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

• Sponsor: Summit Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02858362
• Collaborator: (none)
• Enrollment: 43
• Locations: 16
• Arms: 3
• Actual Duration (Months): 27.3
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Jun 1, 2016
• Actual Primary Completion Date: Apr 11, 2018
• Actual Study Completion Date: Sep 11, 2018

Arms and Interventions

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 Names: 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 Names: 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 Names: SMT C1100

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles [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 [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) [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) [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) [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) [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 [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 [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 [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) [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) [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) [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) [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) [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) [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) [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 [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 [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 [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 [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) [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) [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 [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) [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) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA-David Geffen School of Medicine	Los Angeles	California	United States
2	Children's Hosptial of Colorado	Aurora	Colorado	United States
3	Nemours Children's Clinic	Orlando	Florida	United States
4	Boston Children's Hospital	Boston	Massachusetts	United States
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States
6	Oregon Health and Science University	Portland	Oregon	United States
7	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States
8	Vanderbilt University Medical Center	Nashville	Tennessee	United States
9	University of Utah Hospital and Clinics	Salt Lake City	Utah	United States
10	Heart of England NHS Foundation Trust - Heartlands Hospital	Birmingham		United Kingdom
11	Bristol Children's Hospital	Bristol		United Kingdom
12	Addenbrooke's Hospital	Cambridge		United Kingdom
13	Alder Hey Children's NHS Foundation Trust	Liverpool		United Kingdom
14	Great Ormond Street Hospital for Children NHS Foundation Trust	London		United Kingdom
15	Royal Manchester Children's Hospital - Central Manchester University Hospitals NHS Foundation Trust	Manchester		United Kingdom
16	The Freeman Hospital, Newcastle Upon Tyne Hospitals	Newcastle		United Kingdom

Sponsors and Collaborators

• Summit Therapeutics

Investigators

• Study Director: Medical Monitor, Summit (Oxford) Limited

Study Documents (Full-Text)

• Study Protocol - Feb 24, 2017
• Statistical Analysis Plan - Apr 5, 2018

More Information

Publications

None provided.

• Responsible Party: Summit Therapeutics
• ClinicalTrials.gov Identifier: NCT02858362
• Other Study ID Numbers: SMT C11005; 2015-004333-27
• First Posted: Aug 8, 2016
• Last Update Posted: Jan 2, 2020
• Last Verified: Dec 1, 2019

• Keywords provided by Summit Therapeutics: DMD; Muscular Dystrophy; Utrophin; Duchenne; PhaseOut DMD
• Additional relevant MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne

Study Results

Participant Flow

Recruitment Details	Participants were enrolled in 16 sites across the United Kingdom (UK) and United States (US) between the dates of 16 June 2016 (First Patient In) and 11 September 2018 (Last Patient Out). Cohort 1 was conducted in the UK and US, Cohort 2 was conducted in the US only, and Cohort 3 was conducted in the UK only.

Arm/Group Title	Cohort 1: SMT C1100 Formulation 1	Cohort 2: SMT C1100 Formulation 2	Cohort 3: SMT C1100 Formulation 1
Arm/Group Description	Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.	Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.	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.
Period Title: Overall Study
STARTED	30	10	3
Did Not Enter Extension Phase	1	2	0
COMPLETED	28	9	0
NOT COMPLETED	2	1	3

Baseline Characteristics

Arm/Group Title	Cohort 1: SMT C1100 Formulation 1	Cohort 2: SMT C1100 Formulation 2	Cohort 3: SMT C1100 Formulation 1	Total
Arm/Group Description	Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.	Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.	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.	Total of all reporting groups
Overall Participants	30	10	3	43
Age, Customized (Count of Participants)
Children (2-11 years)	30 100%	10 100%	1 33.3%	41 95.3%
Adolescents (12-17 years)	0 0%	0 0%	2 66.7%	2 4.7%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	30 100%	10 100%	3 100%	43 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.3%	2 20%	0 0%	3 7%
Not Hispanic or Latino	29 96.7%	8 80%	3 100%	40 93%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 3.3%	1 10%	0 0%	2 4.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	26 86.7%	9 90%	3 100%	38 88.4%
More than one race	2 6.7%	0 0%	0 0%	2 4.7%
Unknown or Not Reported	1 3.3%	0 0%	0 0%	1 2.3%
Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) Vastus Lateralis (Percentage of fat in the muscle) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of fat in the muscle]	13.78 (13.317)	18.36 (13.664)	14.95 (13.379)
Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) Soleus (Percentage of fat in the muscle) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of fat in the muscle]	8.57 (8.240)	10.79 (9.996)	9.12 (8.631)
Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) Vastus Lateralis (Milliseconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Milliseconds]	32.24 (1.980)	32.17 (2.146)	32.23 (1.995)
Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) Soleus (Milliseconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Milliseconds]	31.88 (1.936)	31.87 (1.988)	31.88 (1.923)
Development Heavy Chain Myosin (MHCd) Expression in Muscle Fibres (Percent of muscle fibres expressing MHCd) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent of muscle fibres expressing MHCd]	12.185 (3.8454)	11.587 (4.1344)	12.032 (3.8748)
Muscle Fibre Diameter (Micrometer) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Micrometer]	43.662 (5.3837)	42.086 (6.1878)	43.258 (5.5598)
Utrophin Intensity (Arbitrary Units) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Arbitrary Units]	0.368 (0.0480)	0.349 (0.0507)	0.364 (0.0486)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles
Description	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.
Time Frame	Baseline, Week 12, Week 24, Week 36 and Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication and had at least one assessment of the endpoint (which could be their baseline assessment).

Arm/Group Title	Cohorts 1 and 2: SMT C1100
Arm/Group Description	Cohort 1 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	40
Vastus Lateralis: Week 12 Change from Baseline	1.779
Vastus Lateralis: Week 24 Change from Baseline	3.914
Vastus Lateralis: Week 36 Change from Baseline	5.238
Vastus Lateralis: Week 48 Change from Baseline	7.142
Soleus: Week 12 Change from Baseline	0.615
Soleus: Week 24 Change from Baseline	1.108
Soleus: Week 36 Change from Baseline	2.384
Soleus: Week 48 Change from Baseline	2.584

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication and had at least one assessment of the endpoint (which could be their baseline assessment).

Arm/Group Title	Cohorts 1 and 2: SMT C1100
Arm/Group Description	Cohort 1 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	40
Vastus Lateralis: Week 12 Change from Baseline	-0.559
Vastus Lateralis: Week 24 Change from Baseline	-0.486
Vastus Lateralis: Week 36 Change from Baseline	-0.849
Vastus Lateralis: Week 48 Change from Baseline	-0.822
Soleus: Week 12 Change from Baseline	-0.655
Soleus: Week 24 Change from Baseline	-0.861
Soleus: Week 36 Change from Baseline	-0.447
Soleus: Week 48 Change from Baseline	-0.119

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants in Cohorts 1 or 2 who received at least one dose of study medication and had at least one concentration measurement (which could be below the limit of quantification). No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohort 1: SMT C1100 Formulation 1	Cohort 2: SMT C1100 Formulation 2
Arm/Group Description	Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.	Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	30	10
SMT C1100	17 (140)	80 (83.1)
DHD 1	155 (61)	365 (55)
DHD 3	484 (67)	1206 (68)

4. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants in Cohorts 1 or 2 who received at least one dose of study medication and had at least one concentration measurement (which could be below the limit of quantification). No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohort 1: SMT C1100 Formulation 1	Cohort 2: SMT C1100 Formulation 2
Arm/Group Description	Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.	Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	30	10
SMT C1100	135	415
DHD 1	1897	2829
DHD 3	3162	4652

5. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants in Cohorts 1 or 2 who received at least one dose of study medication and had at least one concentration measurement (which could be below the limit of quantification). No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohort 1: SMT C1100 Formulation 1	Cohort 2: SMT C1100 Formulation 2
Arm/Group Description	Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.	Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	30	10
SMT C1100	54	163
DHD 1	742	1109
DHD 3	1359	2211

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication.

Arm/Group Title	Cohort 1: SMT C1100 Formulation 1	Cohort 2: SMT C1100 Formulation 2	Cohort 3: SMT C1100 Formulation 1
Arm/Group Description	Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.	Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.	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.
Measure Participants	30	10	3
Count of Participants [Participants]	30 100%	10 100%	3 100%

7. Secondary Outcome

Title	Change From Baseline in Utrophin Intensity
Description	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.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication and had at least one assessment of the endpoint (which could be their baseline assessment). For the summaries of changes from baseline only those participants in this population who had measurements at both baseline and the relevant post-baseline visit were included.

Arm/Group Title	Cohorts 1 and 2: SMT C1100
Arm/Group Description	Cohort 1 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	37
Change from baseline at Week 24	0.0232 (0.0601)
Change from baseline at Week 48	0.0114 (0.0574)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohorts 1 and 2: SMT C1100
	Comments	Week 24 Change from Baseline
	Type of Statistical Test	Other
	Comments	Difference in least square means. All 23 participants in the population were included in the statistical analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.023
	Confidence Interval	(2-Sided) 95%; -0.002 to 0.048
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohorts 1 and 2: SMT C1100
	Comments	Week 48 Change from Baseline
	Type of Statistical Test	Other
	Comments	Difference in least square means. All 16 participants in the population were included in the statistical analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.006
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.042
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Developmental Heavy Chain Myosin (MHCd) Expression
Description	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.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication and had at least one assessment of the endpoint (which could be their baseline assessment). For the summaries of changes from baseline only those participants in this population who had measurements at both baseline and the relevant post-baseline visit were included.

Arm/Group Title	Cohorts 1 and 2: SMT C1100
Arm/Group Description	Cohort 1 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	38
Change from baseline at Week 24	-2.3166 (3.9180)
Change from baseline at Week 48	1.2248 (4.2596)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohorts 1 and 2: SMT C1100
	Comments	Week 24 Change from Baseline
	Type of Statistical Test	Other
	Comments	Difference in least square means. All 24 participants in the population were included in the statistical analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.611
	Confidence Interval	(2-Sided) 95%; -4.324 to -0.898
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohorts 1 and 2: SMT C1100
	Comments	Week 48 Change from Baseline
	Type of Statistical Test	Other
	Comments	Difference in least square means. All 16 participants in the population were included in the statistical analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.166
	Confidence Interval	(2-Sided) 95%; -1.103 to 3.435
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Muscle Fibre Diameter
Description	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.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication and had at least one assessment of the endpoint (which could be their baseline assessment). For the summaries of changes from baseline only those participants in this population who had measurements at both baseline and the relevant post-baseline visit were included.

Arm/Group Title	Cohorts 1 and 2: SMT C1100
Arm/Group Description	Cohort 1 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	38
Change from baseline at Week 24	-1.9205 (4.7250)
Change from baseline at Week 48	2.0636 (4.1267)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohorts 1 and 2: SMT C1100
	Comments	Week 24 Change from Baseline
	Type of Statistical Test	Other
	Comments	Difference in least square means. All 24 participants in the population were included in the statistical analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.837
	Confidence Interval	(2-Sided) 95%; -3.989 to 0.315
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohorts 1 and 2: SMT C1100
	Comments	Week 48 Change from Baseline
	Type of Statistical Test	Other
	Comments	Difference in least square means. All 16 participants in the population were included in the statistical analysis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.21
	Confidence Interval	(2-Sided) 95%; 0.096 to 4.324
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication. No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	38
Week 12 Change from Baseline	-3.4 (20.86)
Week 24 Change from Baseline	-2.5 (24.88)
Week 36 Change from Baseline	-7.3 (24.26)
Week 48 Change from Baseline	2.0 (18.31)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication. No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	39
Week 12 Change from Baseline	-4.0 (16.31)
Week 24 Change from Baseline	1.1 (16.75)
Week 36 Change from Baseline	-3.4 (18.39)
Week 48 Change from Baseline	1.1 (16.29)

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication. No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	36
Week 12 Change from Baseline	3.6 (32.68)
Week 24 Change from Baseline	3.0 (25.00)
Week 36 Change from Baseline	9.0 (18.40)
Week 48 Change from Baseline	8.7 (20.30)

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication. No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	35
Week 12 Change from Baseline	1.8 (17.97)
Week 24 Change from Baseline	2.5 (22.95)
Week 36 Change from Baseline	-1.0 (23.53)
Week 48 Change from Baseline	6.5 (20.09)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication. No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	34
Week 12 Change from Baseline	0.5 (20.65)
Week 24 Change from Baseline	-0.1 (23.86)
Week 36 Change from Baseline	-0.4 (23.46)
Week 48 Change from Baseline	9.6 (30.09)

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohort 3: SMT C1100 Formulation 1
Arm/Group Description	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.
Measure Participants	0

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohort 3: SMT C1100 Formulation 1
Arm/Group Description	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.
Measure Participants	0

17. Secondary Outcome

Title	Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements
Description	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.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication. No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	40
< 20% change	28 93.3%
≥ 20% reduction and no < 20% increase	2 6.7%
≥ 20% Increase and no < 20% reduction	10 33.3%
≥ 20% reduction and ≥ 20% increase	0 0%
< 20% change	19 63.3%
≥ 20% reduction and no < 20% increase	11 36.7%
≥ 20% Increase and no < 20% reduction	10 33.3%
≥ 20% reduction and ≥ 20% increase	0 0%
< 20% change	21 70%
≥ 20% reduction and no < 20% increase	6 20%
≥ 20% Increase and no < 20% reduction	13 43.3%
≥ 20% reduction and ≥ 20% increase	0 0%

18. Secondary Outcome

Title	Number of Participants That Experienced a Clinically Significant in Physical Examination Result
Description	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.
Time Frame	Day 1 to Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	43
Count of Participants [Participants]	1 3.3%

19. Secondary Outcome

Title	Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements
Description	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.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication. No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	40
PRI: <170 ms	37 123.3%
PRI: ≥170 ms	3 10%
PRI: < 20% change	35 116.7%
PRI: ≥ 20% reduction and no < 20% increase	2 6.7%
PRI: ≥ 20% increase and no < 20% reduction	3 10%
PRI: ≥ 20% reduction and ≥ 20% increase	0 0%
HR: < 20% change	7 23.3%
HR: ≥ 20% reduction and no < 20% increase	6 20%
HR: ≥ 20% increase and no < 20% reduction	22 73.3%
HR: ≥ 20% reduction and ≥ 20% increase	5 16.7%
QTcF: < 450 ms	40 133.3%
QTcF: ≥ 450 ms	0 0%
IQTcF: < 30 ms	32 106.7%
IQTcF: 30 - 59 ms	8 26.7%
IQTcF: >= 60 ms	0 0%

20. Secondary Outcome

Title	Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement
Description	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.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication. No evaluable data was collected from Cohort 3 participants due to early study termination.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	40
Normal	38 126.7%
Abnormal, Not Clinically Significant	2 6.7%
Abnormal, Clinically Significant	0 0%
Normal	33 110%
Abnormal, Not Clinically Significant	5 16.7%
Abnormal, Clinically Significant	0 0%
Normal	33 110%
Abnormal, Not Clinically Significant	2 6.7%
Abnormal, Clinically Significant	1 3.3%

21. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	43
Count of Participants [Participants]	0 0%

22. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	43
Count of Participants [Participants]	3 10%

23. Secondary Outcome

Title	Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result
Description	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.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication.

Arm/Group Title	Cohorts 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	43
ALT >= upper limit of normal (ULN)	43 143.3%
ALT >= 2*ULN	43 143.3%
ALT >= 3*ULN	42 140%
AST >= ULN	43 143.3%
AST >= 2*ULN	42 140%
AST >= 3*ULN	42 140%
TB >= ULN	0 0%
TB >= 2*ULN	0 0%
ALP >= 1.5*ULN	0 0%
GLDH >= ULN excluding haemolysed samples	27 90%
GLDH >= ULN including haemolysed samples	30 100%
GLDH >= 2.5*ULN Excluding Haemolysed Samples	2 6.7%
GLDH >= 2.5*ULN including haemolysed samples	2 6.7%
Participants meeting Hy's law	0 0%

24. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication.

Arm/Group Title	Cohort 1, 2 and 3: SMT C1100
Arm/Group Description	Cohorts 1 and 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.
Measure Participants	43
Count of Participants [Participants]	0 0%

25. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication in Cohorts 2 and 3 only.

Arm/Group Title	Cohorts 2 and 3 SMT C1100
Arm/Group Description	Cohort 2 participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks. Cohort 3 participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.
Measure Participants	13
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	Day 1 to a maximum of 96 weeks
Adverse Event Reporting Description	Treatment Emergent Adverse Events.
Arm/Group Title	Cohort 1: SMT C1100 Formulation 1		Cohort 2: SMT C1100 Formulation 2		Cohort 3: SMT C1100 Formulation 1
Arm/Group Description	Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks.		Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks.		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.
All Cause Mortality
	Cohort 1: SMT C1100 Formulation 1		Cohort 2: SMT C1100 Formulation 2		Cohort 3: SMT C1100 Formulation 1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/10 (0%)		0/3 (0%)
Serious Adverse Events
	Cohort 1: SMT C1100 Formulation 1		Cohort 2: SMT C1100 Formulation 2		Cohort 3: SMT C1100 Formulation 1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/30 (13.3%)		0/10 (0%)		0/3 (0%)
Gastrointestinal disorders
Abdominal pain	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Vomiting	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
General disorders
Peripheral swelling	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Non-cardiac chest pain	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Infections and infestations
Viral infection	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Tonsillitis bacterial	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Gastritis viral	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Spinal compression fracture	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle spasms	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Rhabdomyolysis	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Renal and urinary disorders
Chromaturia	1/30 (3.3%)	1	0/10 (0%)	0	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort 1: SMT C1100 Formulation 1		Cohort 2: SMT C1100 Formulation 2		Cohort 3: SMT C1100 Formulation 1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/30 (100%)		10/10 (100%)		3/3 (100%)
Congenital, familial and genetic disorders
Cryptorchism	0/30 (0%)		1/10 (10%)		0/3 (0%)
Ear and labyrinth disorders
Ear pain	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Eye disorders
Vitreous floaters	0/30 (0%)		1/10 (10%)		0/3 (0%)
Gastrointestinal disorders
Faeces pale	18/30 (60%)		3/10 (30%)		3/3 (100%)
Vomiting	17/30 (56.7%)		6/10 (60%)		0/3 (0%)
Diarrhoea	12/30 (40%)		4/10 (40%)		2/3 (66.7%)
Abdominal pain upper	8/30 (26.7%)		3/10 (30%)		1/3 (33.3%)
Abdominal pain	7/30 (23.3%)		0/10 (0%)		0/3 (0%)
Nausea	5/30 (16.7%)		1/10 (10%)		1/3 (33.3%)
Constipation	2/30 (6.7%)		1/10 (10%)		1/3 (33.3%)
