This is a multi-stage, phase 2, open-label, multicenter, multinational, ascending dose cohort, repeated intravenous (IV) infusion study of avalglucosidase alfa in pediatric patients with Infantile-Onset Pompe Disease (IOPD) who have been previously treated with alglucosidase alfa for a minimum of 6 months immediately prior to study entry and have demonstrated clinical decline or unsatisfactory clinical response.
The duration of the study for each participant will be up to 9 years and 4 months that will consist of a 14-day screening period, that may be extended to up to 4 weeks in pre-specified situations. This is followed by a 25-week treatment period and an up to a 462-week treatment extension period and a 4-week post-treatment observation period. Cohort 1 and 2 (Cohort 1: avalglucosidase alfa 20 milligrams per kilogram \[mg/kg\], Cohort 2: avalglucosidase alfa 40 mg/kg) will be non-randomized and Cohort 3 (Cohort 3a: avalglucosidase alfa 40 mg/kg \[maximum tolerated dose\] and Cohort 3b: alglucosidase alfa) will be randomized.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Pharmaceutical form: powder for concentrate for solution for infusion, Route of administration: IV
Pharmaceutical form: powder for concentrate for solution for infusion, Route of administration: IV
Regional Medical Genetics Center of New York Site Number : 8400002
Valhalla, New York, United States
Duke University Medical Center Site Number : 8400001
Durham, North Carolina, United States
Seattle Childrens Hospital and Regional Medical Center- Site Number : 8400005
Seattle, Washington, United States
Investigational Site Number : 2500004
Nantes, France
Investigational Site Number : 2500003
Paris, France
Investigational Site Number : 2500002
Paris, France
Investigational Site Number : 2500001
Tours, France
Investigational Site Number : 3920001
Fuchu-shi, Tokyo, Japan
Investigational Site Number : 3920002
Fuchu-shi, Tokyo, Japan
Investigational Site Number : 1580001
Hsinchu, Taiwan
...and 2 more locations
PAP: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI)
Adverse event (AE): any untoward medical occurrence in participant received study drug \& did not necessarily had to have causal relationship with treatment. TEAEs: AEs developed/worsened in grade/become serious during PAP period (from the time of 1st study drug dose up to Week 25). Serious AE(SAE): any untoward medical occurrence at any dose resulted in death, was life-threatening, required inpatient hospitalization, prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect or was medically important event. TEAEs included SAEs \& non-SAEs. AESI:AE (serious/non-serious) of scientific \& medical concern specific to Sponsor's product/program, for which ongoing monitoring \& immediate notification by Investigator to Sponsor required.
Time frame: From Baseline to Week 25
PAP: Number of Participants With Infusion-associated Reactions (IARs)
IARs were defined as AESIs that occurred during either the infusion or the observation period following the infusion which were deemed to be related or possibly related to the study drug. Protocol-defined IARs: An AESIs that occurred during either the infusion or the observation period following the infusion which were deemed to be related or possibly related to study drug. Algorithm-defined IARs: any TEAE meeting either 1 or 2 criteria: 1) event occurred from the start of infusion to the end of infusion plus 24 hours, and considered related to study drug, 2) If an AE time component was missing, compared AE Start date with infusion start date and infusion end date. If an AE Start date was between infusion start date and infusion end date plus one day, and it was related to study drug.
Time frame: From Baseline to Week 25
PAP: Number of Participants With Anti-drug Antibody (ADA) Response
Anti-drug antibody response was categorized as: Treatment induced ADAs: ADAs developed de novo (seroconversion) following administration of study drug. Treatment boosted ADAs: pre-existing ADAs that were boosted at least two titer steps from Baseline (i.e., 4-fold increase in titers) followed by administration of study drug.
Time frame: From Baseline to Week 25
PAP: Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa
Cmax is the maximum observed plasma concentration.
Time frame: Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25 Cohort 2 and 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25
PAP: Pharmacokinetic Parameter: Time to Achieve Maximum Observed Plasma Concentration (Tmax) of Avalglucosidase Alfa
Tmax is the time to achieve maximum plasma concentration.
Time frame: Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25 Cohort 2 and 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25
PAP: Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-last) of Avalglucosidase Alfa
AUC0-last is the area under the plasma concentration versus time curve from time 0 to the time of last quantifiable concentration.
Time frame: Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25 Cohort 2 & 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25
PAP: Pharmacokinetic Parameter: Terminal Half-life (t1/2) of Avalglucosidase Alfa
t1/2 is the time required for the plasma concentration of a drug to decrease by half of its initial concentration.
Time frame: Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25 Cohort 2 & 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25
PAP: Pharmacokinetic Parameter: Clearance (CL) of Avalglucosidase Alfa
CL is defined as a quantitative measure of the rate at which a drug substance is removed from the body.
Time frame: Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25 Cohort 2 and 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25
PAP: Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Avalglucosidase Alfa
Steady state volume of distribution (Vss) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25 Cohort 2 & 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25
PAP: Change From Baseline in Gross Motor Function Measure-88 (GMFM-88) Test Scores at Week 25
GMFM-88 was developed specifically to detect quantitative changes in gross motor function. The GMFM-88 consisted of 88 items organized into 5 dimensions; lying and rolling (17 items); sitting (20 items); crawling and kneeling (14 items); standing (13 items) and walking, running and jumping (24 items). Each item was scored on a 4-point Likert scale with scores range: 0= cannot do; 1 = initiates less then \[\<\] 10 percentage \[%\] of the task; 2 = partially completes \[10% to \<100% of the task\] and 3 = task completion. The score for each dimension was expressed as a % of the maximum score for that dimension.Total percentage score was obtained by adding the percentage scores for each dimension and dividing the sum by the total number of dimensions. Total scores ranged from 0% to 100%; where higher scores indicated better motor functions.
