Clinical trial NCT03729362: A Study Comparing ATB200/AT2221 With Alglucosidase Alfa/Placebo in Adult Subjects With Late-onset Pompe Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pompe Disease (Late-onset)
Keywords: Pompe
rhGAA
Lead sponsor: Amicus Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-11-02
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Pharmacodynamic assessments include measurement of biomarkers of muscle injury (creatine kinase \[CK\]) and disease substrate (urinary hexose tetrasaccharide \[Hex4\]). Blood samples will be collected for determination of total GAA protein levels and AT2221 concentrations in plasma for a population PK analysis. Safety assessments include monitoring of adverse events (AEs), including infusion associated reactions (IARs), clinical laboratory tests (chemistry, hematology, and urinalysis), vital signs, physical examinations including weight, electrocardiograms (ECGs), and immunogenicity. Concomitant medications and nondrug therapies will also be recorded.

Eligibility criteria: Inclusion Criteria:

1. Subject must provide signed informed consent prior to any study-related procedures being performed.
2. Male and female subjects are ≥ 18 years old and weigh ≥ 40 kg at screening.
3. 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.
4. Subject must have a diagnosis of LOPD based on documentation of one of the following:

   1. deficiency of GAA enzyme
   2. GAA genotyping
5. Subject is classified as one of the following with respect to ERT status:

   1. 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
   2. ERT-naïve, defined as never having received investigational or commercially available ERT
6. Subject has a sitting FVC ≥ 30% of the predicted value for healthy adults (National Health and Nutrition Examination Survey III) at screening.
7. Subject performs two 6MWTs at screening that are valid, as determined by the clinical evaluator, and that meet all of the following criteria:

   1. both screening values of 6MWD are ≥ 75 meters
   2. both screening values of 6MWD are ≤ 90% of the predicted value for healthy adults
   3. the lower value of 6MWD is within 20% of the higher value of 6MWD

Exclusion Criteria

1. 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.
2. Subject has received gene therapy for Pompe disease
3. 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.
4. Subject requires the use of invasive or noninvasive ventilation support for \> 6 hours per day while awake.
5. Subject has a hypersensitivity to any of the excipients in ATB200, alglucosidase alfa, or AT2221.
6. 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.
7. Subject, if female, is pregnant or breastfeeding at screening.
8. Subject, whether male or female, is planning to conceive a child during the study.
9. Subject does not have documentation of diagnosis of Pompe disease and refuses to undergo genetic testing.

