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Trial record 1 of 1 for:    PhaseOut DMD
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Proof of Concept Study to Assess Activity and Safety of SMT C1100 (Ezutromid) in Boys With Duchenne Muscular Dystrophy (DMD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02858362
Recruitment Status : Terminated (The study was terminated due to lack of efficacy in Cohorts 1 and 2.)
First Posted : August 8, 2016
Results First Posted : January 2, 2020
Last Update Posted : January 2, 2020
Sponsor:
Information provided by (Responsible Party):
Summit Therapeutics

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

Condition or disease Intervention/treatment Phase
Duchenne Muscular Dystrophy Drug: Ezutromid Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 43 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : June 2016
Actual Primary Completion Date : April 11, 2018
Actual Study Completion Date : September 11, 2018


Arm Intervention/treatment
Experimental: Cohort 1: SMT C1100 Formulation 1
Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.
Drug: Ezutromid
Administered orally.
Other Name: SMT C1100

Experimental: Cohort 2: SMT C1100 Formulation 2
Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Drug: Ezutromid
Administered orally.
Other Name: SMT C1100

Experimental: Cohort 3: SMT C1100 Formulation 1
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
Administered orally.
Other Name: SMT C1100




Primary Outcome Measures :
  1. Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    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.

  2. Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    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.

  3. Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) [ Time Frame: Pre-dose at Weeks 1, 4, 8, 12, 24, 36 and 48 ]
    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.

  4. Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) [ Time Frame: Pre-dose and 3 to 10 hours post-dose at Weeks 1, 4, 8, 12, 24, 36 and 48 ]
    Pharmacokinetic analysis is presented by cohort due to the use of different formulations.

  5. Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) [ Time Frame: Pre-dose and 3 to 10 hours post-dose at Weeks 1, 4, 8, 12, 24, 36 and 48 ]
    Pharmacokinetic analysis is presented by cohort due to the use of different formulations.

  6. Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 to a maximum of Week 96 ]
    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.


Secondary Outcome Measures :
  1. Change From Baseline in Utrophin Intensity [ Time Frame: Baseline, Week 24 and Week 48 ]
    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.

  2. Change From Baseline in Developmental Heavy Chain Myosin (MHCd) Expression [ Time Frame: Baseline, Week 24 and Week 48 ]
    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.

  3. Change From Baseline in Muscle Fibre Diameter [ Time Frame: Baseline, Week 24 and Week 48 ]
    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.

  4. Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.

  5. Change From Baseline in Forced Vital Capacity (FVC) [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.

  6. Change From Baseline in Maximum Inspiratory Pressure (MIP) [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.

  7. Change From Baseline in Maximum Expiratory Pressure (MEP) [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.

  8. Change From Baseline in Peak Expiratory Flow (PEF) [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.

  9. Change From Baseline in Peak Cough Flow (PCF) [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    Analysis of PCF was planned for Cohort 3 only.

  10. Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) [ Time Frame: Baseline, Week 12, Week 24, Week 36 and Week 48 ]
    Analysis of SNIP was planned for Cohort 3 only.

  11. Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements [ Time Frame: Baseline to Week 48 ]

    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.


  12. Number of Participants That Experienced a Clinically Significant in Physical Examination Result [ Time Frame: Day 1 to Week 48 ]
    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.

  13. Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements [ Time Frame: Baseline to Week 48 ]
    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.

  14. Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement [ Time Frame: Baseline, Week 24 and Week 48 ]
    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.

  15. Number of Participants That Experienced a Clinically Significant Haematology Result (Investigator's Assessment) [ Time Frame: Day 1 to Week 48 ]
    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.

  16. Number of Participants Who Experienced a Clinically Significant Biochemistry Result (Investigator's Assessment) [ Time Frame: Day 1 to Week 48 ]
    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.

  17. Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result [ Time Frame: Baseline to Week 48 ]
    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.

  18. Number of Participants That Experienced a Clinically Significant Urinalysis Result (Investigator's Assessment) [ Time Frame: Day 1 to Week 48 ]
    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.

  19. Number of Participants That Experienced a Clinically Significant Coagulation Result (Investigator's Assessment) [ Time Frame: Day 1 to Week 48 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   5 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02858362


Locations
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United States, California
UCLA-David Geffen School of Medicine
Los Angeles, California, United States
United States, Colorado
Children's Hosptial of Colorado
Aurora, Colorado, United States
United States, Florida
Nemours Children's Clinic
Orlando, Florida, United States
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States
United States, Utah
University of Utah Hospital and Clinics
Salt Lake City, Utah, United States
United Kingdom
Heart of England NHS Foundation Trust - Heartlands Hospital
Birmingham, United Kingdom
Bristol Children's Hospital
Bristol, United Kingdom
Addenbrooke's Hospital
Cambridge, United Kingdom
Alder Hey Children's NHS Foundation Trust
Liverpool, United Kingdom
Great Ormond Street Hospital for Children NHS Foundation Trust
London, United Kingdom
Royal Manchester Children's Hospital - Central Manchester University Hospitals NHS Foundation Trust
Manchester, United Kingdom
The Freeman Hospital, Newcastle Upon Tyne Hospitals
Newcastle, United Kingdom
Sponsors and Collaborators
Summit Therapeutics
Investigators
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Study Director: Medical Monitor Summit (Oxford) Limited
  Study Documents (Full-Text)

Documents provided by Summit Therapeutics:
Study Protocol  [PDF] February 24, 2017
Statistical Analysis Plan  [PDF] April 5, 2018

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Responsible Party: Summit Therapeutics
ClinicalTrials.gov Identifier: NCT02858362    
Other Study ID Numbers: SMT C11005
2015-004333-27 ( EudraCT Number )
First Posted: August 8, 2016    Key Record Dates
Results First Posted: January 2, 2020
Last Update Posted: January 2, 2020
Last Verified: December 2019
Keywords provided by Summit Therapeutics:
DMD
Muscular Dystrophy
Utrophin
Duchenne
PhaseOut DMD
Additional relevant MeSH terms:
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Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked