Clinical trial NCT02858362: Proof of Concept Study to Assess Activity and Safety of SMT C1100 (Ezutromid) in Boys With Duchenne Muscular Dystrophy (DMD)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Duchenne Muscular Dystrophy
Keywords: DMD
Muscular Dystrophy
Utrophin
Duchenne
PhaseOut DMD
Lead sponsor: Summit Therapeutics
Sponsor class: INDUSTRY
First posted: 2016-08-08
Enrollment: 43
Sex: MALE
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: 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.

Primary outcomes:
measure: Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3)
timeFrame: Pre-dose at Weeks 1, 4, 8, 12, 24, 36 and 48
measure: Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3)
timeFrame: Pre-dose and 3 to 10 hours post-dose at Weeks 1, 4, 8, 12, 24, 36 and 48
measure: Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3)
timeFrame: Pre-dose and 3 to 10 hours post-dose at Weeks 1, 4, 8, 12, 24, 36 and 48
measure: Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Day 1 to a maximum of Week 96
Secondary outcomes:
measure: Change From Baseline in Utrophin Intensity
timeFrame: Baseline, Week 24 and Week 48
measure: Change From Baseline in Developmental Heavy Chain Myosin (MHCd) Expression
timeFrame: Baseline, Week 24 and Week 48
measure: Change From Baseline in Muscle Fibre Diameter
timeFrame: Baseline, Week 24 and Week 48
measure: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Forced Vital Capacity (FVC)
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Maximum Inspiratory Pressure (MIP)
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Maximum Expiratory Pressure (MEP)
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Peak Expiratory Flow (PEF)
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Peak Cough Flow (PCF)
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP)
timeFrame: Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements
timeFrame: Baseline to Week 48
measure: Number of Participants That Experienced a Clinically Significant in Physical Examination Result
timeFrame: Day 1 to Week 48
measure: Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements
timeFrame: Baseline to Week 48
measure: Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement
timeFrame: Baseline, Week 24 and Week 48
measure: Number of Participants That Experienced a Clinically Significant Haematology Result (Investigator's Assessment)
timeFrame: Day 1 to Week 48
measure: Number of Participants Who Experienced a Clinically Significant Biochemistry Result (Investigator's Assessment)
timeFrame: Day 1 to Week 48
measure: Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result
timeFrame: Baseline to Week 48
measure: Number of Participants That Experienced a Clinically Significant Urinalysis Result (Investigator's Assessment)
timeFrame: Day 1 to Week 48
measure: Number of Participants That Experienced a Clinically Significant Coagulation Result (Investigator's Assessment)
timeFrame: Day 1 to Week 48
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA-David Geffen School of Medicine
state: California
city: Aurora
country: United States
facility: Children's Hosptial of Colorado
state: Colorado
city: Orlando
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah Hospital and Clinics
state: Utah
city: Birmingham
country: United Kingdom
facility: Heart of England NHS Foundation Trust - Heartlands Hospital
city: Bristol
country: United Kingdom
facility: Bristol Children's Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's NHS Foundation Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital - Central Manchester University Hospitals NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: The Freeman Hospital, Newcastle Upon Tyne Hospitals
Study officials:
affiliation: Summit (Oxford) Limited
name: Medical Monitor
role: STUDY_DIRECTOR
References: