Duchenne Muscular Dystrophy
Conditions
Keywords
DMD, Muscular Dystrophy, Utrophin, Duchenne, PhaseOut DMD
Brief summary
To Assess the Activity and Safety of SMT C1100 (Ezutromid) in Paediatric Male Participants with Duchenne Muscular Dystrophy (DMD).
Detailed description
This is a Phase 2, open label, study to assess the activity and safety of utrophin modulation with SMT C1100 (ezutromid) administered twice-daily orally in ambulatory paediatric male participants with DMD. This study will be conducted in a multi-centre setting in both the United Kingdom and the United States of America and comprises of a Screening and Baseline Phase of up to 28 days, a 48-week open label Treatment Phase, and either a 30-day Safety Follow up Phase or an optional extension phase where study treatment is provided until discontinuation of the program or regulatory approvals as applicable.
Interventions
DRUGEzutromid
Administered orally.
Sponsors
Summit Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
5 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United Kingdom, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: SMT C1100 Formulation 1 Participants received 2.5 g SMT C1100 formulation 1 orally twice-daily for at least 48 weeks. | 30 |
| Cohort 2: SMT C1100 Formulation 2 Participants received 1 g SMT C1100 formulation 2 orally twice-daily for at least 48 weeks. | 10 |
| 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. | 3 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Early Study Termination | 0 | 0 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: SMT C1100 Formulation 1 | Cohort 2: SMT C1100 Formulation 2 | Cohort 3: SMT C1100 Formulation 1 | Total |
|---|---|---|---|---|
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Age, Customized Children (2-11 years) | 30 Participants | 10 Participants | 1 Participants | 41 Participants |
| Development Heavy Chain Myosin (MHCd) Expression in Muscle Fibres | 12.185 Percent of muscle fibres expressing MHCd STANDARD_DEVIATION 3.8454 | 11.587 Percent of muscle fibres expressing MHCd STANDARD_DEVIATION 4.1344 | — | 12.032 Percent of muscle fibres expressing MHCd STANDARD_DEVIATION 3.8748 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 8 Participants | 3 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) Soleus | 8.57 Percentage of fat in the muscle STANDARD_DEVIATION 8.24 | 10.79 Percentage of fat in the muscle STANDARD_DEVIATION 9.996 | — | 9.12 Percentage of fat in the muscle STANDARD_DEVIATION 8.631 |
| Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) Vastus Lateralis | 13.78 Percentage of fat in the muscle STANDARD_DEVIATION 13.317 | 18.36 Percentage of fat in the muscle STANDARD_DEVIATION 13.664 | — | 14.95 Percentage of fat in the muscle STANDARD_DEVIATION 13.379 |
| Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) Soleus | 31.88 Milliseconds STANDARD_DEVIATION 1.936 | 31.87 Milliseconds STANDARD_DEVIATION 1.988 | — | 31.88 Milliseconds STANDARD_DEVIATION 1.923 |
| Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) Vastus Lateralis | 32.24 Milliseconds STANDARD_DEVIATION 1.98 | 32.17 Milliseconds STANDARD_DEVIATION 2.146 | — | 32.23 Milliseconds STANDARD_DEVIATION 1.995 |
| Muscle Fibre Diameter | 43.662 Micrometer STANDARD_DEVIATION 5.3837 | 42.086 Micrometer STANDARD_DEVIATION 6.1878 | — | 43.258 Micrometer STANDARD_DEVIATION 5.5598 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 26 Participants | 9 Participants | 3 Participants | 38 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 10 Participants | 3 Participants | 43 Participants |
| Utrophin Intensity | 0.368 Arbitrary Units STANDARD_DEVIATION 0.048 | 0.349 Arbitrary Units STANDARD_DEVIATION 0.0507 | — | 0.364 Arbitrary Units STANDARD_DEVIATION 0.0486 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 10 | 0 / 3 |
| other Total, other adverse events | 30 / 30 | 10 / 10 | 3 / 3 |
| serious Total, serious adverse events | 4 / 30 | 0 / 10 | 0 / 3 |
Outcome results
Primary
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.
Time frame: Baseline, Week 12, Week 24, Week 36 and Week 48
Population: 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 | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | Vastus Lateralis: Week 12 Change from Baseline | -0.559 Milliseconds |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | Vastus Lateralis: Week 24 Change from Baseline | -0.486 Milliseconds |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | Vastus Lateralis: Week 36 Change from Baseline | -0.849 Milliseconds |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | Vastus Lateralis: Week 48 Change from Baseline | -0.822 Milliseconds |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | Soleus: Week 12 Change from Baseline | -0.655 Milliseconds |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | Soleus: Week 24 Change from Baseline | -0.861 Milliseconds |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | Soleus: Week 36 Change from Baseline | -0.447 Milliseconds |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline for Magnetic Resonance Spectroscopy (MRS) Water Transverse Relaxation Time (WTRT) for Leg Muscles | Soleus: Week 48 Change from Baseline | -0.119 Milliseconds |
Primary
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.
Time frame: Baseline, Week 12, Week 24, Week 36 and Week 48
Population: 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 | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | Vastus Lateralis: Week 12 Change from Baseline | 1.779 Percentage of fat in the muscle |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | Vastus Lateralis: Week 24 Change from Baseline | 3.914 Percentage of fat in the muscle |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | Vastus Lateralis: Week 36 Change from Baseline | 5.238 Percentage of fat in the muscle |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | Vastus Lateralis: Week 48 Change from Baseline | 7.142 Percentage of fat in the muscle |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | Soleus: Week 12 Change from Baseline | 0.615 Percentage of fat in the muscle |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | Soleus: Week 24 Change from Baseline | 1.108 Percentage of fat in the muscle |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | Soleus: Week 36 Change from Baseline | 2.384 Percentage of fat in the muscle |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Magnetic Resonance Spectroscopy (MRS) Fat Fraction (FF) for Leg Muscles | Soleus: Week 48 Change from Baseline | 2.584 Percentage of fat in the muscle |
Primary
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.
Time frame: Day 1 to a maximum of Week 96
Population: All participants who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) | 30 Participants |
| Cohort 2: SMT C1100 Formulation 2 | Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) | 10 Participants |
| Cohort 3: SMT C1100 Formulation 1 | Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
Primary
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.
Time frame: Pre-dose at Weeks 1, 4, 8, 12, 24, 36 and 48
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | SMT C1100 | 17 ng/mL | Geometric Coefficient of Variation 140 |
| Cohorts 1 and 2: SMT C1100 | Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 1 | 155 ng/mL | Geometric Coefficient of Variation 61 |
| Cohorts 1 and 2: SMT C1100 | Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 3 | 484 ng/mL | Geometric Coefficient of Variation 67 |
| Cohort 2: SMT C1100 Formulation 2 | Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | SMT C1100 | 80 ng/mL | Geometric Coefficient of Variation 83.1 |
| Cohort 2: SMT C1100 Formulation 2 | Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 1 | 365 ng/mL | Geometric Coefficient of Variation 55 |
| Cohort 2: SMT C1100 Formulation 2 | Observed Trough Plasma Concentration (Ctrough) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 3 | 1206 ng/mL | Geometric Coefficient of Variation 68 |
Primary
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.
Time frame: Pre-dose and 3 to 10 hours post-dose at Weeks 1, 4, 8, 12, 24, 36 and 48
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | SMT C1100 | 54 ng/mL |
| Cohorts 1 and 2: SMT C1100 | Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 1 | 742 ng/mL |
| Cohorts 1 and 2: SMT C1100 | Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 3 | 1359 ng/mL |
| Cohort 2: SMT C1100 Formulation 2 | Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | SMT C1100 | 163 ng/mL |
| Cohort 2: SMT C1100 Formulation 2 | Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 1 | 1109 ng/mL |
| Cohort 2: SMT C1100 Formulation 2 | Simulated Average Plasma Concentration (Cav) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 3 | 2211 ng/mL |
Primary
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.
Time frame: Pre-dose and 3 to 10 hours post-dose at Weeks 1, 4, 8, 12, 24, 36 and 48
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | SMT C1100 | 135 ng/mL |
| Cohorts 1 and 2: SMT C1100 | Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 1 | 1897 ng/mL |
| Cohorts 1 and 2: SMT C1100 | Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 3 | 3162 ng/mL |
| Cohort 2: SMT C1100 Formulation 2 | Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | SMT C1100 | 415 ng/mL |
| Cohort 2: SMT C1100 Formulation 2 | Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 1 | 2829 ng/mL |
| Cohort 2: SMT C1100 Formulation 2 | Simulated Maximum Plasma Concentration (Cmax) for SMT C1100, Dihydrodiol 1 (DHD1) and Dihydrodiol III (DHD 3) | DHD 3 | 4652 ng/mL |
Secondary
Change From Baseline in Developmental Heavy Chain Myosin (MHCd) Expression
A maximum of two muscle biopsies were taken, one at baseline and the other at Week 24 or Week 48. MHCd expression was analyzed using a semiautomated quantitative assay on the biopsy samples. A positive change from baseline represents an increase in MHCd expression, no change from baseline represents maintenance of MHCd expression and a negative change from baseline represents a reduction in MHCd expression. The endpoint was measured for Cohorts 1 and 2 only. Results for Cohorts 1 and 2 are pooled as specified in the protocol.
