Limb-Girdle Muscular Dystrophy
Conditions
Brief summary
This study is designed to evaluate the safety and efficacy of deflazacort in participants with LGMD2I. Most participants enrolled will have a screening visit and 3 additional visits (after 1, 13, and 26 weeks of treatment).
Interventions
DRUGDeflazacort
Deflazacort tablet will be administered as per the dose and schedule specified in the arm.
Sponsors
PTC Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Genetic diagnosis of LGMD2I (confirmed mutation in the fukutin-related protein \[FKRP\] gene). * Ability to ascend 4 stairs greater than or equal to (≥) 2.5 seconds and be able to complete the ascent and descent both at screening and baseline. * Ability to understand the nature of the study and the consent form and to comply with study related procedures. * Must weigh between 35 to 112.5 kilograms (kg).
Exclusion criteria
* Received ≥4 weeks of continuous, systemic corticosteroid therapy within 3 months of study screening visit. * Presence of significant cardiomyopathy as defined by echocardiogram (left ventricular ejection fraction less than (\<) 30 percent \[%\]) at screening. * Requires fulltime ventilator support. * History of chronic systemic fungal or viral infections. * History of recent bacterial infection (including tuberculosis) per discretion of the Investigator. * Diagnosis of diabetes mellitus (controlled and/or uncontrolled) defined as glycated hemoglobin (HbA1c) ≥6.5% (based on historical or present diagnosis). * History of immunosuppression or other contraindications to glucocorticosteroid therapy. * Requires concomitant use or greater than (\>) 1 week of drugs or substances that are moderate to strong cytochrome P3A4 (CYP3A4) inhibitors (for example, clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) or moderate or strong CYP3A4 inducers (that is, rifampin, efavirenz, carbamazepine, phenytoin) at baseline. * Participated in an interventional clinical trial within the last 3 months prior the baseline visit. * Unable or unwilling to comply with the contraceptive requirements of the protocol. * Female participants who are pregnant and/or breastfeeding. * Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, neurologic, psychiatric, or allergic disease.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Time to Climb 4 Stairs After 26 Weeks of Treatment With Deflazacort | Baseline, Week 26 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-Minute Walk Test After 26 Weeks of Treatment of Deflazacort | Baseline, Week 26 | — |
| Change From Baseline in Time to up and go After 26 Weeks of Treatment With Deflazacort | Baseline, Week 26 | — |
| Change From Baseline in Time to Descend 4 Stairs After 26 Weeks of Treatment With Deflazacort | Baseline, Week 26 | — |
| Change From Baseline in Time to Run/Walk 10 Meters After 26 Weeks of Treatment With Deflazacort | Baseline, Week 26 | — |
| Change From Baseline in Maximal Inspiratory Pressure (MIP) and Maximal Expiratory Pressure (MEP) After 26 Weeks of Treatment With Deflazacort | Baseline, Week 26 | — |
| Change From Baseline in Hand-Held Myometry After 26 Weeks of Treatment With Deflazacort | Baseline, Week 26 | — |
| Change From Baseline in Forced Vital Capacity (FVC) After 26 Weeks of Treatment With Deflazacort | Baseline, Week 26 | — |
| Number of Participants With Adverse Events (AEs) | Baseline up to Week 52 | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. AEs were summarized separately for Stage 1 and for the overall ataluren experience. |
| Area Under the Concentration Curve From Time Zero to t (AUC0-t) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13 | — |
| Area Under the Concentration Curve From Time Zero to Infinity (AUC0-inf) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13 | — |
| Maximum Observed Plasma Concentration (Cmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13 | — |
| Time to Reach Cmax (Tmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13 | — |
| Half-Life (t1/2) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13 | — |
| Change From Baseline in Global T2 Relaxation Time of Selected Upper and Lower Limb Muscles After 26 Weeks of Treatment With Deflazacort | Baseline, Week 26 | — |
Countries
Canada, Denmark, France, Germany, Norway, Russia, Sweden, United States
Participant flow
Pre-assignment details
Participants enrolled under protocol v3.0 were 1:1 randomized to get placebo or deflazacort. After protocol v4.0, the study became an open-label study and all participants received deflazacort. Per planned analysis, participants who took at least 1 dose of deflazacort were pooled in the safety and efficacy summaries.
