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

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ClinicalTrials.gov Identifier: NCT03729362
Recruitment Status : Recruiting
First Posted : November 2, 2018
Last Update Posted : February 8, 2019
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 : October 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. 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

  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. 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.

  4. 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'.

  5. 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.

  6. 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".

  7. 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).

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  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



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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


Contacts
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Contact: For Site 609-662-2000 PompeSiteInfo@amicusrx.com
Contact: For Patient 609-662-2000 patientadvocacy@amicusrx.com

Locations
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United States, Arizona
Neuromuscular Research Center Recruiting
Phoenix, Arizona, United States, 85028
United States, California
University of California, Irvine Recruiting
Irvine, California, United States, 92868
United States, Florida
UF Helath: University of Florida Clinical Research Center Recruiting
Gainesville, Florida, United States, 32610
United States, Georgia
Emory Clinic Recruiting
Atlanta, Georgia, United States, 30322
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
United States, Virginia
Lysosomal and Rare Disorders Research Recruiting
Fairfax, Virginia, United States, 22030
Australia, South Australia
Royal Adelaide Hospital Recruiting
Adelaide, South Australia, Australia, 5000
Sponsors and Collaborators
Amicus Therapeutics

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Responsible Party: Amicus Therapeutics
ClinicalTrials.gov Identifier: NCT03729362     History of Changes
Other Study ID Numbers: ATB200-03
First Posted: November 2, 2018    Key Record Dates
Last Update Posted: February 8, 2019
Last Verified: February 2019
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