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PROPEL Study - A Study Comparing ATB200/AT2221 With Alglucosidase/Placebo in Adult Subjects With LOPD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03729362
Recruitment Status : Active, not recruiting
First Posted : November 2, 2018
Last Update Posted : March 20, 2020
Sponsor:
Information provided by (Responsible Party):
Amicus Therapeutics

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.

Condition or disease Intervention/treatment Phase
Pompe Disease (Late-onset) Drug: AT2221 Biological: alglucosidase alfa Biological: ATB200 Phase 3

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, Gower, and Chair maneuver [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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Double-blind masking
Primary Purpose: Treatment
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
Actual Study Start Date : December 4, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : January 2021


Arm Intervention/treatment
Experimental: ATB200/AT2221
Participants received ATB200 co-administered with AT2221 capsule (Miglustat)
Drug: AT2221
Participants received ATB200 co-administered with AT2221 (Miglustat)
Other Name: Miglustat

Biological: ATB200
Enzyme Replacement Therapy via intravenous infusion

Active Comparator: alglucosidase alfa/placebo
Participants received alglucosidase alfa co-administered with placebo capsules.
Biological: alglucosidase alfa
alglucosidase alfa via intravenous infusion as prescribed by the participant's treating physician and in accordance with the approved prescribing information via intravenous infusion as prescribed by the participant's treating physician and in accordance with the approved prescribing information




Primary Outcome Measures :
  1. 6-Minute Walk Test [ Time Frame: 12 months ]
    Change in 6MWD from baseline to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo


Secondary Outcome Measures :
  1. Pulmonary Function - Forced vital capacity (FVC) [ Time Frame: 12 months ]
    Change from baseline in FVC (sitting and supine) to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo

  2. Manual Muscle Strength [ Time Frame: 12 months ]
    Change in manual muscle strength from baseline to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo

  3. Quantitative Muscle Strength [ Time Frame: 12 months ]
    Change in Quantitative muscle strength from baseline to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo

  4. PROMIS instruments questionnaires [ Time Frame: 12 months ]
    Change from baseline in scores of PROMIS instruments for physical function, fatigue, dyspnea, and upper extremity questionnaire to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo. The PROMIS instruments for physical function (20 items), d upper extremity (7 items) measure signs and symptoms using general questions without a temporal reference. The PROMIS instruments for fatigue (8 items) and dyspnea severity (10 items) measure signs and symptoms over the past 7 days. A 5-point scale is used for each instrument (though responses may vary within or among instruments), and a total score is generated for each instrument.

  5. Motor Function - Gait, Stairs, Gower, Chair (GSGC) test [ Time Frame: 12 months ]
    Change from baseline in GSGC score to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo. The GSGC consists of a 10-meter walk for evaluation of gait, a 4-stair climb, Gower's maneuver, and arising from a chair. Results of the GSGC include the time required to complete the individual tests, individual scores for each of the tests (1 to 7 points for each of gait, 4-stair climb, and Gower's maneuver and 1 to 6 points for arising from a chair), and a total score. The total score ranges from a minimum of 4 points (normal performance) to a maximum of 27 points (worst score).

  6. Motor Function - Timed Up and Go (TUG) [ Time Frame: 12 months ]
    Change from baseline in TUG to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo. The TUG test measures the time it takes for the subject to rise from a chair, walk 3 meters, turn around, walk back to the chair, and sit down will be recorded.

  7. The Rasch-built Pompe-specific activity (R-PAct) questionnaires [ Time Frame: 12 months ]
    Change from baseline in scores of R-PAct scale questionnaire to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo. The R-PAct scale is an 18-item questionnaire to measure limitations in activities and restriction in social participation. Possible responses to questions are as follows: unable to perform, able to perform, but with difficulty, and able to perform without difficulty. A raw score ranging from 0 to 36 points is generated. The low score indicates the highest level of disability.

  8. EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaires [ Time Frame: 12 months ]
    Change from baseline in scores of EQ-5D-5L questionnaire to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo. The EQ-5D-5L comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Subjects are asked to indicate their health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. The subject's self rated health is also recorded on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'.

  9. Subject's Global Impression of Change questionnaires [ Time Frame: 12 months ]
    Change from baseline in scores of Subject's Global Impression of Change (SGIC) questionnaire to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo. The Subject's Global Impression of Change is designed to record the subjects' impression of their functional status since starting study drug using a 7-point scale ranging from "very much worse" to "very much improved".

  10. Physician Overall Clinical Impression [ Time Frame: 12 months ]
    Change in the Physician's Global Impression of Change (PGIC) evaluation to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo

  11. Pulmonary Function - Slow Vital Capacity (SVC) [ Time Frame: 12 months ]
    Change from baseline in SVC (sitting and supine) to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo

  12. Pulmonary Function - Maximum Inspiratory Pressure (MIP) [ Time Frame: 12 months ]
    Change from baseline in MIP to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo

  13. Pulmonary Function - Maximum Expiratory Pressure [ Time Frame: 12 months ]
    Change from baseline in MEP to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo

  14. Pulmonary Function - Sniff Nasal Inspiratory Pressure (SNIP) [ Time Frame: 12 months ]
    Change from baseline in SNIP to assess the efficacy of ATB200/AT2221 co-administration compared with alglucosidase alfa/placebo

  15. Number of participants with TEAEs and SARs [ Time Frame: 12 months ]
    Evaluation of Treatment Emergent Adverse Events (TEAEs) begins after written informed consent is provided, including study related events that occur as a direct result of a study procedure to assess the safety, tolerability of ATB200/AT2221 co administration compared with alglucosidase alfa/placebo

  16. Immunogenicity [ Time Frame: 12 months ]
    Measurement of anti-rhGAA Abs (total, cross-reactive, and neutralizing) to assess the Immunogenicity of ATB200/AT2221 co administration compared with alglucosidase alfa/placebo

  17. Biomarkers/Pharmacodynamics of muscle injury and disease substrate [ Time Frame: 12 months ]
    Change from baseline in Creatine Kinase and Urinary Hexose Tetrasaccharide

  18. popPK: Cmax [ Time Frame: 12 months ]
    Maximum observed plasma concentration

  19. popPK: Tmax [ Time Frame: 12 months ]
    time to reach Tmax

  20. popPK: AUC0-inf [ Time Frame: 12 months ]
    Area under the curve from time 0 extrapolated to infinite time

  21. popPK: t1/2 [ Time Frame: 12 months ]
    terminal elimination half-live

  22. popPK: CLT [ Time Frame: 12 months ]
    Total Body Clearance



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03729362


Locations
Hide Hide 73 study locations
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United States, Arizona
Neuromuscular Research Center
Phoenix, Arizona, United States, 85028
United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205
United States, California
University of California, Irvine
Irvine, California, United States, 92868
United States, Florida
UF Helath: University of Florida Clinical Research Center
Gainesville, Florida, United States, 32610
University of South Florida Research Center
Tampa, Florida, United States, 33612
United States, Georgia
Emory Clinic
Atlanta, Georgia, United States, 30322
United States, Indiana
Indiana University Health Neuroscience Center
Indianapolis, Indiana, United States, 46202
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66205
United States, Minnesota
University of Minnesota Clinical Research Unit
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, Montana
Billings Clinic
Billings, Montana, United States, 59101
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
The Feinstein Institute for Medical Research
Manhasset, New York, United States, 11030
NYU School of Medicine
New York, New York, United States, 10017
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
University of Cincinnati Neurology
Cincinnati, Ohio, United States, 45219
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
The Ohio State University Wexner Medical Center
Columbus, Ohio, United States, 43210
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Penn State Health Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
University of Texas Health Science Center San Antonio
San Antonio, Texas, United States, 78229
United States, Utah
University of Utah, Center for Clinical and Translational Sciences
Salt Lake City, Utah, United States, 84108
United States, Virginia
Lysosomal and Rare Disorders Research
Fairfax, Virginia, United States, 22030
Argentina
Hospital Universitario Austral
Buenos Aires, Argentina, B1629ODT
Australia, Queensland
Royal Brisbane & Women's Hospital
Herston, Queensland, Australia, 4029
Australia, South Australia
Royal Adelaide Hospital
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Monash Medical Centre
Melbourne, Victoria, Australia, 3168
Australia
Westmead Hospital
Westmead, Australia, 2145
Austria
Medizinische Universität Innsbruck
Innsbruck, Austria
Belgium
UZ Leuven
Leuven, Belgium, 3000
Bosnia and Herzegovina
University Clinical Centre of the Republic of Srpska
Banja Luka, Bosnia and Herzegovina, 78000
Bulgaria
UMHAT Alexandrovska
Sofia, Bulgaria
Canada, Alberta
Heritage Medical Research Clinic, University of Calgary
Calgary, Alberta, Canada, T2N 4Z6
Canada, Ontario
McMaster University Medical Centre
Hamilton, Ontario, Canada, L8N 3Z5
Denmark
Aarhus Universitets Hospital
Aarhus N, Denmark, 8200
Rigshospitalet Copenhagen Neuromuscular Center
Copenhagen, Denmark, 2100
France
Hôpital Neurologique Pierre Wertheimer
Bron, France, 69677
Hôpital Raymond Poincaré
Garches, France, 92380
Hôpital Salengro
Lille, France, 59037
Hôpital de la Timone
Marseille, France, 13385
Hôpital Pasteur
Nice, France, 06001
Germany
Friedrich-Baur Institut
Munich, Bavaria, Germany, 80336
Universitätsklinikum Bonn
Bonn, NRW, Germany, 53105
Universitätsklinikum Münster
Münster, NRW, Germany, 48149
Universitätsklinikum Halle (Saale)
Halle (Saale), Sachsen-Anhalt, Germany, 06120
Greece
Eginition Hospital
Athens, Attica, Greece, 11528
Hungary
Semmelweis University, Institute of Genomic Medicine and Rare Disease
Budapest, Hungary, 1083
University of Pécs
Pécs, Hungary, 7623
University of Szeged
Szeged, Hungary, 6725
Italy
UOC di Neurologia e Malattie Neuromuscolari
Messina, NAP, Italy, 98125
UOC Genetica Medica
Napoli, NAP, Italy, 80131
Japan
Hokkaido University Hospital
Sapporo, Hokkaido, Japan, 060 8648
Fukuoka University Hospital
Fukuoka, Japan, 814-0180
Kagoshima University Hospital
Kagoshima, Japan
Izumi City General Hospital
Osaka, Japan
The Jikei University Hospital
Tokyo, Japan, 105-8471
National Center of Neurology and Psychiatry
Tokyo, Japan
Korea, Republic of
Pusan National University
Yangsan, Gyeongsangnam-do, Korea, Republic of, 50612
Seoul National University Hospital
Seoul, Korea, Republic of, 03080
Netherlands
Erasmus MC
Rotterdam, Netherlands, 3015GD
New Zealand
University of Auckland
Auckland, New Zealand
Poland
Szpital Uniwersytecki w Krakowie
Małogoskie, Poland, 31-066
Centrum Medyczne
Rzeszów, Poland, 35-326
Slovenia
University Medical Centre Ljubljana
Ljubljana, Slovenia, 1000
Spain
Hospital de la Santa Creu I Sant Pau
Barcelona, Spain, 08026
Sweden
Sahlgrenska University Hospital
Gothenburg, Sweden, 41345
Taiwan
National Taiwan University Hospital
Taipei, Taiwan, 100
United Kingdom
Queen Elizabeth Hospital Birmingham
Birmingham, United Kingdom
Cambridge University Hospitals
Cambridge, United Kingdom
Royal Free Hospital NHS
London, United Kingdom, NW3 2QG
Salford Royal NHS Foundation Trust
Salford, United Kingdom, M6 8HD
Sponsors and Collaborators
Amicus Therapeutics
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Responsible Party: Amicus Therapeutics
ClinicalTrials.gov Identifier: NCT03729362    
Other Study ID Numbers: ATB200-03
First Posted: November 2, 2018    Key Record Dates
Last Update Posted: March 20, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amicus Therapeutics:
Pompe
rhGAA
Additional relevant MeSH terms:
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Glycogen Storage Disease Type II
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Glycogen Storage Disease
Carbohydrate Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Miglustat
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Glycoside Hydrolase Inhibitors
Hypoglycemic Agents
Physiological Effects of Drugs