Myotonic Dystrophy 1
Conditions
Brief summary
The purpose of this study is to determine whether Tideglusib is safe and efficacious in the treatment of adolescents and adults with congenital and juvenile-onset Myotonic Dystrophy. The pharmacokinetics of tideglusib and its primary metabolite will also be investigated.
Interventions
DRUGTideglusib
Tideglusib for oral suspension,
Sponsors
AMO Pharma Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
12 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Adolescents or adults with diagnosis of congenital or juvenile-onset type 1 myotonic dystrophy (DM-1) * Diagnosis must be genetically confirmed * Subjects must be male or female aged 12 years to 45 years * Subjects must have a Clinical Global Impression - Severity (CGI-S) score of 4 or greater at Screening and Run-in (V2) * Subjects must be ambulatory and able to complete the 10 metre walk/run test (splints allowed) * Subject's legally authorized representative (LAR) must provide written informed consent and there must be written consent or assent (as age applicable and developmentally appropriate) by the subject before any study-related procedures are conducted
Exclusion criteria
* Non-ambulatory (full time) wheel chair user * Receiving stimulant medication * Receiving other medications/therapies not stable (changed) within 4 weeks prior to Run-in (V2) * Medical illness or other concern which would cause investigator to conclude subjects will not be able to perform the study procedures or assessments or would confound interpretation of data obtained during assessment. * Current enrolment in a clinical trial of an investigational drug or enrolment in a clinical trial of an investigational drug in the last 6 months * Women of child bearing potential who are pregnant, lactating or not willing to use a protocol defined acceptable contraception method if sexually active and not surgically sterile. * Gastrointestinal disease which may interfere with the absorption, distribution, metabolism or excretion of the study medication and impact the interpretability of the study results * Current clinically significant (as determined by the investigator) cardiovascular, renal, hepatic, endocrine or respiratory disease * Clinically significant heart disease (in the opinion of the investigator) or second or third degree heart block, atrial flutter, atrial fibrillation, ventricular arrhythmias, or is receiving medication for treatment of a cardiac arrhythmia * A history of chronic liver disease with current out of range values for Alanine transaminase (ALT), clinically relevant hepatic steatosis or other clinical manifestations of ongoing liver disease * A history of significant drug allergy (such as Steven-Johnson syndrome, anaphylaxis) * A history of alcohol or substance use disorders
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety (Adverse Events) | 12 weeks | Incidence of Adverse events (AEs), including serious adverse events (SAEs), between baseline to end of study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Pharmacokinetics of Tideglusib | 12 weeks | Pharmacokinetic samples were collected to determine time of the maximum plasma concentration and terminal elimination half-life of tideglusib |
| Area Under the Plasma Concentration vs. Time Curve of Tideglusib | 12 weeks | Pharmacokinetic samples were collected to determine area under the plasma concentration vs. time curve from 0 to 12 h and area under the plasma concentration vs. time curve from 0 to 24 h of tideglusib |
| 10 Metre Walk/Run Test | 12 weeks | The 10-metre walk/run test is a performance measure used to assess walking speed in metres per second over a short distance and was used as an assessment of functional mobility. Time taken to complete the 10m walk/run test at fastest and preferred speed is measured. |
| Computerised Handgrip Myometer Measure of Grip Strength and Muscle Relaxation Time | 12 weeks | Handgrip myometry is used as a measure of myotonia and muscle strength for the dominant hand |
| Respiratory Forced Vital Capacity (FVC) | 12 weeks | FVC is a measure of lung function (the total amount of air exhaled during a Forced Expiratory Volume is measured using a spirometer) |
