events that may jeopardize the patient or participant and may require medical or surgical intervention to prevent one of the outcomes listed above; and/or new invasive ventilator use.
Time Frame	From Baseline up to 18 months

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety set population that included participants who received at least 1 dose of alglucosidase alfa in the study.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	1	3
Any TEAE	1 100%	3 100%
Any Treatment-emergent SAE	1 100%	3 100%
Any TEAE leading to withdrawal from study	0 0%	1 33.3%
Any TEAE leading to death	0 0%	1 33.3%

2. Other Pre-specified Outcome

Title	Number of Participants With Anti-Recombinant Human Acid Alpha-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibodies at Month 18
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description

Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >= 25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	0	0

3. Other Pre-specified Outcome

Title	Number of Participants With Recombinant Human Acid Alpha-glucosidase (rhGAA) Inhibitory Antibody at Month 18
Description	Participants with positive anti-rhGAA IgG antibody were planned to be 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.
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description

Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	0	0

4. Other Pre-specified Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time interval from the date of first IMP administration to the date of death due to any cause.
Time Frame	From randomization until death or study cut-off whichever comes earlier (up to 18 months)

Outcome Measure Data

Analysis Population Description

Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	0	0

5. Other Pre-specified Outcome

Title	Number of Participants With Ventilator Use
Time Frame	From Baseline up to 18 months

Outcome Measure Data

Analysis Population Description

Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	0	0

6. Other Pre-specified Outcome

Title	Left Ventricular Mass (LVM) Z-Score and LVM Index
Description	LVM Z-score and LVM index were assessed by echocardiograms (ECHOs). LVM Z-Score is an indicator of degree of standard deviations from the mean in a normal distribution. The normal range for LVM Z-Score is -2 to 2. Values <-2 or >2 indicate abnormal LVM Z-Score. Values less than 0 (negative values) indicate a smaller LVM than mean and values higher than 0 indicate a larger LVM than the mean. 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 square meter (g/m^2) were considered as normal and LVM index values >=65 g/m^2 were considered as abnormal.
Time Frame	From Baseline up to 18 months

Outcome Measure Data

Analysis Population Description

Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	0	0

7. Other Pre-specified Outcome

Title	Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) Score
Description	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; and walking, running and jumping. Each item is scored on a 4-point Likert scale (0=cannot do; 1=initiates [<10 percent (%) 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.
Time Frame	From Baseline up to 18 months

Outcome Measure Data

Analysis Population Description

Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	0	0

8. Other Pre-specified Outcome

Title	Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) Score
Description	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 are scored as "observed" or "not observed". Items in observed range create a motor window. When scoring, subscale scores are calculated by giving child credit (1 point) for observed items within motor window in addition to being given credit (1 point) for all of the less mature items before motor window. AIMS total score is calculated by summing scores for 58 items and ranges from 0-58, with lower score indicating less mature motor development and higher score indicating more mature motor development.
Time Frame	From Baseline up to 18 months

Outcome Measure Data

Analysis Population Description

Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	0	0

9. Other Pre-specified Outcome

Title	Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Score
Description	Pompe PEDI is a disease specific version of PEDI which assesses functional capabilities and performance in children with Pompe disease from 2 months through adolescence.It consists of all items of original PEDI (197 functional skill items in 3 domains: self-care; mobility; and social function) and additional items in functional skills, mobility, and self-care domains to reflect clinically relevant functional skills. Each domain consists of 2 subdomains: functional skill performance and caregiver assistance scale. Norm-based scoring was developed for these additional items, and scoring algorithms for PEDI have been adjusted to reflect additional normative data collected for Pompe PEDI. Total score range for each domain (mean of subdomains) and subdomains ranges from 0-100, higher score indicates higher capability.
Time Frame	From Baseline up to 18 months

Outcome Measure Data

Analysis Population Description

Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.

Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide	Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.	CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
Measure Participants	0	0