Time frame: Baseline, Week 25
PAP: Number of Participants in Gross Motor Function Classification System-Expanded and Revised (GMFCS-E and R) Scores at Baseline and Week 25
GMFCS-E\&R was a 5 level classification system for specific age ranges; observations were performed on 5 levels based on self-initiated movement, with emphasis on sitting, transfers, and mobility: Level I (walks without limitations), Level II (walks with limitations), Level III (walks using a hand-held mobility device), Level IV (self-mobility with limitations; may use powered mobility) and level V (transported in a manual wheel chair) (I to V). The distinctions between levels were based on functional limitations, the need for assistive mobility devices, and to a much lesser extent, quality of movement, and were designed to be meaningful in daily life. The lower level represented good motor functioning and higher level represented low motor functioning. Number of participants in each level of classification at Baseline and Week 25 were reported.
Time frame: Baseline, Week 25
PAP: Change From Baseline in Pompe Pediatric Evaluation of Disability Inventory (Pompe-PEDI) Functional Skills Scale: Mobility Domain Test Score-Scaled Score at Week 25
Pompe-PEDI: disease specific version to assess functional capabilities and performance in children with Pompe disease from 2 months through adolescence. It comprised of Functional Skills Scale and Caregiver Assistance Scale; both scales had 3 domains: Self Care, Mobility, and Social Function. Mobility domain was used to measure change in mobility due to changes in muscle strength; consisted of 160 mobility items for participant/legal guardian. The total number of mobility items the child was capable of, was converted to a scaled score with a range of 0 to 100, where scores near "0" indicated low capability and scores near "100" indicated high capability), where higher score was indicative of greater functional ability. Scaled scores were used to interpret individual function and progress over time.
Time frame: Baseline, Week 25
PAP: Change From Baseline in Quick Motor Function Test (QMFT) Scores at Week 25
QMFT was observer administered test comprised of 16 items specifically difficult for participants with Pompe disease. Each item was scored on 5-point ordinal scale ranged from 0 to 4 (higher score indicated better outcome). Total QMFT score was obtained by adding the scores of all items and ranged from 0 (unable to perform motor function tests) to 64 (normal muscle function), where higher score indicated better outcome/greater motor function.
Time frame: Baseline, Week 25
PAP: Echo-Left Ventricular Mass Z-Score (LVM Z-score) M-mode at Baseline, Week 25, and Change From Baseline at Week 25
Cardiac function was evaluated using LVM Z-score as assessed by echocardiogram in M-mode. Z-Scores indicated the number of standard deviations (SD) from the mean in a normal distribution. The normal range is -2 to 2 and greater than 2 may indicate left ventricular hypertrophy. A negative change from Baseline indicated a decrease and positive change from Baseline indicated an increase in LVM Z-score. In this OM, absolute scores at Baseline and Week 25 along with Change from Baseline at Week 25 in LVM Z-score were reported.
Time frame: Baseline, Week 25
PAP: Change From Baseline in Eyelid Position Measurements: Interpalpebral Fissure Distance (IPFD) - Left Non-Flash and Right Non-Flash at Week 25
IPFD is the widest vertical distance (in millimeters) between the upper eyelid and the lower eyelid when the participant is looking in "primary gaze" (i.e. normal gaze when looking straight forward). Images were taken while the participants was wearing a pair of empty eyeglass frames with millimeters rulers attached as a standardized tool to measure eyelid position without camera flash. A negative change from Baseline indicated a decrease and positive change from Baseline indicated an increase in measured distance.
Time frame: Baseline, Week 25
PAP: Change From Baseline in Eyelid Position Measurements: Left and Right Margin Reflex Distance (MRD) at Week 25
The MRD is the vertical distance (in millimeters) between the light reflex and the upper eyelid when the participant was looking in "primary gaze" while fixating on a light source. Images were taken while the participants was wearing a pair of empty eyeglass frames with millimeters rulers attached as a standardized tool to measure eyelid position. A negative change from Baseline indicated a decrease and positive change from Baseline indicated an increase in measured distance.
Time frame: Baseline, Week 25
PAP: Change From Baseline in Eyelid Position Measurements Assessed by Margin Pupil Distance (MPD) - Left Non-Flash and Right Non-Flash at Week 25
The MPD is the vertical distance (in millimeters) between the center of the pupil and the upper eyelid margin. Images were taken while the participants was wearing a pair of empty eyeglass frames with millimeters rulers attached as a standardized tool to measure eyelid position without camera flash. A negative change from Baseline indicated a decrease and positive change from Baseline indicated an increase in measured distance.
Time frame: Baseline, Week 25
PAP: Change From Baseline in Creatine Kinase Value at Week 25
Change from Baseline in Creatine kinase value (to assess muscle damage) at Week 25 were reported in this OM.
Time frame: Baseline, Week 25
ETP: Number of Participants With Treatment Emergent Adverse Events, Serious Treatment Emergent Adverse Events, and Adverse Event of Special Interest
Data for this outcome measure will be reported at the time of anticipated last participant last visit results posting (August 2028).
Time frame: Up to 9 years and 4 months
ETP: Number of Participants With Infusion-associated Reactions
Data for this outcome measure will be reported at the time of anticipated last participant last visit results posting (August 2028).
Time frame: Up to 9 years and 4 months
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