| Dual-energy X-ray Absorptiometry (DXA) | 12 weeks | DXA utilises two low energy X-ray beams, with different energy levels, which are aimed at the subject's bones. The DXA scan is more typically used to measure bone mineral density, however it can also be used to measure total lean muscle mass |
| Clinical Global Impressions- Severity (CGI-S) | 12 weeks | The CGI-S is a 7-point Likert type scale that requires the clinician to rate the severity of the subject's illness at the time of assessment, relative to the clinician's past experience with subjects who have the same diagnosis. Considering total clinical experience, a subject is assessed on severity of illness at the time of rating 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. Change in CGI-S was observed in only 1 subject. Consequently statistical analysis was not conducted. |
| Clinical Global Impressions- Improvement (CGI-I) | 12 weeks | The CGI-I requires the clinician to rate how much the subject's illness has improved or worsened relative to a baseline state. A seven point Likert type scale is used from 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. |
| Actigraphy (3-minute Bouts of Activity) | 12 weeks | Actigraphy is a non-invasive method of monitoring physical activity via an actigraph device. The actigraph device was worn on the waist during waking hours, according to the device's instruction manual. |
| Plasma Concentration of Tideglusib | 12 weeks | Pharmacokinetic samples were collected to determine Tideglusib plasma concentration |
| Actigraphy (Steps) | 12 weeks | Actigraphy is a non-invasive method of monitoring physical activity via an actigraph device. The actigraph device was worn on the waist during waking hours, according to the device's instruction manual. |
| Nine Hole Peg Test (NHPT) | 12 weeks | Measure of fine manual dexterity. Time to taken to complete the NHPT (dominant hand) is recorded. |
| Top 3 Concerns Visual Analogue Scale (VAS) Score | 12 weeks | The Top 3 concerns VAS allows caregivers to identify their main three causes of concern, related to the subject's myotonic dystrophy, rather than these being pre-specified within a scale and then rating how these concerns have changed at specific time-points during the study. Subjects, where possible, and caregivers were asked to rate three causes for concern by drawing a vertical mark on a 10 cm long visual analogue scale with anchors of not at all severe at the left end (0 cm) and very severe at the right end (10 cm). A score for each concern was to be determined by measuring the number of centimeters on the 10 cm VAS line from the anchor point on the left side of the line. A total VAS score for each subject was calculated as the sum of the scores for the 3 concerns (minimum = 0 cm, maximum = 30 cm). A higher score represents a worse outcome. |
| Ohio State University (OSU) Autism Rating Scale (OARS) | 12 weeks | The OARS-4 contains the autism signs and symptoms in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. These were to be rated with the degree of impairment the subject experiences for the given symptom. The symptoms were to be elicited in a semi-structured interview with the subject's primary caregiver. The assessor was to take both frequency/duration and degree of impairment into account and how much the item interferes with relationships, learning, and/or activities of daily living. The scores for this assessment were from 0 (Never or Rarely; Not a Problem) to 3 (Very Often; A Severe Problem): a score for each symptom of social impairment, communication impairment and restricted patterns were averaged to provide a total impairment score. A higher score represents a worse outcome (minimum = 0, maximum 3). |
| Ohio State University (OSU) Autism Clinical Global Impression (CGI) | 12 weeks | The OSU Autism CGI scale contains separate subscales for symptom severity and for global improvement. These are rated in a similar way to the National Institute of Mental Health (NIMH) CGI Severity scale, but it is focused on autism spectrum symptoms. OSU Autism CGI-severity and OSU Autism CGI-improvement scores use a seven point Likert rating scale from 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. |