Time frame: Baseline, Week 24 and Week 48
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Developmental Heavy Chain Myosin (MHCd) Expression | Change from baseline at Week 24 | -2.3166 Percent of muscle fibres expressing MHCd | Standard Deviation 3.918 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Developmental Heavy Chain Myosin (MHCd) Expression | Change from baseline at Week 48 | 1.2248 Percent of muscle fibres expressing MHCd | Standard Deviation 4.2596 |
Comparison: Week 24 Change from Baseline95% CI: [-4.324, -0.898]
Comparison: Week 48 Change from Baseline95% CI: [-1.103, 3.435]
Secondary
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)
Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Baseline, Week 12, Week 24, Week 36 and Week 48
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | Week 12 Change from Baseline | -3.4 Percentage of FEV1 | Standard Deviation 20.86 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | Week 24 Change from Baseline | -2.5 Percentage of FEV1 | Standard Deviation 24.88 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | Week 36 Change from Baseline | -7.3 Percentage of FEV1 | Standard Deviation 24.26 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | Week 48 Change from Baseline | 2.0 Percentage of FEV1 | Standard Deviation 18.31 |
Secondary
Change From Baseline in Forced Vital Capacity (FVC)
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Forced Vital Capacity (FVC) | Week 12 Change from Baseline | -4.0 Percentage of FVC | Standard Deviation 16.31 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Forced Vital Capacity (FVC) | Week 24 Change from Baseline | 1.1 Percentage of FVC | Standard Deviation 16.75 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Forced Vital Capacity (FVC) | Week 36 Change from Baseline | -3.4 Percentage of FVC | Standard Deviation 18.39 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Forced Vital Capacity (FVC) | Week 48 Change from Baseline | 1.1 Percentage of FVC | Standard Deviation 16.29 |
Secondary
Change From Baseline in Maximum Expiratory Pressure (MEP)
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Maximum Expiratory Pressure (MEP) | Week 24 Change from Baseline | 2.5 cm H2O | Standard Deviation 22.95 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Maximum Expiratory Pressure (MEP) | Week 36 Change from Baseline | -1.0 cm H2O | Standard Deviation 23.53 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Maximum Expiratory Pressure (MEP) | Week 12 Change from Baseline | 1.8 cm H2O | Standard Deviation 17.97 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Maximum Expiratory Pressure (MEP) | Week 48 Change from Baseline | 6.5 cm H2O | Standard Deviation 20.09 |
Secondary
Change From Baseline in Maximum Inspiratory Pressure (MIP)
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Maximum Inspiratory Pressure (MIP) | Week 12 Change from Baseline | 3.6 cm H2O | Standard Deviation 32.68 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Maximum Inspiratory Pressure (MIP) | Week 24 Change from Baseline | 3.0 cm H2O | Standard Deviation 25 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Maximum Inspiratory Pressure (MIP) | Week 36 Change from Baseline | 9.0 cm H2O | Standard Deviation 18.4 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Maximum Inspiratory Pressure (MIP) | Week 48 Change from Baseline | 8.7 cm H2O | Standard Deviation 20.3 |
Secondary
Change From Baseline in Muscle Fibre Diameter
A maximum of two muscle biopsies were taken, one at baseline and the other at Week 24 or Week 48. Muscle fibre diameter was analyzed using a semiautomated quantitative assay on the biopsy samples. The endpoint was measured for Cohorts 1 and 2 only. Results for Cohorts 1 and 2 are pooled as specified in the protocol.
Time frame: Baseline, Week 24 and Week 48
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Muscle Fibre Diameter | Change from baseline at Week 24 | -1.9205 Micrometers (μm) | Standard Deviation 4.725 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Muscle Fibre Diameter | Change from baseline at Week 48 | 2.0636 Micrometers (μm) | Standard Deviation 4.1267 |
Comparison: Week 24 Change from Baseline95% CI: [-3.989, 0.315]
Comparison: Week 48 Change from Baseline95% CI: [0.096, 4.324]
Secondary
Change From Baseline in Peak Cough Flow (PCF)
Analysis of PCF was planned for Cohort 3 only.
Time frame: Baseline, Week 12, Week 24, Week 36 and Week 48
Population: No evaluable data was collected from Cohort 3 participants due to early study termination.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Change From Baseline in Peak Cough Flow (PCF) | Week 12 Change from Baseline | — |
| Unknown | Change From Baseline in Peak Cough Flow (PCF) | Week 24 Change from Baseline | — |
| Unknown | Change From Baseline in Peak Cough Flow (PCF) | Week 36 Change from Baseline | — |
| Unknown | Change From Baseline in Peak Cough Flow (PCF) | Week 48 Change from Baseline | — |
Secondary
Change From Baseline in Peak Expiratory Flow (PEF)
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Peak Expiratory Flow (PEF) | Week 12 Change from Baseline | 0.5 Percentage of PEF | Standard Deviation 20.65 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Peak Expiratory Flow (PEF) | Week 24 Change from Baseline | -0.1 Percentage of PEF | Standard Deviation 23.86 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Peak Expiratory Flow (PEF) | Week 36 Change from Baseline | -0.4 Percentage of PEF | Standard Deviation 23.46 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Peak Expiratory Flow (PEF) | Week 48 Change from Baseline | 9.6 Percentage of PEF | Standard Deviation 30.09 |
Secondary
Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP)
Analysis of SNIP was planned for Cohort 3 only.
Time frame: Baseline, Week 12, Week 24, Week 36 and Week 48
Population: No evaluable data was collected from Cohort 3 participants due to early study termination.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) | Week 12 Change from Baseline | — |
| Unknown | Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) | Week 24 Change from Baseline | — |
| Unknown | Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) | Week 36 Change from Baseline | — |
| Unknown | Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) | Week 48 Change from Baseline | — |
Secondary
Change From Baseline in Utrophin Intensity
A maximum of two muscle biopsies were taken, one at baseline and the other at Week 24 or Week 48. Utrophin intensity was analyzed using a semiautomated quantitative assay on the biopsy samples. A positive change from baseline represents an increase in utrophin expression, no change from baseline represents maintenance of utrophin expression and a negative change from baseline represents a reduction in utrophin expression. The endpoint was measured for Cohorts 1 and 2 only. Results for Cohorts 1 and 2 are pooled as specified in the protocol.
Time frame: Baseline, Week 24 and Week 48
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Utrophin Intensity | Change from baseline at Week 24 | 0.0232 Arbitrary units | Standard Deviation 0.0601 |
| Cohorts 1 and 2: SMT C1100 | Change From Baseline in Utrophin Intensity | Change from baseline at Week 48 | 0.0114 Arbitrary units | Standard Deviation 0.0574 |
Comparison: Week 24 Change from Baseline95% CI: [-0.002, 0.048]
Comparison: Week 48 Change from Baseline95% CI: [-0.03, 0.042]
Secondary
Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements
Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse will be disclosed with the following categories: * All values within 20% of change from baseline (\< 20% change). * At least one value ≥ 20% reduction from baseline, but no increases ≥ 20% from baseline (≥ 20% reduction and no \< 20% increase). * At least one value ≥ 20% increase from baseline, but no reductions ≥ 20% from baseline (≥ 20% Increase and no \< 20% reduction). * At least one value ≥ 20% reduction from baseline and at least one value ≥ 20% increase from baseline (≥ 20% reduction and ≥ 20% increase). Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Baseline to Week 48
Population: 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 | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | DBP | < 20% change | 19 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | SBP | < 20% change | 28 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | SBP | ≥ 20% reduction and no < 20% increase | 2 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | SBP | ≥ 20% Increase and no < 20% reduction | 10 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | SBP | ≥ 20% reduction and ≥ 20% increase | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | DBP | ≥ 20% reduction and no < 20% increase | 11 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | DBP | ≥ 20% Increase and no < 20% reduction | 10 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | DBP | ≥ 20% reduction and ≥ 20% increase | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | Pulse | < 20% change | 21 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | Pulse | ≥ 20% reduction and no < 20% increase | 6 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | Pulse | ≥ 20% Increase and no < 20% reduction | 13 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Change in Vital Signs Measurements | Pulse | ≥ 20% reduction and ≥ 20% increase | 0 Participants |
Secondary
Number of Participants That Experienced a Clinically Significant Coagulation Result (Investigator's Assessment)
Parameters included: activated partial thromboplastin time, prothrombin time and international normalised ratio. Coagulation was only assessed for Cohorts 2 and 3. Results for Cohorts 2 and 3 are pooled as specified in the protocol.
Time frame: Day 1 to Week 48
Population: All participants who received at least one dose of study medication in Cohorts 2 and 3 only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Coagulation Result (Investigator's Assessment) | 0 Participants |
Secondary
Number of Participants That Experienced a Clinically Significant Haematology Result (Investigator's Assessment)
Parameters included: haemoglobin, haematocrit, mean corpuscular volume, white blood cells, red blood cells, neutrophils (percentage and absolute), lymphocytes (percentage and absolute), monocytes (percentage and absolute), eosinophils (percentage and absolute), basophils (percentage and absolute) and platelets. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Day 1 to Week 48
Population: All participants who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Haematology Result (Investigator's Assessment) | 0 Participants |
Secondary
Number of Participants That Experienced a Clinically Significant in Physical Examination Result
Examinations included: ear, nose and throat, cardiovascular system, pulmonary system, skin, abdomen, neurological system, height and weight. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Day 1 to Week 48
Population: All participants who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant in Physical Examination Result | 1 Participants |
Secondary
Number of Participants That Experienced a Clinically Significant Urinalysis Result (Investigator's Assessment)
Parameters included: glucose, bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrites and leucocytes. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Day 1 to Week 48
Population: All participants who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Clinically Significant Urinalysis Result (Investigator's Assessment) | 0 Participants |
Secondary
Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement
Participants were at rest in a supine position for 10 minutes before the measurements were performed. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Baseline, Week 24 and Week 48
Population: 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 | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Week 48 | Abnormal, Clinically Significant | 1 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Baseline | Normal | 38 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Baseline | Abnormal, Not Clinically Significant | 2 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Baseline | Abnormal, Clinically Significant | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Week 24 | Normal | 33 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Week 24 | Abnormal, Not Clinically Significant | 5 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Week 24 | Abnormal, Clinically Significant | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Week 48 | Normal | 33 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Echocardiogram Measurement | Week 48 | Abnormal, Not Clinically Significant | 2 Participants |
Secondary
Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements
PR interval (PRI), heart rate (HR), QTcF and increase from baseline in QTcF (IQTcF) were summarized categorically. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Baseline to Week 48
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | PRI: <170 ms | 37 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | PRI: ≥170 ms | 3 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | PRI: < 20% change | 35 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | PRI: ≥ 20% reduction and no < 20% increase | 2 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | PRI: ≥ 20% increase and no < 20% reduction | 3 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | PRI: ≥ 20% reduction and ≥ 20% increase | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | HR: < 20% change | 7 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | HR: ≥ 20% reduction and no < 20% increase | 6 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | HR: ≥ 20% increase and no < 20% reduction | 22 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | HR: ≥ 20% reduction and ≥ 20% increase | 5 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | QTcF: < 450 ms | 40 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | QTcF: ≥ 450 ms | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | IQTcF: < 30 ms | 32 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | IQTcF: 30 - 59 ms | 8 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Electrocardiogram Measurements | IQTcF: >= 60 ms | 0 Participants |
Secondary
Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result
Laboratory measurements for alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), alkaline phosphatase (ALP), and glutamate dehydrogenase (GLDH). Hy's Law is defined as an increase in ALT, AST and TB, indicating hepatocyte necrosis and functional deficit. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Baseline to Week 48
Population: All participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | ALP >= 1.5*ULN | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | ALT >= upper limit of normal (ULN) | 43 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | ALT >= 2*ULN | 43 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | ALT >= 3*ULN | 42 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | AST >= ULN | 43 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | AST >= 2*ULN | 42 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | AST >= 3*ULN | 42 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | TB >= ULN | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | TB >= 2*ULN | 0 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | GLDH >= ULN excluding haemolysed samples | 27 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | GLDH >= ULN including haemolysed samples | 30 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | GLDH >= 2.5*ULN Excluding Haemolysed Samples | 2 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | GLDH >= 2.5*ULN including haemolysed samples | 2 Participants |
| Cohorts 1 and 2: SMT C1100 | Number of Participants That Experienced a Potentially Clinically Significant Liver Function Result | Participants meeting Hy's law | 0 Participants |
Secondary
Number of Participants Who Experienced a Clinically Significant Biochemistry Result (Investigator's Assessment)
Parameters included: calcium, potassium, sodium, albumin, urea nitrogen, uric acid, creatinine, creatine kinase, fasting glucose, cystatin C, lactate dehydrogenase, amylase, lipase, low density lipoprotein cholesterol, high density lipoprotein (HDL) cholesterol, cholesterol, non-HDL cholesterol, total HDL cholesterol ratio, total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase and glutamate dehydrogenase. Results for Cohorts 1, 2 and 3 are pooled as specified in the protocol.
Time frame: Day 1 to Week 48
Population: All participants who received at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohorts 1 and 2: SMT C1100 | Number of Participants Who Experienced a Clinically Significant Biochemistry Result (Investigator's Assessment) | 3 Participants |