A Phase 3 Double-blind Randomized Study to Assess the Efficacy and Safety of Intravenous ATB200 Co-administered With Oral AT2221 in Adult Subjects With Late-onset Pompe Disease Compared With Alglucosidase Alfa/Placebo
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 125
- 试验地点
- 73
- 主要终点
- Change From Baseline to Week 52 in 6 Minute Walk Distance (6MWD)
研究概览
简要总结
This is a phase 3 double-blind randomized study to study the efficacy and safety of intravenous ATB200 Co-administered with oral AT2221 in adult subjects with Late Onset Pompe Disease compared with Alglucosidase Alfa/placebo.
详细描述
This is a double-blind, randomized, multicenter, international study of ATB200/AT2221 in adult subjects with late-onset Pompe disease (LOPD) who have received enzyme replacement therapy with alglucosidase alfa (ie, ERT-experienced) or who have never received ERT (ie, ERT naïve) compared with alglucosidase alfa/placebo.
The study will consist of a screening period up to 30 days, a 12-month treatment period, and a 30 day safety follow-up period. Subjects who complete this study will have the option to participate in an open label extension study to receive ATB200/AT2221 under a separate protocol.
Enzyme replacement therapy-experienced subjects will continue to take alglucosidase alfa during the screening period; treatment with alglucosidase alfa will then be replaced by study drug (ATB200/AT2221 or alglucosidase alfa/placebo) on the same schedule without interruption (ie, every 2 weeks).
Infusion visits will be scheduled every 2 weeks throughout the study; assessments (eg, clinical laboratory tests) for initial safety monitoring will be performed at these visits for the first 6 weeks of the study. Study visits that include efficacy, safety, and other assessments will be scheduled approximately every 3 months and may occur over 2 days, provided all study assessments and procedures (with the exception of pharmacokinetic [PK] sample collection) are performed before administration of study drug.
Efficacy assessments (ie, functional assessments) include evaluation of ambulatory function (6MWT), motor function tests (Gait, Stair, Gowers' maneuver, and Chair [GSGC] test and Timed Up and Go [TUG] test), muscle strength (manual muscle testing and quantitative muscle testing), and pulmonary function tests (forced vital capacity [FVC], slow vital capacity [SVC], maximal inspiratory pressure [MIP], maximal expiratory pressure [MEP], and sniff nasal inspiratory pressure [SNIP]). Patient reported outcomes (Rasch-built Pompe-specific Activity [R PAct] Scale, EuroQol 5 Dimensions 5 Levels Instrument [EQ-5D-5L], Patient-Reported Outcomes Measurement Information System [PROMIS®] instruments for physical function, fatigue, dyspnea, and upper extremity, and Subject's Global Impression of Change). The Physician's Global Impression of Change will also be performed.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject must provide signed informed consent prior to any study-related procedures being performed.
- •Male and female subjects are ≥ 18 years old and weigh ≥ 40 kg at screening.
- •Female subjects of childbearing potential and male subjects must agree to use medically accepted methods of contraception during the study and for 90 days after the last dose of study drug.
- •Subject must have a diagnosis of LOPD based on documentation of one of the following:
- •deficiency of GAA enzyme
- •GAA genotyping
- •Subject is classified as one of the following with respect to ERT status:
- •ERT-experienced, defined as currently receiving standard of care ERT (alglucosidase alfa) at the recommended dose and regimen (ie, 20 mg/kg dose every 2 weeks) for ≥ 24 months
- •ERT-naïve, defined as never having received investigational or commercially available ERT
- •Subject has a sitting FVC ≥ 30% of the predicted value for healthy adults (National Health and Nutrition Examination Survey III) at screening.
- •Subject performs two 6MWTs at screening that are valid, as determined by the clinical evaluator, and that meet all of the following criteria:
- •both screening values of 6MWD are ≥ 75 meters
- •both screening values of 6MWD are ≤ 90% of the predicted value for healthy adults
- •the lower value of 6MWD is within 20% of the higher value of 6MWD
- •Exclusion Criteria
- •Subject has received any investigational therapy or pharmacological treatment for Pompe disease, other than alglucosidase alfa, within 30 days or 5 half-lives of the therapy or treatment, whichever is longer, before Day 1 or is anticipated to do so during the study.
- •Subject has received gene therapy for Pompe disease
- •Subject is taking any of the following prohibited medications within 30 days before Day 1:
- •miglitol (eg, Glyset)
- •miglustat (eg, Zavesca)
- •acarbose (eg, Precose or Glucobay)
- •voglibose (eg, Volix, Vocarb, or Volibo)
- •Note: None of these medications have a half-life that, when multiplied by 5, is longer than 30 days.
- •Subject requires the use of invasive or noninvasive ventilation support for > 6 hours per day while awake.
- •Subject has a hypersensitivity to any of the excipients in ATB200, alglucosidase alfa, or AT
- •Subject has a medical condition or any other extenuating circumstance that may, in the opinion of the investigator or medical monitor, pose an undue safety risk to the subject or may compromise his/her ability to comply with or adversely impact protocol requirements. This includes clinical depression (as diagnosed by a psychiatrist or other mental health professional) with uncontrolled or poorly controlled symptoms.
- •Subject, if female, is pregnant or breastfeeding at screening.
- •Subject, whether male or female, is planning to conceive a child during the study.