| Clinician-completed Domain Specific Cause for Concern Visual Analogue Scale (VAS): Myotonic Dystrophy | 12 weeks | The Clinician-completed Domain Specific Causes for Concern is a Visual Analogue Scale completed by the clinician that scores the severity of concerns of domains that are clinically relevant in myotonic dystrophy. The severity of the clinician's concern is scored by using a 10 cm visual analogue scale (VAS), with anchors of not at all severe at the left end (0 cm) and very severe at the right end (10 cm). The clinician is asked to make a vertical line indicating his/her level of concern in each domain, using a time frame of the past week for reference. A score is to be determined by measuring the number of centimeters on the 10 cm VAS line from the anchor point on the left side of the line. A total VAS score for each subject was calculated as the sum of the scores for the 17 domains (minimum = 0, maximum = 170 cm). A higher score represents a worse outcome. |
| Peabody Picture Vocabulary Test (PPVT) | 12 weeks | The PPVT-4 scale is a norm-referenced instrument for measuring the receptive (hearing) vocabulary of children and adults. It contains training items and 228 test items, each consisting of four full-colour pictures as response options on a page. For each item, the examiner says a word, and the examinee responds by selecting the picture that best illustrates that word's meaning. Each administration of the test produces a raw score (number of test items answered correctly), which can be converted to a standard score (using age-based norms) with a mean of 100 and a standard deviation of 15. Higher scores mean a better performance/receptive vocabulary. |
| Biomarker - Lymphocyte GSK3β Levels and Activity | 12 weeks | Total levels of GSK3β protein was determined via x-MAP technology in a Luminex 200 platform using the AKT Pathway Total Multispecies 7-Plex Panel from ThermoFisher Scientific. |
| Actigraphy (>10-minute Bouts of Activity) | 12 weeks | Actigraphy is a non-invasive method of monitoring physical activity via an actigraph device. The actigraph device was worn on the waist during waking hours, according to the device's instruction manual. |
Countries
United Kingdom
Participant flow
Pre-assignment details
Subjects were to be male or female aged 12 to 45 years with a diagnosis of genetically confirmed congenital or juvenile-onset type 1 myotonic dystrophy. Subjects were to have a Clinical Global Impression- Severity (CGI-S) score of 4 or greater at Screening and Run-in (V2) and were to be ambulatory and able to complete the 10-metre walk/run test.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 1000 mg tideglusib | 8 |
| Cohort 2 400 mg tideglusib | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Total |
|---|---|---|---|
| Age, Customized Mean | 21.8 years STANDARD_DEVIATION 5.5 | 20.3 years STANDARD_DEVIATION 6.36 | 21 years STANDARD_DEVIATION 5.8 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or latino | 8 Participants | 8 Participants | 16 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 8 / 8 | 6 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Safety (Adverse Events)
Incidence of Adverse events (AEs), including serious adverse events (SAEs), between baseline to end of study.
Time frame: 12 weeks
Population: Safety Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Safety (Adverse Events) | Unrelated to active treatment | 6 Participants |
| Cohort 1 | Safety (Adverse Events) | Related to active treatment | 2 Participants |
| Cohort 1 | Safety (Adverse Events) | Total number of TEAEs | 8 Participants |
| Cohort 1 | Safety (Adverse Events) | Total number of serious TEAEs | 0 Participants |
| Cohort 1 | Safety (Adverse Events) | Total number of TEAEs leading to discontinuation of active treatment | 0 Participants |
| Cohort 1 | Safety (Adverse Events) | Total number of TEAEs leading to withdrawal | 0 Participants |
| Cohort 1 | Safety (Adverse Events) | Total number of TEAEs leading to death | 0 Participants |
| Cohort 1 | Safety (Adverse Events) | Severity: Mild | 3 Participants |
| Cohort 1 | Safety (Adverse Events) | Severity: Moderate | 5 Participants |
| Cohort 1 | Safety (Adverse Events) | Severity: Severe | 0 Participants |
| Cohort 2 | Safety (Adverse Events) | Severity: Mild | 1 Participants |
| Cohort 2 | Safety (Adverse Events) | Unrelated to active treatment | 6 Participants |
| Cohort 2 | Safety (Adverse Events) | Total number of TEAEs leading to withdrawal | 0 Participants |
