A Study to Assess Safety and Efficacy of Avalglucosidase Alfa Administered Every Other Week in Pediatric Patients With Infantile-onset Pompe Disease Previously Treated With Alglucosidase Alfa (Mini-COMET)

• ClinicalTrials.gov Identifier: NCT03019406
• Recruitment Status: Active, not recruiting
• First Posted: January 12, 2017
• Results First Posted: November 22, 2021
• Last Update Posted: May 25, 2022
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Tracking Information

• First Submitted Date: December 20, 2016
• First Posted Date: January 12, 2017
• Results First Submitted Date: August 24, 2021
• Results First Posted Date: November 22, 2021
• Last Update Posted Date: May 25, 2022
• Actual Study Start Date: October 12, 2017
• Actual Primary Completion Date: September 30, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 22, 2021)

• PAP: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI) [ Time Frame: From Baseline to Week 25 ]
  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.
• PAP: Number of Participants With Infusion-associated Reactions (IARs) [ Time Frame: From Baseline to Week 25 ]
  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.

• Original Primary Outcome Measures (submitted: January 10, 2017): Number of participants with adverse events [ Time Frame: Baseline to 6 months ]

Current Secondary Outcome Measures (submitted: October 22, 2021)

• PAP: Number of Participants With Anti-drug Antibody (ADA) Response [ Time Frame: From Baseline to Week 25 ]
  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.
• PAP: Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa [ 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 ]
  Cmax is the maximum observed plasma concentration.
• PAP: Pharmacokinetic Parameter: Time to Achieve Maximum Observed Plasma Concentration (Tmax) of Avalglucosidase Alfa [ 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 ]
  Tmax is the time to achieve maximum plasma concentration.
• 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 [ 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 ]
  AUC0-last is the area under the plasma concentration versus time curve from time 0 to the time of last quantifiable concentration.
• PAP: Pharmacokinetic Parameter: Terminal Half-life (t1/2) of Avalglucosidase Alfa [ 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 ]
  t1/2 is the time required for the plasma concentration of a drug to decrease by half of its initial concentration.
• PAP: Pharmacokinetic Parameter: Clearance (CL) of Avalglucosidase Alfa [ 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 ]
  CL is defined as a quantitative measure of the rate at which a drug substance is removed from the body.
• PAP: Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Avalglucosidase Alfa [ 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 ]
  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.
• PAP: Change From Baseline in Gross Motor Function Measure-88 (GMFM-88) Test Scores at Week 25 [ Time Frame: Baseline, 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.
• PAP: Number of Participants in Gross Motor Function Classification System-Expanded and Revised (GMFCS-E and R) Scores at Baseline and Week 25 [ Time Frame: Baseline, 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.
• 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 [ Time Frame: Baseline, 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.
• PAP: Change From Baseline in Quick Motor Function Test (QMFT) Scores at Week 25 [ Time Frame: Baseline, 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.
• PAP: Echo-Left Ventricular Mass Z-Score (LVM Z-score) M-mode at Baseline, Week 25, and Change From Baseline at Week 25 [ Time Frame: Baseline, 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.
• PAP: Change From Baseline in Eyelid Position Measurements: Interpalpebral Fissure Distance (IPFD) - Left Non-Flash and Right Non-Flash at Week 25 [ Time Frame: Baseline, 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.
• PAP: Change From Baseline in Eyelid Position Measurements: Left and Right Margin Reflex Distance (MRD) at Week 25 [ Time Frame: Baseline, 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.
• PAP: Change From Baseline in Eyelid Position Measurements Assessed by Margin Pupil Distance (MPD) - Left Non-Flash and Right Non-Flash at Week 25 [ Time Frame: Baseline, 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.
• PAP: Change From Baseline in Creatine Kinase Value at Week 25 [ Time Frame: Baseline, Week 25 ]
  Change from Baseline in Creatine kinase value (to assess muscle damage) at Week 25 were reported in this OM.
• ETP: Number of Participants With Treatment Emergent Adverse Events, Serious Treatment Emergent Adverse Events, and Adverse Event of Special Interest [ Time Frame: From Week 26 to Week 371 ]
  Data for this outcome measure will be reported at the time of anticipated last participant last visit results posting (December 2025).
• ETP: Number of Participants With Infusion-associated Reactions [ Time Frame: From Week 26 to Week 371 ]
  Data for this outcome measure will be reported at the time of anticipated last participant last visit results posting (December 2025).