- •Subject does not have documentation of diagnosis of Pompe disease and refuses to undergo genetic testing.
排除标准
- 未提供
研究组 & 干预措施
Cipaglucosidase Alfa/Miglustat
Participants received cipaglucosidase alfa co-administered with miglustat every 2 weeks (Q2W).
干预措施: Cipaglucosidase Alfa (Biological)
Cipaglucosidase Alfa/Miglustat
Participants received cipaglucosidase alfa co-administered with miglustat every 2 weeks (Q2W).
干预措施: Miglustat (Drug)
Alglucosidase Alfa/Placebo
Participants received alglucosidase alfa co-administered with placebo Q2W.
干预措施: Alglucosidase Alfa (Biological)
Alglucosidase Alfa/Placebo
Participants received alglucosidase alfa co-administered with placebo Q2W.
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline to Week 52 in 6 Minute Walk Distance (6MWD)
时间窗: Baseline, Week 52
The efficacy of cipaglucosidase alfa/miglustat co-administration on ambulatory function was measured by the 6MWT. The 6MWD, measured in meters, is the distance walked on the 6MWT. A greater distance indicated greater endurance. An increase from baseline indicated improvement.
次要结局
- Change From Baseline to Week 52 in the Total Score for the PROMIS® - Fatigue(Baseline, Week 52)
- Change From Baseline to Week 52 in the Total Score for the Gait, Stairs, Gowers' Maneuver, and Chair (GSGC)(Baseline, Week 52)
- Change From Baseline to Week 52 in European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L) Based on the EuroQol Visual Analogue Scale (EQ VAS) Quantitative Score(Baseline, Week 52)
- Change From Baseline to Week 52 in Rasch-Built Pompe-Specific Activity (R-PAct) Total Score(Baseline, Week 52)
- Change From Baseline to Week 52 in Maximal Expiratory Pressure (MEP) % Predicted(Baseline, Week 52)
- Change From Baseline to Week 52 in Sniff Nasal Inspiratory Pressure (SNIP) % Predicted(Baseline, Week 52)
- Change From Baseline to Week 52 in Maximal Inspiratory Pressure (MIP) % Predicted(Baseline, Week 52)
- Change From Baseline to Week 52 in Maximum Vital Capacity (Maximum VC) % Predicted(Baseline, Week 52)
- Population Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Experienced Participants Using Plasma Total GAA Protein Level by Signature Peptide Assay and Plasma Miglustat Concentration(Days 1 and 364 (Week 52))
- Population PK: Area Under the Concentration-Time Curve (AUC) of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Experienced Participants Using Plasma Total GAA Protein Level by Signature Peptide Assay and Plasma Miglustat Concentration(Days 1 and 364 (Week 52))
- Population PK: Cmax of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Naïve Participants(Days 1 and 364 (Week 52))
- Change From Baseline to Week 52 in the Quantitative Muscle Test (QMT) Values(Baseline, Week 52)
- Change From Baseline in the Time to Complete Individual GSGC Component Tests and Timed Up and Go (TUG) Test at Week 52(Baseline, Week 52)
- Physician's Global Impression of Change (PGIC) Overall Status at Week 52(Week 52)
- Subject's Global Impression of Change (SGIC) at Week 52(Week 52)
- Comparison of AUC of Cipaglucosidase Alfa in ERT- Experienced and ERT-Naïve Populations(Days 1 and 364 (Week 52))
- Number of Participants Improving on Both 6MWD and % Predicted FVC at Week 52(Week 52)
- Number of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs)(Baseline up to Week 52)
- Population PK: AUC of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Naïve Subjects(Days 1 and 364 (Week 52))
- Noncompartmental Analysis: Cmax of Plasma Total GAA Protein by Signature Peptide T09 in ERT-Naïve Subjects(Day 1)
- Noncompartmental Analysis: AUC From Time 0 (Predose) to the Time of Last Quantifiable Concentration of Plasma Total GAA Protein by Signature Peptide T09 in ERT-Naïve Subjects(Day 1)
- Comparison of Cmax of Cipaglucosidase Alfa in ERT-Experienced and ERT-Naïve Populations(Days 1 and 364 (Week 52))
- Change From Baseline to Week 52 in Sitting Forced Vital Capacity (FVC; % Predicted)(Baseline, Week 52)
- Change From Baseline to Week 52 in the Manual Muscle Test (MMT) Score for the Lower Extremities(Baseline, Week 52)
- Change From Baseline to Week 26 in 6MWD(Baseline, Week 26)
- Change From Baseline to Week 52 in the Total Score for the Patient- Reported Outcomes Measurement Information System (PROMIS®) - Physical Function(Baseline, Week 52)
- Change From Baseline to Week 52 in Sitting Slow Vital Capacity (SVC) % Predicted(Baseline, Week 52)
- Change From Baseline to Week 52 in % Predicted 6MWD(Baseline, Week 52)
- Change From Baseline to Week 52 in Other MMT Scores(Baseline, Week 52)
- Change From Baseline to Week 52 in PROMIS-Dyspnea and Upper Extremities Total Scores(Baseline, Week 52)
- Change From Baseline to Week 52 in Urinary Hexose Tetrasaccharide (Hex4) Level(Baseline, Week 52)
- Change From Baseline to Week 52 in Serum Creatine Kinase (CK) Level(Baseline, Week 52)