Participants by arm
| Arm | Count |
|---|---|
| Deflazacort Participants received deflazacort tablets, administered orally once daily at a target dose of 0.6 mg/kg/day. | 5 |
| Placebo Participants received placebo matched to deflazacort tablets, administered orally once daily for 26 weeks in placebo-controlled period. Participants were then transitioned to receive deflazacort tablets, administered orally once daily at a target dose of 0.6 mg/kg/day for 26 weeks in open-label extension period. | 6 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-Label Extension (26 Weeks) | Study Terminated | 0 | 1 |
| Open-Label Extension (26 Weeks) | Withdrawal by Subject | 1 | 1 |
| Placebo-Controlled Period (26 Weeks) | Adverse Event | 1 | 0 |
| Placebo-Controlled Period (26 Weeks) | Study Terminated | 3 | 2 |
| Placebo-Controlled Period (26 Weeks) | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Deflazacort | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 5 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Change From Baseline in Time to Climb 4 Stairs After 26 Weeks of Treatment With Deflazacort
Time frame: Baseline, Week 26
Population: Safety population included all enrolled participants who received at least 1 dose of deflazacort. Here, 'Number analyzed' = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Change From Baseline in Time to Climb 4 Stairs After 26 Weeks of Treatment With Deflazacort | Baseline | 5.476 seconds | Standard Deviation 2.0178 |
| Deflazacort | Change From Baseline in Time to Climb 4 Stairs After 26 Weeks of Treatment With Deflazacort | Change at Week 26 | -0.200 seconds | — |
Secondary
Area Under the Concentration Curve From Time Zero to Infinity (AUC0-inf) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort
Time frame: Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13
Population: The PK population included all enrolled participants who received at least 1 dose of deflazacort and had at least one PK profile. Here, 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Area Under the Concentration Curve From Time Zero to Infinity (AUC0-inf) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Baseline | 423.6 ng*hr/mL | Standard Deviation 150.16 |
| Deflazacort | Area Under the Concentration Curve From Time Zero to Infinity (AUC0-inf) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 1 | 520.3 ng*hr/mL | Standard Deviation 31.508 |
Secondary
Area Under the Concentration Curve From Time Zero to t (AUC0-t) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort
Time frame: Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13
Population: The pharmacokinetic (PK) population included all enrolled participants who received at least 1 dose of deflazacort and had at least one PK profile. Here, 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Area Under the Concentration Curve From Time Zero to t (AUC0-t) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Baseline | 401.1 nanograms (ng)*hour (hr)/milliliter (mL) | Standard Deviation 139.62 |
| Deflazacort | Area Under the Concentration Curve From Time Zero to t (AUC0-t) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Week 13 | 365.6 nanograms (ng)*hour (hr)/milliliter (mL) | — |
| Deflazacort | Area Under the Concentration Curve From Time Zero to t (AUC0-t) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 1 | 418.2 nanograms (ng)*hour (hr)/milliliter (mL) | Standard Deviation 58.569 |
| Deflazacort | Area Under the Concentration Curve From Time Zero to t (AUC0-t) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 13 | 515.3 nanograms (ng)*hour (hr)/milliliter (mL) | — |
Secondary
Change From Baseline in 2-Minute Walk Test After 26 Weeks of Treatment of Deflazacort
Time frame: Baseline, Week 26
Population: Safety population included all enrolled participants who received at least 1 dose of deflazacort. Here, 'Number analyzed' = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Change From Baseline in 2-Minute Walk Test After 26 Weeks of Treatment of Deflazacort | Baseline | 135.4 meters | Standard Deviation 26.75 |
| Deflazacort | Change From Baseline in 2-Minute Walk Test After 26 Weeks of Treatment of Deflazacort | Change at Week 26 | 2.0 meters | — |
Secondary
Change From Baseline in Forced Vital Capacity (FVC) After 26 Weeks of Treatment With Deflazacort
Time frame: Baseline, Week 26
Population: Due to early termination of the study and missing efficacy assessment data due to missed visits related to COVID-19, data was not collected or analyzed for this secondary efficacy endpoint.
Secondary
Change From Baseline in Global T2 Relaxation Time of Selected Upper and Lower Limb Muscles After 26 Weeks of Treatment With Deflazacort
Time frame: Baseline, Week 26
Population: Due to early termination of the study and missing efficacy assessment data due to missed visits related to COVID-19, data was not collected or analyzed for this secondary efficacy endpoint.
Secondary
Change From Baseline in Hand-Held Myometry After 26 Weeks of Treatment With Deflazacort
Time frame: Baseline, Week 26
Population: Due to early termination of the study and missing efficacy assessment data due to missed visits related to COVID-19, data was not collected or analyzed for this secondary efficacy endpoint.
Secondary
Change From Baseline in Maximal Inspiratory Pressure (MIP) and Maximal Expiratory Pressure (MEP) After 26 Weeks of Treatment With Deflazacort
Time frame: Baseline, Week 26
Population: Due to early termination of the study and missing efficacy assessment data due to missed visits related to COVID-19, data was not collected or analyzed for this secondary efficacy endpoint.
Secondary
Change From Baseline in Time to Descend 4 Stairs After 26 Weeks of Treatment With Deflazacort
Time frame: Baseline, Week 26
Population: Safety population included all enrolled participants who received at least 1 dose of deflazacort. Here, 'Number analyzed' = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Change From Baseline in Time to Descend 4 Stairs After 26 Weeks of Treatment With Deflazacort | Baseline | 3.66 seconds | Standard Deviation 1.707 |
| Deflazacort | Change From Baseline in Time to Descend 4 Stairs After 26 Weeks of Treatment With Deflazacort | Change at Week 26 | 0.10 seconds | — |
Secondary
Change From Baseline in Time to Run/Walk 10 Meters After 26 Weeks of Treatment With Deflazacort
Time frame: Baseline, Week 26
Population: Safety population included all enrolled participants who received at least 1 dose of deflazacort. Here, 'Number analyzed' = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Change From Baseline in Time to Run/Walk 10 Meters After 26 Weeks of Treatment With Deflazacort | Baseline | 8.53 seconds | Standard Deviation 1.897 |
| Deflazacort | Change From Baseline in Time to Run/Walk 10 Meters After 26 Weeks of Treatment With Deflazacort | Change at Week 26 | -0.40 seconds | — |
Secondary
Change From Baseline in Time to up and go After 26 Weeks of Treatment With Deflazacort
Time frame: Baseline, Week 26
Population: Safety population included all enrolled participants who received at least 1 dose of deflazacort. Here, 'Number analyzed' = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Change From Baseline in Time to up and go After 26 Weeks of Treatment With Deflazacort | Baseline | 11.93 seconds | Standard Deviation 4.743 |
| Deflazacort | Change From Baseline in Time to up and go After 26 Weeks of Treatment With Deflazacort | Change at Week 26 | 9.70 seconds | — |
Secondary
Half-Life (t1/2) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort
Time frame: Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13
Population: The PK population included all enrolled participants who received at least 1 dose of deflazacort and had at least one PK profile. Here, 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Half-Life (t1/2) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Baseline | 1.174 hr | Standard Deviation 0.0849 |
| Deflazacort | Half-Life (t1/2) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Week 13 | 1.235 hr | — |
| Deflazacort | Half-Life (t1/2) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 1 | 2.358 hr | Standard Deviation 0.5825 |
| Deflazacort | Half-Life (t1/2) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 13 | 1.95 hr | — |
Secondary
Maximum Observed Plasma Concentration (Cmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort
Time frame: Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13
Population: The PK population included all enrolled participants who received at least 1 dose of deflazacort and had at least one PK profile. Here, 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deflazacort | Maximum Observed Plasma Concentration (Cmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Baseline | 184.8 ng/mL | Standard Deviation 49.054 |
| Deflazacort | Maximum Observed Plasma Concentration (Cmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Week 13 | 171.0 ng/mL | — |
| Deflazacort | Maximum Observed Plasma Concentration (Cmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 1 | 135.8 ng/mL | Standard Deviation 29.205 |
| Deflazacort | Maximum Observed Plasma Concentration (Cmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 13 | 162.0 ng/mL | — |
Secondary
Number of Participants With Adverse Events (AEs)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. AEs were summarized separately for Stage 1 and for the overall ataluren experience.
Time frame: Baseline up to Week 52
Population: Safety population included all enrolled participants who received at least 1 dose of deflazacort. Per planned analysis, participants who took at least 1 dose of deflazacort were pooled in the safety summaries. The participants who received only placebo during the study were not included for safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deflazacort | Number of Participants With Adverse Events (AEs) | 5 Participants |
Secondary
Time to Reach Cmax (Tmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort
Time frame: Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Baseline and Week 13
Population: The PK population included all enrolled participants who received at least 1 dose of deflazacort and had at least one PK profile. Here, 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Deflazacort | Time to Reach Cmax (Tmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Baseline | 0.992 hr |
| Deflazacort | Time to Reach Cmax (Tmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 21-desacetyl deflazacort: Week 13 | 0.525 hr |
| Deflazacort | Time to Reach Cmax (Tmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 1 | 1.000 hr |
| Deflazacort | Time to Reach Cmax (Tmax) of 21-desacetyl Deflazacort and 6β-hydroxy-21-desacetyl Deflazacort | 6β-hydroxy-21-desacetyl deflazacort: Week 13 | 1.550 hr |