Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study Analyzing Pharmacokinetics at Three Dose Levels In Children and Adolescents With Assessment of Safety and Tolerability of Omigapil (CALLISTO)

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,