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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

Tracking Information
First Submitted Date  ICMJE October 10, 2018
First Posted Date  ICMJE November 2, 2018
Last Update Posted Date March 20, 2020
Actual Study Start Date  ICMJE December 4, 2018
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 1, 2018)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 29, 2019)
  • 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
  • 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
  • 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
  • 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.
  • 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).
  • 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.
  • 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.
  • 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'.
  • 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".
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Biomarkers/Pharmacodynamics of muscle injury and disease substrate [ Time Frame: 12 months ]
    Change from baseline in Creatine Kinase and Urinary Hexose Tetrasaccharide
  • popPK: Cmax [ Time Frame: 12 months ]
    Maximum observed plasma concentration
  • popPK: Tmax [ Time Frame: 12 months ]
    time to reach Tmax
  • popPK: AUC0-inf [ Time Frame: 12 months ]
    Area under the curve from time 0 extrapolated to infinite time
  • popPK: t1/2 [ Time Frame: 12 months ]
    terminal elimination half-live
  • popPK: CLT [ Time Frame: 12 months ]
    Total Body Clearance
Original Secondary Outcome Measures  ICMJE
 (submitted: November 1, 2018)
  • 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
  • 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
  • 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.
  • 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'.
  • 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.
  • 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".
  • 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).
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Biomarkers/Pharmacodynamics of muscle injury and disease substrate [ Time Frame: 12 months ]
    Change from baseline in Creatine Kinase and Urinary Hexose Tetrasaccharide
  • popPK: Cmax [ Time Frame: 12 months ]
    Maximum observed plasma concentration
  • popPK: Tmax [ Time Frame: 12 months ]
    time to reach Tmax
  • popPK: AUC0-inf [ Time Frame: 12 months ]
    Area under the curve from time 0 extrapolated to infinite time
  • popPK: t1/2 [ Time Frame: 12 months ]
    terminal elimination half-live
  • popPK: CLT [ Time Frame: 12 months ]
    Total Body Clearance
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PROPEL Study - A Study Comparing ATB200/AT2221 With Alglucosidase/Placebo in Adult Subjects With LOPD
Official Title  ICMJE 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
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, 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:
Double-blind masking
Primary Purpose: Treatment
Condition  ICMJE Pompe Disease (Late-onset)
Intervention  ICMJE
  • Drug: AT2221
    Participants received ATB200 co-administered with AT2221 (Miglustat)
    Other Name: Miglustat
  • 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
  • Biological: ATB200
    Enzyme Replacement Therapy via intravenous infusion
Study Arms  ICMJE
  • Experimental: ATB200/AT2221
    Participants received ATB200 co-administered with AT2221 capsule (Miglustat)
    Interventions:
    • Drug: AT2221
    • Biological: ATB200
  • Active Comparator: alglucosidase alfa/placebo
    Participants received alglucosidase alfa co-administered with placebo capsules.
    Intervention: Biological: alglucosidase alfa
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 1, 2018)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Bosnia and Herzegovina,   Bulgaria,   Canada,   Denmark,   France,   Germany,   Greece,   Hungary,   Italy,   Japan,   Korea, Republic of,   Netherlands,   New Zealand,   Poland,   Slovenia,   Spain,   Sweden,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03729362
Other Study ID Numbers  ICMJE ATB200-03
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Amicus Therapeutics
Study Sponsor  ICMJE Amicus Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Amicus Therapeutics
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP