proof of concept study to assess activity and safety of smt c1100 (ezutromid) in boys with duchenne muscular dystrophy (dmd)

Conditions: Duchenne Muscular Dystrophy

Summary: to assess the activity and safety of smt c1100 (ezutromid) in paediatric male participants with duchenne muscular dystrophy (dmd).

this is a phase 2, open label, study to assess the activity and safety of utrophin modulation with smt c1100 (ezutromid) administered twice-daily orally in ambulatory paediatric male participants with dmd. this study will be conducted in a multi-centre setting in both the united kingdom and the united states of america and comprises of a screening and baseline phase of up to 28 days, a 48-week open label treatment phase, and either a 30-day safety follow up phase or an optional extension phase where study treatment is provided until discontinuation of the program or regulatory approvals as applicable.

Eligibility criteria:
inclusion criteria: * be able to provide written informed consent/assent as per local requirements. * be male. * have phenotypic evidence of dystrophinopathy based on the onset of characteristic clinical symptoms or signs (e.g., proximal muscle weakness, waddling gait, and gowers' manoeuvre), an elevated serum creatinine kinase level, and ongoing difficulty with walking. * have prior confirmation of the duchenne muscular dystrophy (dmd) diagnosis through: documentation of the presence of a mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by the college of american pathologists, the clinical laboratory improvement act/amendment or an equivalent organisation or documentation of the absence of dystrophin in the muscle (via biopsy). * be able to undergo mri examination. * participants must have used stable systemic corticosteroids (prednisone, prednisolone or deflazacort) for a minimum of 6 months immediately prior to the start of the treatment phase, with no significant change in dosage or dosing regimen (not related to body weight change) and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study. * confirmed screening laboratory values within the central laboratory ranges (haematology, renal and serum electrolyte parameters and serum chemistry parameters) or considered not clinically significant in the opinion of the investigator. variations in specific parameters expected in a dmd population classed by the investigator as not clinically significant will not exclude the participant. * be willing and able to comply with scheduled visits, drug administration plan, study procedures, laboratory tests and study restrictions. cohort 1 and 2 specific inclusion criteria: * be aged ≥5 years to \<10 years of age (from 5th birthday to 10th birthday). * be willing and able to comply with 2 muscle biopsy procedures. * have the ability to walk at least 300 meters unassisted during the screening 6 minute walk distance (6mwd) and be below the protocol-specified threshold for 80%-predicted 6mwd. * have results of 2 6mwd by baseline determined as valid. the results of the second 6mwd (baseline) must be within 20% of the first 6mwd (screening). * have cardiac echocardiogram (echo) measurements showing an ejection fraction of ≥55% and fractional shortening of ≥28%. cohort 3 specific inclusion criteria: * have taken part in a prior smt c1100 study. exclusion criteria: * have physical exam findings that in the investigator's opinion should be exclusionary e.g., lower limb injury that may affect 6mwd performance. * have any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation or reinitiation) in prophylaxis/treatment for congestive heart failure (chf) within 3 months prior to the start of study treatment. * have uncontrolled clinical symptoms and signs of chf (american college of cardiology/american heart association stage c or stage d). * have abnormal glutamate dehydrogenase (gldh) at baseline (\>1.5 x upper limit of normal \[uln\]). * have abnormal coagulation times at baseline (\>1.5 x uln). * have an abnormal electrocardiograms (ecg). * use herbal supplements and be unwilling to stop these for the duration of the study. * have been exposed to another investigational drug or dmd interventional agent within 3 months prior to start of the treatment phase. prior exposure to smt c1100 or participation in an approved deflazacort access program within this period would not exclude the participant (provided they have been on stable treatment for 6 months). * have a history of major surgical procedure within 12 weeks prior to the start of the treatment phase (week 1). * be undertaking ongoing immunosuppressive therapy (other than corticosteroids). * require daytime ventilator assistance. * have a prior or ongoing medical condition, medical history, ecg findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results. * be dairy or lactose intolerant or have any other dietary restrictions that might interfere with the conduct of the study. * be a smoker, use other tobacco or nicotine products or be exposed to daily passive smoking (including parent/legal guardian, siblings) so as to minimise environmental factors causing cyp1a induction. * be using an approved dmd medication or anticipates using one during the duration of the study. participants who are taking part in the for-dmd and access dmd studies will be allowed to take part. * be using an inducer of cyp1a1 or cyp1a2. * be using a substrate of cyp2b6. * all prescription, over the counter, and herbal products that are known cyp2b6 sensitive substrates will be excluded 14 days prior to study conduct (beginning at screening) through 14 days after study conduct completion. please note, this is not an exhaustive list of cyp2b6 substrates and a discussion with the medical monitor may be warranted. * be using drugs that have serotonergic, norepinephrinergic or dopaminergic activity, or treatments used in attention deficit hyperactivity disorder. * use of substrates of brcp. cohort 1 and 2 specific exclusion criteria: * use beta blockers (however, if during the course of the study they are clinically indicated they can be initiated). cohort 1 and 3 specific exclusion criteria: * have a known hypersensitivity to any of the ingredients or excipients of the investigational medicinal product: poloxamer 188, methylparaben, propylparaben, hydroxypropylmethyl cellulose, glycerol, non-crystallising sorbitol \[70%\], xanthan gum, strawberry cream flavour \[phs-132963\]. cohort 2 specific exclusion criteria: * have a known hypersensitivity to any of the ingredients or excipients of the investigational medicinal product: hypromellose acetate succinate.

Keywords: dmd muscular dystrophy utrophin duchenne phaseout dmd