Clinical trial NCT03019406: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Glycogen Storage Disease Type II-Pompe's Disease
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2017-01-12
Enrollment: 22
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: The duration of the study for each participant will be up to 8 years and 9 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 430-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.

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:

Participants are excluded from the study if any of the following criteria apply:

* 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.

Primary outcomes:
measure: PAP: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI)
timeFrame: From Baseline to Week 25
measure: PAP: Number of Participants With Infusion-associated Reactions (IARs)
timeFrame: From Baseline to Week 25
Secondary outcomes:
measure: PAP: Number of Participants With Anti-drug Antibody (ADA) Response
timeFrame: From Baseline to Week 25
measure: PAP: Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa
timeFrame: 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
measure: PAP: Pharmacokinetic Parameter: Time to Achieve Maximum Observed Plasma Concentration (Tmax) of Avalglucosidase Alfa
timeFrame: 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
measure: 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
timeFrame: 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
measure: PAP: Pharmacokinetic Parameter: Terminal Half-life (t1/2) of Avalglucosidase Alfa
timeFrame: 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
measure: PAP: Pharmacokinetic Parameter: Clearance (CL) of Avalglucosidase Alfa
timeFrame: 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
measure: PAP: Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Avalglucosidase Alfa
timeFrame: 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
measure: PAP: Change From Baseline in Gross Motor Function Measure-88 (GMFM-88) Test Scores at Week 25
timeFrame: Baseline, Week 25
measure: PAP: Number of Participants in Gross Motor Function Classification System-Expanded and Revised (GMFCS-E and R) Scores at Baseline and Week 25
timeFrame: Baseline, Week 25
measure: 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
timeFrame: Baseline, Week 25
measure: PAP: Change From Baseline in Quick Motor Function Test (QMFT) Scores at Week 25
timeFrame: Baseline, Week 25
measure: PAP: Echo-Left Ventricular Mass Z-Score (LVM Z-score) M-mode at Baseline, Week 25, and Change From Baseline at Week 25
timeFrame: Baseline, Week 25
measure: PAP: Change From Baseline in Eyelid Position Measurements: Interpalpebral Fissure Distance (IPFD) - Left Non-Flash and Right Non-Flash at Week 25
timeFrame: Baseline, Week 25
measure: PAP: Change From Baseline in Eyelid Position Measurements: Left and Right Margin Reflex Distance (MRD) at Week 25
timeFrame: Baseline, Week 25
measure: PAP: Change From Baseline in Eyelid Position Measurements Assessed by Margin Pupil Distance (MPD) - Left Non-Flash and Right Non-Flash at Week 25
timeFrame: Baseline, Week 25
measure: PAP: Change From Baseline in Creatine Kinase Value at Week 25
timeFrame: Baseline, Week 25
measure: ETP: Number of Participants With Treatment Emergent Adverse Events, Serious Treatment Emergent Adverse Events, and Adverse Event of Special Interest
timeFrame: Up to 8 years and 9 months
measure: ETP: Number of Participants With Infusion-associated Reactions
timeFrame: Up to 8 years and 9 months
Other outcomes:
Locations:
city: Valhalla
country: United States
facility: Regional Medical Genetics Center of New York Site Number : 8400002
state: New York
city: Durham
country: United States
facility: Duke University Medical Center Site Number : 8400001
state: North Carolina
city: Seattle
country: United States
facility: Seattle Childrens Hospital and Regional Medical Center Site Number : 8400005
state: Washington
city: Nantes
country: France
facility: Investigational Site Number : 2500004
city: Paris
country: France
facility: Investigational Site Number : 2500003
city: Paris
country: France
facility: Investigational Site Number : 2500002
city: Tours Cedex 1
country: France
facility: Investigational Site Number : 2500001
city: Fuchu-shi
country: Japan
facility: Investigational Site Number : 3920001
state: Tokyo
city: Fuchu-shi
country: Japan
facility: Investigational Site Number : 3920002
state: Tokyo
city: Hsinchu City
country: Taiwan
facility: Investigational Site Number : 1580001
city: London
country: United Kingdom
facility: Investigational Site Number : 8260001
state: London, City Of
city: Manchester
country: United Kingdom
facility: Investigational Site Number : 8260002
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: