Congenital Muscular Dystrophy
Conditions
Brief summary
The purpose of the study is to establish the pharmacokinetic profile of omigapil in paediatric and adolescent patients with CMD and to evaluate the safety and tolerability of omigapil. Funding source - FDA OOPD
Interventions
DRUGOmigapil
Cohort 1 0.02 mg/kg/day Cohort 2 0.08 mg/kg/day Cohort 3a 0.04 mg/kg/day Cohort 3b 0.06 mg/kg/day
Sponsors
Santhera Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Ambulatory and non-ambulatory patients from age 5 - 16 years (5 years old and \<17 years old) at time of screening with a clinical picture (see below) consistent with COL6-related dystrophy (COL6-RD) or LAMA2-related dystrophy (LAMA2-RD) * Under regular review at a neuromuscular center * On adequate double-barrier contraception (if of child-bearing potential) * Stable on any allowed concomitant medications for 1 month prior to run in Phase * Forced Vital Capacity (FVC) 30-80% of the predicted value and confirmed at Screening and Baseline visit(s) For patients with Collagen VI-related dystrophy (COL6-RD)- required clinical picture: • Muscle weakness: inability to walk or, if patient is still ambulatory, inability to run and \> 5 s for 10 m walk Genetic and Pathology: • Molecular diagnosis of COL6-RD, defined by one dominant or two recessive mutation(s) in COL6A1, COL6A2 or COL6A3 known to cause the clinical picture,, OR • Histological diagnosis showing (i) absent or significantly decreased expression of collagen VI in muscle (overall reduction or basal lamina specific) or (ii) absent or significantly abnormal matrix in skin fibroblast culture For patients with Laminin alpha 2 related dystrophy (LAMA2-RD) - required clinical picture: • Muscle weakness: Inability to walk; if patient is still ambulatory, inability to run and \> 5 s for 10 m walk. Genetics and Pathology: • Either: 2 identified pathologic or probable pathologic mutations in LAMA2 gene OR: • 1 identified pathologic or probable pathologic mutation in LAMA 2 gene with evidence of decrease in laminin alpha 2 staining on muscle or skin biopsy OR: • Evidence of decrease in laminin alpha 2 staining on muscle or skin biopsy with matching clinical phenotype and no suspicion of alpha dystroglycanopathy (aDG-RD) (clinically or by staining on muscle biopsy)
Exclusion criteria
* Use of any investigational drug other than the study medication within 12 weeks of study start. * Recurrent hospitalisation for chest infections in previous 2 years (≥2 per year) * Patients with respiratory parameters (eg: low pulmonary function test value i.e. \<30% or need for brief course of daytime non-invasive ventilation) currently affected by short term medications, or acute illness/ conditions (conduct baseline assessments when the patient has recovered and no longer taking acute medication) * Any need for surgery (scoliosis, gastrostomy, other) in the preceding 24 weeks or foreseen during the course of the study. * Patient has an intercurrent significant medical condition or situation which in the opinion of the Investigator or the study Medical Monitor may put the patient at significant risk, confound the study results or interfere significantly with the patient's participation in the study * Failure to thrive, defined as: * Falling 20 percentiles (20/100) in body weight in the 12 weeks preceding Screening/Baseline (based on family report of weight loss and acquiring relevant medical records) * In patients below the 3rd percentile, any further drop in body weight percentile in the 12 weeks preceding Screening/Baseline (based on family report of weight loss and acquiring relevant medical records) * Weight less than 17kg at Baseline * Morbidly obese or grossly overweight (≥86 percentile BMI in children) * History of epilepsy or on antiepileptic medication at Screening/Baseline * Diabetes * On daytime Non Invasive Ventilation (NIV) * Intake of prohibited medication (as listed in Appendix I) * Anticipated need for anesthesia during the course of this study * Patients with renal impairment defined as urinary protein concentration ≥ 0.2 g/L * Patients with moderate to severe hepatic impairment * ALT ≥ 8x upper limit of normal (ULN) and total bilirubin 2x ULN (plus \>35% 'direct' bilirubin), or * ALT ≥ 8x ULN and INR \>1.5 or ALT \>2x baseline levels, and total bilirubin \> 2x ULN (plus \>35% 'direct' bilirubin), or * ALT \>2x baseline levels, and INR greater than 1.5,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | 0.5, 1, 1.5, 2, 4 and 8 hours post-dose on Day 1, Week 4 and Week 12 |
| Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | 0.5, 1, 1.5, 2, 4 and 8 hours post-dose on Day 1, Week 4 and Week 12 |
| Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | 0 to 8 hours post-dose on Day 1, Week 4, Week 12 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of All Treatment-emergent Adverse Events (TEAEs) | 12 weeks | TEAEs reported during the treatment period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 0.02 mg/kg/Day Omigapil treatment, oral administration once per day after breakfast | 4 |
| Cohort 2 0.08 mg/kg/Day Omigapil treatment, oral administration once per day after breakfast | 4 |
| Cohort 3a 0.04 mg/kg/Day Omigapil treatment, oral administration once per day after breakfast | 4 |
| Cohort 3b 0.06 mg/kg/Day Omigapil treatment, oral administration once per day after breakfast | 8 |
| Total | 20 |
Baseline characteristics
| Characteristic | Total | Cohort 1 0.02 mg/kg/Day | Cohort 2 0.08 mg/kg/Day | Cohort 3a 0.04 mg/kg/Day | Cohort 3b 0.06 mg/kg/Day |
|---|---|---|---|---|---|
| Age, Continuous | 10.2 years STANDARD_DEVIATION 3.3 | 8.9 years STANDARD_DEVIATION 2.9 | 10.2 years STANDARD_DEVIATION 1.4 | 9.3 years STANDARD_DEVIATION 1.4 | 11.2 years STANDARD_DEVIATION 4.6 |
| Race/Ethnicity, Customized Aisan | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 18 Participants | 4 Participants | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Female | 13 Participants | 2 Participants | 3 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 8 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 4 / 4 | 8 / 8 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 8 |
