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

NCT02858362 | Terminated Phase 2 Results DMC

• 2 other identifiers: SMT C110052015-004333-27
• Study Type: interventional
• Target: 43
• Locations: 2 countries
• Sites: 16

Brief Summary

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

Conditions

Duchenne Muscular Dystrophy

Keywords

DMD; Muscular Dystrophy; Utrophin; Duchenne; PhaseOut DMD

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (19)

• Change From Baseline in Utrophin Intensity

  Baseline, Week 24 and Week 48

• Change From Baseline in Developmental Heavy Chain Myosin (MHCd) Expression

  Baseline, Week 24 and Week 48

• Change From Baseline in Muscle Fibre Diameter

  Baseline, Week 24 and Week 48

• Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)

  Baseline, Week 12, Week 24, Week 36 and Week 48

• Change From Baseline in Forced Vital Capacity (FVC)

  Baseline, Week 12, Week 24, Week 36 and Week 48

Study Arms (3)

Cohort 1: SMT C1100 Formulation 1

EXPERIMENTAL

Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.

Drug: Ezutromid

Cohort 2: SMT C1100 Formulation 2

EXPERIMENTAL

Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.

Drug: Ezutromid

Cohort 3: SMT C1100 Formulation 1

EXPERIMENTAL

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

Interventions

Ezutromid DRUG

Administered orally.

Also known as: SMT C1100

Cohort 1: SMT C1100 Formulation 1; Cohort 2: SMT C1100 Formulation 2; Cohort 3: SMT C1100 Formulation 1

Eligibility Criteria

• Age: 5 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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%.
• Have taken part in a prior SMT C1100 study.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Summit Therapeutics: lead

Study Sites (16)

UCLA-David Geffen School of Medicine

Los Angeles, California, United States

Location

Children's Hosptial of Colorado

Aurora, Colorado, United States

Location

Nemours Children's Clinic

Orlando, Florida, United States

Location

Boston Children's Hospital

Boston, Massachusetts, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Location

Oregon Health and Science University

Portland, Oregon, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Location

University of Utah Hospital and Clinics

Salt Lake City, Utah, United States

Location

Heart of England NHS Foundation Trust - Heartlands Hospital

Birmingham, United Kingdom

Location

Bristol Children's Hospital

Bristol, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, United Kingdom

Location

Alder Hey Children's NHS Foundation Trust

Liverpool, United Kingdom

Location

Great Ormond Street Hospital for Children NHS Foundation Trust

London, United Kingdom

Location

Royal Manchester Children's Hospital - Central Manchester University Hospitals NHS Foundation Trust

Manchester, United Kingdom

Location

The Freeman Hospital, Newcastle Upon Tyne Hospitals

Newcastle, United Kingdom

Location

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne; Muscular Dystrophies

Interventions

ezutromid; SMT C1100

Condition Hierarchy (Ancestors)

Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Limitations and Caveats

Analysis of the data collected from Cohort 3 was limited as the study was terminated prior to the first participant's Week 24 visit.

Results Point of Contact

• Title: Clinical Disclosure
• Organization: Summit Therapeutics

clinicaltrials@summitplc.com

Please Email

Study Officials

• Medical Monitor

  Summit (Oxford) Limited

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2016
• First Posted: August 8, 2016
• Study Start: June 1, 2016
• Primary Completion: April 11, 2018
• Study Completion: September 11, 2018
• Last Updated: January 2, 2020
• Results First Posted: January 2, 2020

Record last verified: 2019-12

Locations

GB (7); US (9)