| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult Subjects With Late Onset Pompe Disease (LOPD) |
| възрастни пациенти с късно проявяваща се болест на Помпе |
|
| E.1.1.1 | Medical condition in easily understood language |
| A change in the genetic material resulting in lower levels of an enzyme called acid alpha-glucosidase (GAA). The GAA enzyme helps the body to break down glycogen, a type of stored sugar. |
| При промяна в генетичния материал се наблюдават по-ниски нива от ензим, наречен алфаглюкозидаза (GAA). Този ензим помага на организма да разгражда гликоген - вид захарен запас. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10075702 |
| E.1.2 | Term | Pompe's disease late onset |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objective is to assess the efficacy of ATB200/AT2221 co-administration on ambulatory function, as measured by the 6 Minute Walk Test (6MWT), compared with alglucosidase alfa/placebo |
|
| E.2.2 | Secondary objectives of the trial |
-To assess the efficacy of ATB200/AT2221 co-administration (compared with alglucosidase alfa/placebo) on:pulmonary function as measured by sitting forced vital capacity (FVC)(%predicted),muscle strength,health-related PRO,motor function,overall clinical impression as assessed by both physician and subject
-To assess safety,tolerability, and immunogenicity of ATB200/AT2221 co administration compared with alglucosidase alfa/placebo
- To assess the effect of ATB200/AT2221 co-administration on biomarkers of muscle injury and disease substrate compared with alglucosidase alfa/placebo
-To characterize population PK of ATB200 and alglucosidase alfa in ERTexperienced subjects using plasma total GAAprotein level by signature peptide assay and plasma AT2221 concentration
- To characterize PK of ATB200/ alglucosidase alfa/AT2221 in ERT-na?ve subjects using noncompartmental analysis
-To explore exposure-response relationship for ATB200/AT2221 and alglucosidase alfa/placebo co-administration |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 ≥ 40kg 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
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 naive, 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
|
|
| E.4 | Principal 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from baseline to Week 52 in 6MWD. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At visits Week 12, 26 and Week 52. |
|
| E.5.2 | Secondary end point(s) |
- change from baseline to Week 52 in sitting FVC (% predicted)
- 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 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Almost all timepoint evaluations happen at visit week 52. Change from baseline for 6MWT is also measured at visit week 26. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Effect on biomarkers of muscle injury and disease substrate
Explore the exposure-response relationship for ATB200/AT2221 and alglucosidase alfa/placebo co-administration |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Bosnia and Herzegovina |
| Bulgaria |
| Canada |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Romania |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LPLV (November 2020) |
| ПППУ (Ноември 2020) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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