Proof of Concept Study to Assess Activity and Safety of SMT C1100 (Ezutromid) in Boys With Duchenne Muscular Dystrophy (DMD)

Study Overview
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Brief Summary
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To Assess the Activity and Safety of SMT C1100 (Ezutromid) in Paediatric Male Participants with Duchenne Muscular Dystrophy (DMD).

Detailed Description
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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.

Official Title
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Phaseout DMD: A Phase 2 Clinical Study to Assess the Activity and Safety of Utrophin Modulation With Ezutromid in Ambulatory Paediatric Male Subjects With Duchenne Muscular Dystrophy (SMT C11005)

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: Ezutromid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: SMT C1100 Formulation 1<br>Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. | Drug: Ezutromid<br>* Administered orally.<br>* Other names: SMT C1100;|
| Experimental: Cohort 2: SMT C1100 Formulation 2<br>Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks. | Drug: Ezutromid<br>* Administered orally.<br>* Other names: SMT C1100;|
| Experimental: Cohort 3: SMT C1100 Formulation 1<br>Participants in this cohort had previously received SMT C1100, but were not eligible for Cohorts 1 or 2. Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. | Drug: Ezutromid<br>* Administered orally.<br>* Other names: SMT C1100;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | MRS FF was analysed for vastus lateralis and soleus leg muscles. The endpoints were measured for Cohorts 1 and 2 only. Results for Cohorts 1 and 2 are pooled as specified in the protocol. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | MRS WTRT was analysed for the vastus lateralis and soleus leg muscles. The endpoints were measured for Cohorts 1 and 2 only. Results for Cohorts 1 and 2 are pooled as specified in the protocol. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | Pharmacokinetic analysis is presented by cohort due to the use of different formulations. The median pre-dose concentration was derived for each participant and then summarized across participants. | Pre-dose at Weeks 1, 4, 8, 12, 24, 36 and 48 | 
| Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | Pharmacokinetic analysis is presented by cohort due to the use of different formulations. | Pre-dose and 3 to 10 hours post-dose at Weeks 1, 4, 8, 12, 24, 36 and 48 | 
| Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | Pharmacokinetic analysis is presented by cohort due to the use of different formulations. | Pre-dose and 3 to 10 hours post-dose at Weeks 1, 4, 8, 12, 24, 36 and 48 | 
| Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A TEAE is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug. | Day 1 to a maximum of Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Utrophin Intensity | A maximum of two muscle biopsies were taken, one at baseline and the other at Week 24 or Week 48. Utrophin intensity was analyzed using a semiautomated quantitative assay on the biopsy samples. A positive change from baseline represents an increase in utrophin expression, no change from baseline represents maintenance of utrophin expression and a negative change from baseline represents a reduction in utrophin expression. The endpoint was measured for Cohorts 1 and 2 only. Results for Cohorts 1 and 2 are pooled as specified in the protocol. | Baseline, Week 24 and Week 48 | 
| Change From Baseline in Developmental Heavy Chain Myosin (MHCd) Expression | A maximum of two muscle biopsies were taken, one at baseline and the other at Week 24 or Week 48. MHCd expression was analyzed using a semiautomated quantitative assay on the biopsy samples. A positive change from baseline represents an increase in MHCd expression, no change from baseline represents maintenance of MHCd expression and a negative change from baseline represents a reduction in MHCd expression. The endpoint was measured for Cohorts 1 and 2 only. Results for Cohorts 1 and 2 are pooled as specified in the protocol. | Baseline, Week 24 and Week 48 | 
| Change From Baseline in Muscle Fibre Diameter | A maximum of two muscle biopsies were taken, one at baseline and the other at Week 24 or Week 48. Muscle fibre diameter was analyzed using a semiautomated quantitative assay on the biopsy samples. The endpoint was measured for Cohorts 1 and 2 only. Results for Cohorts 1 and 2 are pooled as specified in the protocol. | Baseline, Week 24 and Week 48 | 
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in Forced Vital Capacity (FVC) | Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in Maximum Inspiratory Pressure (MIP) | Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in Maximum Expiratory Pressure (MEP) | Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in Peak Expiratory Flow (PEF) | Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in Peak Cough Flow (PCF) | Analysis of PCF was planned for Cohort 3 only. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) | Analysis of SNIP was planned for Cohort 3 only. | Baseline, Week 12, Week 24, Week 36 and Week 48 | 
| Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse will be disclosed with the following categories: All values within 20% of change from baseline (< 20% change). At least one value ≥ 20% reduction from baseline, but no increases ≥ 20% from baseline (≥ 20% reduction and no < 20% increase). At least one value ≥ 20% increase from baseline, but no reductions ≥ 20% from baseline (≥ 20% Increase and no < 20% reduction). At least one value ≥ 20% reduction from baseline and at least one value ≥ 20% increase from baseline (≥ 20% reduction and ≥ 20% increase). Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline to Week 48 | 
| Number of Participants That Experienced a Clinically Significant in Physical Examination Result | Examinations included: ear, nose and throat, cardiovascular system, pulmonary system, skin, abdomen, neurological system, height and weight. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Day 1 to Week 48 | 
| Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | PR interval (PRI), heart rate (HR), QTcF and increase from baseline in QTcF (IQTcF) were summarized categorically. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline to Week 48 | 
| Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Participants were at rest in a supine position for 10 minutes before the measurements were performed. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline, Week 24 and Week 48 | 
| Number of Participants That Experienced a Clinically Significant Haematology Result (Investigator's Assessment) | Parameters included: haemoglobin, haematocrit, mean corpuscular volume, white blood cells, red blood cells, neutrophils (percentage and absolute), lymphocytes (percentage and absolute), monocytes (percentage and absolute), eosinophils (percentage and absolute), basophils (percentage and absolute) and platelets. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Day 1 to Week 48 | 
| Number of Participants Who Experienced a Clinically Significant Biochemistry Result (Investigator's Assessment) | Parameters included: calcium, potassium, sodium, albumin, urea nitrogen, uric acid, creatinine, creatine kinase, fasting glucose, cystatin C, lactate dehydrogenase, amylase, lipase, low density lipoprotein cholesterol, high density lipoprotein (HDL) cholesterol, cholesterol, non-HDL cholesterol, total HDL cholesterol ratio, total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase and glutamate dehydrogenase. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Day 1 to Week 48 | 
| Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | Laboratory measurements for alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), alkaline phosphatase (ALP), and glutamate dehydrogenase (GLDH). Hy's Law is defined as an increase in ALT, AST and TB, indicating hepatocyte necrosis and functional deficit. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Baseline to Week 48 | 
| Number of Participants That Experienced a Clinically Significant Urinalysis Result (Investigator's Assessment) | Parameters included: glucose, bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrites and leucocytes. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol. | Day 1 to Week 48 | 
| Number of Participants That Experienced a Clinically Significant Coagulation Result (Investigator's Assessment) | Parameters included: activated partial thromboplastin time, prothrombin time and international normalised ratio. Coagulation was only assessed for Cohorts 2 and 3. Results for Cohorts 2 and 3 are pooled as specified in the protocol. | Day 1 to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DMD, Muscular Dystrophy, Utrophin, Duchenne, PhaseOut DMD