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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 22
- 试验地点
- 17
- 主要终点
- PAP: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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).
干预措施: Avalglucosidase alfa (GZ402666) (Drug)
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.
干预措施: Avalglucosidase alfa (GZ402666) (Drug)
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.
干预措施: Avalglucosidase alfa (GZ402666) (Drug)
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.
干预措施: Avalglucosidase alfa (GZ402666) (Drug)
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.
干预措施: Alglucosidase alfa (GZ419829) (Drug)
结局指标
主要结局
PAP: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI)
时间窗: 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)
时间窗: 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.
次要结局
- PAP: Number of Participants With Anti-drug Antibody (ADA) Response(From Baseline to Week 25)
- PAP: Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa(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(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(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(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(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(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(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(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(Baseline, Week 25)
- PAP: Change From Baseline in Quick Motor Function Test (QMFT) Scores at Week 25(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(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(Baseline, Week 25)
- PAP: Change From Baseline in Eyelid Position Measurements: Left and Right Margin Reflex Distance (MRD) at Week 25(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(Baseline, Week 25)
- PAP: Change From Baseline in Creatine Kinase Value at Week 25(Baseline, Week 25)
- ETP: Number of Participants With Treatment Emergent Adverse Events, Serious Treatment Emergent Adverse Events, and Adverse Event of Special Interest(Up to 9 years and 4 months)
- ETP: Number of Participants With Infusion-associated Reactions(Up to 9 years and 4 months)