Original Secondary Outcome Measures (submitted: January 10, 2017)

• Assessment of pharmacokinetic parameter: maximum concentration (Cmax) [ Time Frame: Baseline to 6 months ]
• Assessment of pharmacokinetic parameter: area under curve (AUC) [ Time Frame: Baseline to 6 months ]
• Change from baseline in Gross Motor Function Measure-88 Test [ Time Frame: Baseline to 6 months ]
• Change from revised Gross Motor Function Classification System score [ Time Frame: Baseline to 6 months ]
• Change from baseline in Pompe specific Pediatric Evaluation of Disability Inventory (Pompe PEDI) Functional Skills Scale: Mobility Domain Test score (normative standard score) [ Time Frame: Baseline to 6 months ]
• Change from baseline in Pompe specific Pediatric Evaluation of Disability Inventory (Pompe PEDI) Functional Skills Scale: Mobility Domain Test score (scaled score) [ Time Frame: Baseline to 6 months ]
• Change from baseline in Quick Motor Function Test scores [ Time Frame: Baseline to 6 months ]
• Change from baseline in Left Ventricular Mass Index [ Time Frame: Baseline to 6 months ]
• Change from baseline in Left Ventricular Mass Index Z score [ Time Frame: Baseline to 6 months ]
• Change from baseline in Eyelid position measurements: Interpalpebral fissure distance (IPFD) [ Time Frame: Baseline to 6 months ]
• Change from baseline in Eyelid position measurements: Margin reflex distance-1 (MRD-1) [ Time Frame: Baseline to 6 months ]
• Change from baseline in Eyelid position measurements: Margin pupil distance (MPD) [ Time Frame: Baseline to 6 months ]
• Change from baseline in Creatine kinase value [ Time Frame: Baseline to 6 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess Safety and Efficacy of Avalglucosidase Alfa Administered Every Other Week in Pediatric Patients With Infantile-onset Pompe Disease Previously Treated With Alglucosidase Alfa
• Official Title: An Open-label Ascending Dose Cohort Study to Assess the Safety, Pharmacokinetics, and Preliminary Efficacy of Avalglucosidase Alfa (NeoGAA, GZ402666) in Patients With Infantile-onset Pompe Disease Treated With Alglucosidase Alfa Who Demonstrate Clinical Decline or Sub-optimal Clinical Response

Brief Summary

Primary Objective:

To evaluate the safety profile of avalglucosidase alfa in participants with infantile-onset Pompe disease previously treated with alglucosidase alfa.

Secondary Objective:

To characterize the pharmacokinetic profile of avalglucosidase alfa and to evaluate the preliminary efficacy of avalglucosidase alfa in comparison to alglucosidase alfa.

• Detailed Description: The duration of the study for each participant will be up to approximately 7 years, and consists 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 346-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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Glycogen Storage Disease Type II-Pompe's Disease

Intervention

• Drug: Avalglucosidase alfa (GZ402666)

  Pharmaceutical form: powder for concentrate for solution for infusion,

  Route of administration: IV

  Other Name: neoGAA
• Drug: Alglucosidase alfa (GZ419829)

  Pharmaceutical form: powder for concentrate for solution for infusion,

  Route of administration: IV

  Other Names:

  • Myozyme®
  • Lumizyme®

Study Arms

• Experimental: Cohort 1: Avalglucosidase Alfa 20 mg/kg
  Avalglucosidase alfa, 20 mg/kg intravenous (IV) infusion every other week (qow) for 25 weeks in the Primary Analysis Period (PAP), followed by same treatment from Week 26 up to Week 371 in extension treatment period (ETP).
  Intervention: Drug: Avalglucosidase alfa (GZ402666)
• Experimental: Cohort 2: Avalglucosidase Alfa 40 mg/kg
  Avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in the PAP, followed by same treatment from Week 26 up to Week 371 in ETP.
  Intervention: Drug: Avalglucosidase alfa (GZ402666)
• Experimental: Cohort 3a: Avalglucosidase Alfa 40 mg//kg
  After determination of the highest tolerated avalglucosidase alfa dose in Cohort 1 and Cohort 2 (after at least 5 participants in each Cohort 1 and Cohort 2 had received the 7th dose of avalglucosidase alfa or completed Week 13 with a minimum of 6 infusions), participants received avalglucosidase alfa 40 mg/kg (the highest tolerated dose) IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.
  Intervention: Drug: Avalglucosidase alfa (GZ402666)
• Experimental: Cohort 3b: Alglucosidase Alfa in PAP
  After determination of the highest tolerated avalglucosidase alfa dose in Cohort 1 and Cohort 2 (after at least 5 participants in each Cohort 1 and Cohort 2 had received the 7th dose of avalglucosidase alfa or completed Week 13 with a minimum of 6 infusions), participants received alglucosidase alfa at their current stable dose (defined as dose [between 20 mg/kg qow and 40 mg/kg weekly as per physician] administered regularly for a minimum of 6 months immediately prior to entry in this study) IV infusion for 25 weeks in PAP. After PAP, participants received avalglucosidase alfa 40mg/kg IV infusion qow from Week 26 up to Week 371 in ETP.
  Interventions:

  • Drug: Avalglucosidase alfa (GZ402666)
  • Drug: Alglucosidase alfa (GZ419829)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 7, 2019): 22
• Original Estimated Enrollment (submitted: January 10, 2017): 20
• Estimated Study Completion Date: December 2024
• Actual Primary Completion Date: September 30, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• The participants has confirmed acid alpha-glucosidase (GAA) enzyme deficiency from any tissue source.
• The participants who has reached legal age of majority as defined by local regulation, or the participant's legal guardian(s) must provide signed informed consent prior to performing any study-related procedures. If the participant is legally minor per local regulations, assent shall be obtained from participants, if applicable.
• The participants (and participant's legal guardian if participant is legally minor as defined by local regulation) must have the ability to comply with the clinical protocol.
• The participants is less than 18 years old.
• The participants, if female and of childbearing potential, must have a negative serum pregnancy test (beta-human chorionic gonadotropin) and must not breastfeeding at screening/Baseline.
• The participant has cardiomyopathy at the time of diagnosis: i.e., left ventricular mass index (LVMI) equivalent to mean age specific LVMI plus 2 standard deviations.
• The participant has been receiving a stable dose of alglucosidase alfa regularly for a minimum of 6 months immediately prior to study entry.
• For participants in Stage 1: The participant has documented evidence of clinical decline in at least 1 of the following parameters related to Pompe Disease and not related to intercurrent illness as assessed by the Investigator: respiratory function, motor skills, and/or cardiac parameters.
• For participants in Stage 2: The participant has documented evidence of suboptimal clinical response in at least 1 of the following parameters related to Pompe Disease and not related to intercurrent illness as assessed by the Investigator: respiratory function, motor skills, and/or new onset of ptosis.

Exclusion criteria:

• The participant has high antibody titer to alglucosidase alfa.
• The participant has a high risk for a severe allergic reaction to neoGAA (avalglucosidase alfa).
• The participant requires any prohibited concomitant medications (e.g., immune modulatory treatment) for the duration of the study.
• The participant has previously participated in any ACT14132 study cohort.
• Female participant of childbearing potential not protected by highly effective contraceptive method of birth control and/or who is unwilling or unable to tested for pregnancy.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Japan, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03019406
• Other Study ID Numbers: ACT14132; 2016-003475-21 ( EudraCT Number ); U1111-1179-4616 ( Other Identifier: UTN )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

• Current Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
• Original Responsible Party: Same as current
• Current Study Sponsor: Genzyme, a Sanofi Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: May 2022