Adverse Events

Time Frame	All Adverse Events (AEs) were collected from first IMP administration up to 18 months
Adverse Event Reporting Description	Reported AEs and deaths are treatment-emergent adverse events i.e. AEs that developed/worsened and deaths that occurred during the 'on treatment period' (time from first IMP administration until 18 months). Analysis was performed on safety population.
Arm/Group Title	Regimen A: Alglucosidase Alfa and Cyclophosphamide		Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
Arm/Group Description	Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was <6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered q4w after Myozyme® infusion for 6 months.		CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers >=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was <6 months of age at time of enrollment). In addition,rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
All Cause Mortality
	Regimen A: Alglucosidase Alfa and Cyclophosphamide		Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		1/3 (33.3%)
Serious Adverse Events
	Regimen A: Alglucosidase Alfa and Cyclophosphamide		Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Neutropenia	0/1 (0%)	0	1/3 (33.3%)	1
Cardiac disorders
Atrial Thrombosis	1/1 (100%)	2	0/3 (0%)	0
Cardiac Hypertrophy	1/1 (100%)	1	0/3 (0%)	0
Cyanosis	1/1 (100%)	1	0/3 (0%)	0
Hypertrophic Cardiomyopathy	1/1 (100%)	1	0/3 (0%)	0
Tachycardia	0/1 (0%)	0	1/3 (33.3%)	1
Gastrointestinal disorders
Vomiting	1/1 (100%)	1	0/3 (0%)	0
General disorders
General Physical Health Deterioration	0/1 (0%)	0	1/3 (33.3%)	1
Pyrexia	1/1 (100%)	2	1/3 (33.3%)	3
Infections and infestations
Influenza	0/1 (0%)	0	1/3 (33.3%)	1
Pneumonia	1/1 (100%)	4	1/3 (33.3%)	1
Pneumonia Streptococcal	0/1 (0%)	0	1/3 (33.3%)	1
Pneumonia Viral	0/1 (0%)	0	1/3 (33.3%)	1
Upper Respiratory Tract Infection	1/1 (100%)	2	0/3 (0%)	0
Investigations
Blood Pressure Decreased	1/1 (100%)	1	0/3 (0%)	0
Oxygen Saturation Decreased	1/1 (100%)	1	0/3 (0%)	0
Staphylococcus Test Positive	0/1 (0%)	0	1/3 (33.3%)	1
Metabolism and nutrition disorders
Dehydration	0/1 (0%)	0	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/1 (100%)	1	1/3 (33.3%)	1
Dyspnoea	0/1 (0%)	0	1/3 (33.3%)	1
Hypercapnia	1/1 (100%)	1	0/3 (0%)	0
Hypoxia	0/1 (0%)	0	1/3 (33.3%)	1
Increased Upper Airway Secretion	1/1 (100%)	1	0/3 (0%)	0
Pneumonitis	0/1 (0%)	0	1/3 (33.3%)	1
Respiratory Distress	0/1 (0%)	0	1/3 (33.3%)	3
Respiratory Failure	0/1 (0%)	0	2/3 (66.7%)	2
Skin and subcutaneous tissue disorders
Cold Sweat	1/1 (100%)	1	0/3 (0%)	0
Urticaria	1/1 (100%)	1	0/3 (0%)	0
Vascular disorders
Pallor	1/1 (100%)	1	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Regimen A: Alglucosidase Alfa and Cyclophosphamide		Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Leukocytosis	0/1 (0%)	0	1/3 (33.3%)	1
Cardiac disorders
Bradycardia	1/1 (100%)	5	0/3 (0%)	0
Tachycardia	0/1 (0%)	0	1/3 (33.3%)	3
Ventricular Hypertrophy	0/1 (0%)	0	1/3 (33.3%)	1
Ear and labyrinth disorders
Conductive Deafness	0/1 (0%)	0	1/3 (33.3%)	2
Deafness Bilateral	0/1 (0%)	0	1/3 (33.3%)	1
Mixed Deafness	0/1 (0%)	0	1/3 (33.3%)	1
Eye disorders
Conjunctivitis	0/1 (0%)	0	1/3 (33.3%)	2
Gastrointestinal disorders
Abdominal Distension	1/1 (100%)	1	0/3 (0%)	0
Constipation	1/1 (100%)	5	1/3 (33.3%)	1
Diarrhoea	0/1 (0%)	0	1/3 (33.3%)	2
Faecaloma	1/1 (100%)	2	0/3 (0%)	0
Faeces Hard	1/1 (100%)	3	0/3 (0%)	0
Nausea	1/1 (100%)	1	0/3 (0%)	0
Retching	0/1 (0%)	0	1/3 (33.3%)	1
Vomiting	1/1 (100%)	4	1/3 (33.3%)	1
General disorders
Catheter Site Phlebitis	1/1 (100%)	2	0/3 (0%)	0
Medical Device Complication	1/1 (100%)	2	0/3 (0%)	0
Oedema Peripheral	1/1 (100%)	1	0/3 (0%)	0
Pain	0/1 (0%)	0	1/3 (33.3%)	1
Pyrexia	1/1 (100%)	10	2/3 (66.7%)	10
Thrombosis In Device	0/1 (0%)	0	1/3 (33.3%)	1
Infections and infestations
Bacterial Tracheitis	0/1 (0%)	0	1/3 (33.3%)	1
Otitis Media	0/1 (0%)	0	3/3 (100%)	3
Otitis Media Acute	0/1 (0%)	0	2/3 (66.7%)	2
Pharyngitis	1/1 (100%)	1	0/3 (0%)	0
Pneumonia	1/1 (100%)	1	0/3 (0%)	0
Staphylococcal Bacteraemia	1/1 (100%)	1	0/3 (0%)	0
Tracheitis	0/1 (0%)	0	1/3 (33.3%)	1
Upper Respiratory Tract Infection	0/1 (0%)	0	2/3 (66.7%)	7
Urinary Tract Infection	0/1 (0%)	0	1/3 (33.3%)	1
Injury, poisoning and procedural complications
Arthropod Bite	0/1 (0%)	0	1/3 (33.3%)	2
Excoriation	0/1 (0%)	0	1/3 (33.3%)	1
Feeding Tube Complication	1/1 (100%)	1	0/3 (0%)	0
Thermal Burn	0/1 (0%)	0	1/3 (33.3%)	1
Tracheal Haemorrhage	0/1 (0%)	0	1/3 (33.3%)	1
Investigations
Alanine Aminotransferase Increased	0/1 (0%)	0	1/3 (33.3%)	3
Blood Creatine Phosphokinase Mb Increased	0/1 (0%)	0	1/3 (33.3%)	3
Blood Creatine Phosphokinase Increased	0/1 (0%)	0	1/3 (33.3%)	2
Blood Immunoglobulin M Increased	0/1 (0%)	0	1/3 (33.3%)	1
Blood Magnesium Decreased	0/1 (0%)	0	1/3 (33.3%)	1
Blood Potassium Decreased	0/1 (0%)	0	1/3 (33.3%)	2
Body Temperature Increased	0/1 (0%)	0	3/3 (100%)	10
Heart Rate Increased	0/1 (0%)	0	1/3 (33.3%)	4
Lymphocyte Count Decreased	0/1 (0%)	0	1/3 (33.3%)	1
Lymphocyte Percentage Decreased	0/1 (0%)	0	1/3 (33.3%)	1
Muscle Enzyme Increased	1/1 (100%)	1	0/3 (0%)	0
Neutrophil Count Decreased	0/1 (0%)	0	1/3 (33.3%)	1
Neutrophil Percentage Increased	0/1 (0%)	0	1/3 (33.3%)	1
Oxygen Saturation Decreased	1/1 (100%)	3	1/3 (33.3%)	1
Urine Output Decreased	0/1 (0%)	0	1/3 (33.3%)	2
White Blood Cell Count Decreased	0/1 (0%)	0	2/3 (66.7%)	2
White Blood Cells Urine Positive	0/1 (0%)	0	1/3 (33.3%)	1
Musculoskeletal and connective tissue disorders
Joint Contracture	0/1 (0%)	0	1/3 (33.3%)	1
Nervous system disorders
Clonus	0/1 (0%)	0	1/3 (33.3%)	1
Hypokinesia	0/1 (0%)	0	2/3 (66.7%)	2
Psychiatric disorders
Agitation	0/1 (0%)	0	1/3 (33.3%)	1
Insomnia	0/1 (0%)	0	1/3 (33.3%)	1
Restlessness	1/1 (100%)	1	0/3 (0%)	0
Renal and urinary disorders
Hydronephrosis	1/1 (100%)	1	0/3 (0%)	0
Oliguria	1/1 (100%)	2	0/3 (0%)	0
Urinary Retention	1/1 (100%)	5	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Aspiration	0/1 (0%)	0	1/3 (33.3%)	1
Atelectasis	1/1 (100%)	1	0/3 (0%)	0
Cough	0/1 (0%)	0	1/3 (33.3%)	2
Dyspnoea	1/1 (100%)	1	0/3 (0%)	0
Haemoptysis	0/1 (0%)	0	1/3 (33.3%)	1
Hypoxia	0/1 (0%)	0	1/3 (33.3%)	3
Increased Bronchial Secretion	1/1 (100%)	3	0/3 (0%)	0
Increased Upper Airway Secretion	0/1 (0%)	0	1/3 (33.3%)	1
Pleural Effusion	1/1 (100%)	1	0/3 (0%)	0
Pneumonia Aspiration	1/1 (100%)	1	0/3 (0%)	0
Pneumonitis	0/1 (0%)	0	1/3 (33.3%)	1
Pneumothorax	0/1 (0%)	0	1/3 (33.3%)	1
Pulmonary Oedema	0/1 (0%)	0	1/3 (33.3%)	1
Respiratory Distress	1/1 (100%)	1	1/3 (33.3%)	1
Rhinorrhoea	1/1 (100%)	2	1/3 (33.3%)	1
Skin and subcutaneous tissue disorders
Decubitus Ulcer	1/1 (100%)	1	0/3 (0%)	0
Dermatitis Diaper	0/1 (0%)	0	1/3 (33.3%)	1
Erythema	1/1 (100%)	1	1/3 (33.3%)	1
Papule	0/1 (0%)	0	1/3 (33.3%)	1
Pruritus	1/1 (100%)	1	0/3 (0%)	0
Rash	0/1 (0%)	0	1/3 (33.3%)	2
Red Man Syndrome	0/1 (0%)	0	1/3 (33.3%)	1
Skin Discolouration	0/1 (0%)	0	1/3 (33.3%)	1
Skin Exfoliation	0/1 (0%)	0	1/3 (33.3%)	1
Skin Irritation	0/1 (0%)	0	1/3 (33.3%)	1
Skin Swelling	0/1 (0%)	0	1/3 (33.3%)	3
Urticaria	1/1 (100%)	2	2/3 (66.7%)	6
Vascular disorders
Hypertension	1/1 (100%)	1	0/3 (0%)	0
Hypotension	1/1 (100%)	1	0/3 (0%)	0
Phlebitis	1/1 (100%)	2	0/3 (0%)	0

Limitations/Caveats

Due to low number of enrollment and exploratory nature of outcome measure, only safety data were summarized and reported.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.