Abdominal discomfort	2/30 (6.7%)		1/10 (10%)		0/3 (0%)
Toothache	3/30 (10%)		0/10 (0%)		0/3 (0%)
Faeces discoloured	1/30 (3.3%)		1/10 (10%)		0/3 (0%)
Gastritis	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Dyspepsia	3/30 (10%)		1/10 (10%)		0/3 (0%)
Lip swelling	3/30 (10%)		0/10 (0%)		0/3 (0%)
General disorders
Pyrexia	7/30 (23.3%)		1/10 (10%)		0/3 (0%)
Fatigue	4/30 (13.3%)		1/10 (10%)		0/3 (0%)
Catheter site bruise	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Chest pain	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Infections and infestations
Nasopharyngitis	6/30 (20%)		5/10 (50%)		0/3 (0%)
Rhinitis	3/30 (10%)		1/10 (10%)		0/3 (0%)
Upper respiratory tract infection	4/30 (13.3%)		0/10 (0%)		0/3 (0%)
Ear infection	1/30 (3.3%)		2/10 (20%)		0/3 (0%)
Gastroenteritis	2/30 (6.7%)		1/10 (10%)		0/3 (0%)
Otitis media	3/30 (10%)		0/10 (0%)		0/3 (0%)
Sinusitis	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Viral upper respiratory tract infection	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Campylobacter gastroenteritis	0/30 (0%)		1/10 (10%)		0/3 (0%)
Gastroenteritis viral	0/30 (0%)		1/10 (10%)		0/3 (0%)
Pharyngitis	0/30 (0%)		1/10 (10%)		0/3 (0%)
Injury, poisoning and procedural complications
Fall	7/30 (23.3%)		1/10 (10%)		0/3 (0%)
Procedural pain	7/30 (23.3%)		0/10 (0%)		0/3 (0%)
Contusion	3/30 (10%)		0/10 (0%)		0/3 (0%)
Head injury	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Joint injury	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Ligament sprain	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Skin abrasion	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Spinal fracture	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Foot fracture	0/30 (0%)		1/10 (10%)		0/3 (0%)
Investigations
Glutamate dehydrogenase increased	3/30 (10%)		1/10 (10%)		0/3 (0%)
Gamma-glutamyltransferase increased	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Metabolism and nutrition disorders
Decreased appetite	3/30 (10%)		0/10 (0%)		0/3 (0%)
Increased appetite	1/30 (3.3%)		1/10 (10%)		0/3 (0%)
Vitamin D deficiency	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Musculoskeletal and connective tissue disorders
Back pain	10/30 (33.3%)		0/10 (0%)		0/3 (0%)
Pain in extremity	7/30 (23.3%)		1/10 (10%)		0/3 (0%)
Arthralgia	3/30 (10%)		1/10 (10%)		1/3 (33.3%)
Neck pain	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	3/30 (10%)		0/10 (0%)		0/3 (0%)
Nervous system disorders
Headache	9/30 (30%)		1/10 (10%)		1/3 (33.3%)
Dizziness	0/30 (0%)		1/10 (10%)		0/3 (0%)
Psychiatric disorders
Aggression	2/30 (6.7%)		1/10 (10%)		0/3 (0%)
Abnormal behaviour	1/30 (3.3%)		1/10 (10%)		0/3 (0%)
Anger	0/30 (0%)		1/10 (10%)		1/3 (33.3%)
Belligerence	0/30 (0%)		1/10 (10%)		0/3 (0%)
Depressed mood	0/30 (0%)		0/10 (0%)		1/3 (33.3%)
Enuresis	0/30 (0%)		1/10 (10%)		0/3 (0%)
Irritability	0/30 (0%)		1/10 (10%)		0/3 (0%)
Mood altered	0/30 (0%)		1/10 (10%)		0/3 (0%)
Renal and urinary disorders
Pollakiuria	0/30 (0%)		0/10 (0%)		1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Cough	8/30 (26.7%)		4/10 (40%)		0/3 (0%)
Oropharyngeal pain	8/30 (26.7%)		2/10 (20%)		0/3 (0%)
Rhinorrhoea	2/30 (6.7%)		1/10 (10%)		0/3 (0%)
Sinus congestion	1/30 (3.3%)		1/10 (10%)		0/3 (0%)
Wheezing	0/30 (0%)		1/10 (10%)		0/3 (0%)
Skin and subcutaneous tissue disorders
Rash	5/30 (16.7%)		0/10 (0%)		0/3 (0%)
Swelling face	3/30 (10%)		0/10 (0%)		0/3 (0%)
Dry skin	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Erythema	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Pruritus	2/30 (6.7%)		0/10 (0%)		0/3 (0%)
Skin discolouration	1/30 (3.3%)		1/10 (10%)		0/3 (0%)

Limitations/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.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.