The objective of the study is to asses the efficacy and safety of intravenous ATB200 co-administration with oral AT2221 by evaluating the changes in key clinical outcome measures (eg, motor, respiratory, fatigue) in adult subjects with late-onset…
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Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
- Musculoskeletal and connective tissue disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the change from baseline to Week 52 in 6MWD.
Secondary outcome
Key secondary efficacy endpoints are as follows:
• change from baseline to Week 52 in the manual muscle test score for the lower
extremities
• change from baseline to Week 52 in the total score for the PROMIS - physical
function
• change from baseline to Week 52 in the total score for the PROMIS - fatigue
• change from baseline to Week 52 in GSGC total score
• change from baseline to Week 52 in sitting FVC (% predicted)
• change from baseline to Week 26 in 6MWD
Other secondary efficacy endpoints are as follows:
• change from baseline to Week 52 in the following variables related to motor
function:
* time to complete the 10-meter walk (ie, assessment of gait) of the GSGC test
* time to complete the 4-stair climb of the GSGC test
* time to complete the Gower*s maneuver of the GSGC test
* time to arise from a chair as part of the GSGC test
* time to complete the TUG test
• change from baseline to Week 52 in the following variables related to muscle
strength:
* manual muscle test score for the upper extremities
* manual muscle test total score
* quantitative muscle test value (kg) for the upper extremities
* quantitative muscle test value (kg) for the lower extremities
* quantitative muscle test total value (kg)
• change from baseline to Week 52 in the following variables from
patient-reported outcome measures:
* total score for the PROMIS - dyspnea
* total score for the PROMIS - upper extremity
* R-PAct Scale total score
* EQ-5D-5L health status
• actual value of the subject*s functional status (improving, stable, or
declining) pertaining to the effects of study drug in the following areas of
life at Week 52, as measured by the Subject*s Global Impression of Change
* overall physical wellbeing
* effort of breathing
* muscle strength
* muscle function
* ability to move around
* activities of daily living
* energy level
* level of muscular pain
• actual value of the subject*s functional status (improving, stable, or
declining) at Week 52, as measured by the Physician*s Global Impression of
Change
• change from baseline to Week 52 in the following measures of pulmonary
function, as
follows:
* sitting SVC (% predicted)
* MIP (cmH2O)
* MIP (% predicted)
* MEP (cmH2O)
* MEP (% predicted)
* SNIP (cmH2O)
Pharmacodynamic endpoints are as follows:
• change from baseline to Week 52 in serum CK level
• change from baseline to Week 52 in urinary Hex4 level
Pharmacokinetic endpoints from a population PK analysis of total GAA protein
level and AT2221 concentration will be provided in a separate modeling and
simulation plan. The safety profile of ATB200/AT2221 will be characterized
using incidence of treatment-emergent adverse events (TEAEs), serious adverse
events (SAEs), and AEs leading to discontinuation of study drug, frequency and
severity of immediate and late IARs, and any abnormalities noted in other
safety assessments. Immunogenicity to ATB200 and alglucosidase alfa will also
be described.
Background summary
Pompe disease, also known as acid maltase deficiency or glycogen storage
disease type II, is an autosomal recessive genetic disorder caused by mutations
in the GAA gene that encodes acid α-glucosidase (GAA), an enzyme that catalyzes
the breakdown of lysosomal glycogen.The objective of the study is to assess the
efficacy and safety of intravenous ATB200 co-administration with oral AT2221 in
adult subjects with late-onset pompe disease compared with alglucosidase
alfa/placebo.
Study objective
The objective of the study is to asses the efficacy and safety of intravenous
ATB200 co-administration with oral AT2221 by evaluating the changes in key
clinical outcome measures (eg, motor, respiratory, fatigue) in adult subjects
with late-onset Pompe disease (LOPD) in comparison with the standard-of-care
enzyme replacement therapy, alglucosidase alfa, with placebo.
Study design
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.
Intervention
Investigational Product, dosage and mode of administration:
ATB200/AT2221 will be administered as a combination treatment regimen,
consisting of AT2221 260 mg (4 × 65 mg oral capsules), followed approximately 1
hour later by ATB200 20 mg/kg (reconstituted lyophilized drug product for
intravenous [IV] infusion, 105 mg/vial). The ATB200/AT2221 combination regimen
will be administered every 2 weeks.
Reference Therapy, dosage and mode of administration:
Alglucosidase alfa/placebo will be administered as a combination treatment
regimen, consisting of placebo (4 × placebo oral capsules) followed
approximately 1 hour later by alglucosidase alfa 20 mg/kg (reconstituted
lyophilized drug product for IV infusion, 50 mg/vial). The alglucosidase
alfa/placebo combination regimen will be administered every 2 weeks.
Study burden and risks
Participation in this study will include 13 months. During this study the
following study procedures will be performed:
Questions about health and medication, physical exam (including blood pressure,
heart rate, temperature, breathing, height and weight), ECG, questionnaires
((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 and Physician's Global Impression of Change), 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]), muscle strength testing (manual muscle testing
and quantitative muscle testing), motor function testing including six-minute
walk test (additional tests; (Gait, Stair, Gower, and Chair maneuver [GSGC]
test and Timed Up and Go [TUG] test), blood tests (venapuncture), urine
collection, genetics test and pregnancy test.
Risks: When taking the bloodsamples redness, swelling and/or pin can occur at
the site of injection. When removing the ECG some irritation of the skin can
occur. The genetic test for Pompe disease can be uncomfortable for the
subjects.
Cedar Brook Drive 1
Cranbury NJ 08512
US
Cedar Brook Drive 1
Cranbury NJ 08512
US
Listed location countries
Age
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 >= 50 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:
a. deficiency of GAA enzyme
b. GAA genotyping
c. muscle biopsy
5. Subject is classified as one of the following with respect to ERT status:
a. 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
b. 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:
a. both screening values of 6MWD are >= 75 meters
b. both screening values of 6MWD are <= 90% of the predicted value for healthy adults
c. 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 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.
6. Subject, if female, is pregnant or breastfeeding at screening.
7. Subject, whether male or female, is planning to conceive a child during the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000755-40-NL |
| ClinicalTrials.gov | NCT03729362 |
| CCMO | NL68006.078.18 |