Outcome results
Primary
Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8)
Time frame: 0 to 8 hours post-dose on Day 1, Week 4, Week 12
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Day 1 | 3.37 mg.h/ml | Geometric Coefficient of Variation 23 |
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Week 12 | 3.79 mg.h/ml | Geometric Coefficient of Variation 47.9 |
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Week 4 | 3.47 mg.h/ml | Geometric Coefficient of Variation 48.2 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Day 1 | 15.7 mg.h/ml | Geometric Coefficient of Variation 38.5 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Week 12 | 37.5 mg.h/ml | Geometric Coefficient of Variation 31 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Week 4 | 29.7 mg.h/ml | Geometric Coefficient of Variation 64.1 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Week 4 | 8.28 mg.h/ml | Geometric Coefficient of Variation 15.7 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Day 1 | 7.12 mg.h/ml | Geometric Coefficient of Variation 34.4 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Week 12 | 6.91 mg.h/ml | Geometric Coefficient of Variation 18.5 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Day 1 | 10.8 mg.h/ml | Geometric Coefficient of Variation 69.5 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Week 12 | 12.5 mg.h/ml | Geometric Coefficient of Variation 91.6 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil Area Under the Plasma Concentration Versus Time Curve From Time Zero to 8h Post-dose (AUC0-8) | Week 4 | 11.0 mg.h/ml | Geometric Coefficient of Variation 77.8 |
Primary
Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil
Time frame: 0.5, 1, 1.5, 2, 4 and 8 hours post-dose on Day 1, Week 4 and Week 12
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Day1 | 1.05 ng/mL | Geometric Coefficient of Variation 32.4 |
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Week 12 | 1.25 ng/mL | Geometric Coefficient of Variation 37.8 |
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Week 4 | 1.10 ng/mL | Geometric Coefficient of Variation 55.1 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Day1 | 4.75 ng/mL | Geometric Coefficient of Variation 24.9 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Week 12 | 11.6 ng/mL | Geometric Coefficient of Variation 51.6 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Week 4 | 10.5 ng/mL | Geometric Coefficient of Variation 57.3 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Week 4 | 1.98 ng/mL | Geometric Coefficient of Variation 31.2 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Day1 | 2.15 ng/mL | Geometric Coefficient of Variation 62.8 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Week 12 | 1.95 ng/mL | Geometric Coefficient of Variation 31.9 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Day1 | 3.27 ng/mL | Geometric Coefficient of Variation 86.4 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Week 12 | 3.43 ng/mL | Geometric Coefficient of Variation 55.2 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil:Maximum Observed Plasma Concentration (Cmax) of Omigapil | Week 4 | 2.90 ng/mL | Geometric Coefficient of Variation 96.1 |
Primary
Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil
Time frame: 0.5, 1, 1.5, 2, 4 and 8 hours post-dose on Day 1, Week 4 and Week 12
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Week 4 | 0.6 h | Geometric Coefficient of Variation 1.5 |
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Week 12 | 1.00 h | Geometric Coefficient of Variation 1.6 |
| Cohort 1 0.02 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Day 1 | 0.8 h | Geometric Coefficient of Variation 3.9 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Day 1 | 0.8 h | Geometric Coefficient of Variation 1.5 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Week 12 | 0.9 h | Geometric Coefficient of Variation 1.4 |
| Cohort 2 0.08 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Week 4 | 0.5 h | Geometric Coefficient of Variation 2 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Week 4 | 0.5 h | Geometric Coefficient of Variation 1 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Day 1 | 0.8 h | Geometric Coefficient of Variation 3.9 |
| Cohort 3a 0.04 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Week 12 | 0.8 h | Geometric Coefficient of Variation 1 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Day 1 | 0.5 h | Geometric Coefficient of Variation 4 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Week 12 | 1.0 h | Geometric Coefficient of Variation 4 |
| Cohort 3b 0.06 mg/kg/Day | Pharmacokinetic Profile of Omigapil: Time at Which Cmax Was Apparent (Tmax) of Omigapil | Week 4 | 1.0 h | Geometric Coefficient of Variation 4 |
Secondary
Summary of All Treatment-emergent Adverse Events (TEAEs)
TEAEs reported during the treatment period
Time frame: 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 0.02 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent TEAEs | 41 number of events |
| Cohort 1 0.02 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Fatal TEAEs | 0 number of events |
| Cohort 1 0.02 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 0 number of events |
| Cohort 2 0.08 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent TEAEs | 40 number of events |
| Cohort 2 0.08 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Fatal TEAEs | 0 number of events |
| Cohort 2 0.08 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 0 number of events |
| Cohort 3a 0.04 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 0 number of events |
| Cohort 3a 0.04 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent TEAEs | 29 number of events |
| Cohort 3a 0.04 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Fatal TEAEs | 0 number of events |
| Cohort 3b 0.06 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent TEAEs | 75 number of events |
| Cohort 3b 0.06 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Fatal TEAEs | 0 number of events |
| Cohort 3b 0.06 mg/kg/Day | Summary of All Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 0 number of events |