Primary outcomes:
measure: Change From Baseline to Week 52 in 6 Minute Walk Distance (6MWD)
timeFrame: Baseline, Week 52
Secondary outcomes:
measure: Change From Baseline to Week 52 in Sitting Forced Vital Capacity (FVC; % Predicted)
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in the Manual Muscle Test (MMT) Score for the Lower Extremities
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 26 in 6MWD
timeFrame: Baseline, Week 26
measure: Change From Baseline to Week 52 in the Total Score for the Patient- Reported Outcomes Measurement Information System (PROMIS®) - Physical Function
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in the Total Score for the PROMIS® - Fatigue
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in the Total Score for the Gait, Stairs, Gowers' Maneuver, and Chair (GSGC)
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Rasch-Built Pompe-Specific Activity (R-PAct) Total Score
timeFrame: Baseline, Week 52
measure: 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
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Sitting Slow Vital Capacity (SVC) % Predicted
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Maximal Inspiratory Pressure (MIP) % Predicted
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Maximal Expiratory Pressure (MEP) % Predicted
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Sniff Nasal Inspiratory Pressure (SNIP) % Predicted
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in % Predicted 6MWD
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in the Quantitative Muscle Test (QMT) Values
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Other MMT Scores
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Maximum Vital Capacity (Maximum VC) % Predicted
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in PROMIS-Dyspnea and Upper Extremities Total Scores
timeFrame: Baseline, Week 52
measure: Change From Baseline in the Time to Complete Individual GSGC Component Tests and Timed Up and Go (TUG) Test at Week 52
timeFrame: Baseline, Week 52
measure: Physician's Global Impression of Change (PGIC) Overall Status at Week 52
timeFrame: Week 52
measure: Subject's Global Impression of Change (SGIC) at Week 52
timeFrame: Week 52
measure: Number of Participants Improving on Both 6MWD and % Predicted FVC at Week 52
timeFrame: Week 52
measure: Number of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs)
timeFrame: Baseline up to Week 52
measure: Change From Baseline to Week 52 in Urinary Hexose Tetrasaccharide (Hex4) Level
timeFrame: Baseline, Week 52
measure: Change From Baseline to Week 52 in Serum Creatine Kinase (CK) Level
timeFrame: Baseline, Week 52
measure: 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
timeFrame: Days 1 and 364 (Week 52)
measure: 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
timeFrame: Days 1 and 364 (Week 52)
measure: Population PK: Cmax of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Naïve Participants
timeFrame: Days 1 and 364 (Week 52)
measure: Population PK: AUC of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Naïve Subjects
timeFrame: Days 1 and 364 (Week 52)
measure: Noncompartmental Analysis: Cmax of Plasma Total GAA Protein by Signature Peptide T09 in ERT-Naïve Subjects
timeFrame: Day 1
measure: 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
timeFrame: Day 1
measure: Comparison of Cmax of Cipaglucosidase Alfa in ERT-Experienced and ERT-Naïve Populations
timeFrame: Days 1 and 364 (Week 52)
measure: Comparison of AUC of Cipaglucosidase Alfa in ERT- Experienced and ERT-Naïve Populations
timeFrame: Days 1 and 364 (Week 52)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Neuromuscular Research Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Gainesville
country: United States
facility: UF Helath: University of Florida Clinical Research Center
state: Florida
city: Tampa
country: United States
facility: University of South Florida Research Center
state: Florida
city: Atlanta
country: United States
facility: Emory Clinic
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University Health Neuroscience Center
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Minneapolis
country: United States
facility: University of Minnesota Clinical Research Unit
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Billings
country: United States
facility: Billings Clinic
state: Montana
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Manhasset
country: United States
facility: The Feinstein Institute for Medical Research
state: New York
city: New York
country: United States
facility: NYU School of Medicine
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Neurology
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: San Antonio
country: United States
facility: University of Texas Health Science Center San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Center for Clinical and Translational Sciences
state: Utah
city: Fairfax
country: United States
facility: Lysosomal and Rare Disorders Research
state: Virginia
city: Buenos Aires
country: Argentina
facility: Hospital Universitario Austral
city: Herston
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Westmead
country: Australia
facility: Westmead Hospital
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Leuven
country: Belgium
facility: UZ Leuven
city: Banja Luka
country: Bosnia and Herzegovina
facility: University Clinical Centre of the Republic of Srpska
city: Sofia
country: Bulgaria
facility: UMHAT Alexandrovska
city: Calgary
country: Canada
facility: Heritage Medical Research Clinic, University of Calgary
state: Alberta
city: Hamilton
country: Canada
facility: McMaster University Medical Centre
state: Ontario
city: Aarhus N
country: Denmark
facility: Aarhus Universitets Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet Copenhagen Neuromuscular Center
city: Bron
country: France
facility: Hôpital Neurologique Pierre Wertheimer
city: Garches
country: France
facility: Hôpital Raymond Poincaré
city: Lille
country: France
facility: Hôpital Salengro
city: Marseille
country: France
facility: Hôpital de la Timone
city: Nice
country: France
facility: Hôpital Pasteur
city: Munich
country: Germany
facility: Friedrich-Baur Institut
state: Bavaria
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
state: NRW
city: Münster
country: Germany
facility: Universitätsklinikum Münster
state: NRW
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle (Saale)
state: Sachsen-Anhalt
city: Athens
country: Greece
facility: Eginition Hospital
state: Attica
city: Budapest
country: Hungary
facility: Semmelweis University, Institute of Genomic Medicine and Rare Disease
city: Pécs
country: Hungary
facility: University of Pécs
city: Szeged
country: Hungary
facility: University of Szeged
city: Messina
country: Italy
facility: UOC di Neurologia e Malattie Neuromuscolari
state: NAP
city: Napoli
country: Italy
facility: UOC Genetica Medica
state: NAP
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Fukuoka
country: Japan
facility: Fukuoka University Hospital
city: Kagoshima
country: Japan
facility: Kagoshima University Hospital
city: Osaka
country: Japan
facility: Izumi City General Hospital
city: Tokyo
country: Japan
facility: The Jikei University Hospital
city: Tokyo
country: Japan
facility: National Center of Neurology and Psychiatry
city: Yangsan
country: Korea, Republic of
facility: Pusan National University
state: Gyeongsangnam-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Auckland
country: New Zealand
facility: University of Auckland
city: Małogoskie
country: Poland
facility: Szpital Uniwersytecki w Krakowie
city: Rzeszów
country: Poland
facility: Centrum Medyczne
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu I Sant Pau
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital Birmingham
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals
city: London
country: United Kingdom
facility: Royal Free Hospital NHS
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
Study officials:
References:
citation: Schoser B, Roberts M, Byrne BJ, Sitaraman S, Jiang H, Laforet P, Toscano A, Castelli J, Diaz-Manera J, Goldman M, van der Ploeg AT, Bratkovic D, Kuchipudi S, Mozaffar T, Kishnani PS; PROPEL Study Group. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol. 2021 Dec;20(12):1027-1037. doi: 10.1016/S1474-4422(21)00331-8.