| Cohort 2 | Safety (Adverse Events) | Related to active treatment | 0 Participants |
| Cohort 2 | Safety (Adverse Events) | Severity: Severe | 1 Participants |
| Cohort 2 | Safety (Adverse Events) | Total number of TEAEs | 6 Participants |
| Cohort 2 | Safety (Adverse Events) | Total number of TEAEs leading to death | 0 Participants |
| Cohort 2 | Safety (Adverse Events) | Total number of serious TEAEs | 0 Participants |
| Cohort 2 | Safety (Adverse Events) | Severity: Moderate | 4 Participants |
| Cohort 2 | Safety (Adverse Events) | Total number of TEAEs leading to discontinuation of active treatment | 0 Participants |
Secondary
10 Metre Walk/Run Test
The 10-metre walk/run test is a performance measure used to assess walking speed in metres per second over a short distance and was used as an assessment of functional mobility. Time taken to complete the 10m walk/run test at fastest and preferred speed is measured.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | 10 Metre Walk/Run Test | Fastest speed (observed value at week 12) | 4.2515 seconds | Standard Deviation 2.41439 |
| Cohort 1 | 10 Metre Walk/Run Test | Preferred speed (change from baseline at week 12) | -0.6616 seconds | Standard Deviation 1.9637 |
| Cohort 1 | 10 Metre Walk/Run Test | Fastest speed (change from baseline at week 12) | -0.3894 seconds | Standard Deviation 0.32806 |
| Cohort 1 | 10 Metre Walk/Run Test | Preferred speed (observed value at week 12) | 9.1041 seconds | Standard Deviation 1.34351 |
| Cohort 2 | 10 Metre Walk/Run Test | Fastest speed (change from baseline at week 12) | -0.0650 seconds | Standard Deviation 0.46428 |
| Cohort 2 | 10 Metre Walk/Run Test | Preferred speed (change from baseline at week 12) | -0.6529 seconds | Standard Deviation 0.86109 |
| Cohort 2 | 10 Metre Walk/Run Test | Fastest speed (observed value at week 12) | 4.4833 seconds | Standard Deviation 2.72809 |
| Cohort 2 | 10 Metre Walk/Run Test | Preferred speed (observed value at week 12) | 9.1475 seconds | Standard Deviation 1.72651 |
Comparison: Change from baseline to week 12 in the time taken (seconds) to complete 10-metre walk/run test at the preferred speedp-value: 0.048495% CI: [-1.334, -0.0051]Mixed Models Analysis
Comparison: Change from baseline to week 12 in the time taken (seconds) to complete 10-metre walk/run test at the preferred speedp-value: 0.056595% CI: [-1.3094, 0.0195]Mixed Models Analysis
Secondary
Actigraphy (>10-minute Bouts of Activity)
Actigraphy is a non-invasive method of monitoring physical activity via an actigraph device. The actigraph device was worn on the waist during waking hours, according to the device's instruction manual.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Actigraphy (>10-minute Bouts of Activity) | Weekly total number of >10 minute bouts of activity (observed value at week 12) | 0.048 10 minute bouts of activity per hour | Standard Deviation 0.0621 |
| Cohort 1 | Actigraphy (>10-minute Bouts of Activity) | Weekly total number of >10 minute bouts of activity (change from baseline at week 12) | -0.010 10 minute bouts of activity per hour | Standard Deviation 0.06 |
| Cohort 2 | Actigraphy (>10-minute Bouts of Activity) | Weekly total number of >10 minute bouts of activity (observed value at week 12) | 0.020 10 minute bouts of activity per hour | Standard Deviation 0.0245 |
| Cohort 2 | Actigraphy (>10-minute Bouts of Activity) | Weekly total number of >10 minute bouts of activity (change from baseline at week 12) | 0.006 10 minute bouts of activity per hour | Standard Deviation 0.0313 |
Secondary
Actigraphy (3-minute Bouts of Activity)
Actigraphy is a non-invasive method of monitoring physical activity via an actigraph device. The actigraph device was worn on the waist during waking hours, according to the device's instruction manual.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Actigraphy (3-minute Bouts of Activity) | Weekly total number of 3 minute bouts of activity (observed value at week 12) | 1.465 3 minute bouts of activity per hour | Standard Deviation 0.178 |
| Cohort 1 | Actigraphy (3-minute Bouts of Activity) | Weekly total number of 3 minute bouts of activity (change from baseline at week 12) | -0.200 3 minute bouts of activity per hour | Standard Deviation 0.3959 |
| Cohort 2 | Actigraphy (3-minute Bouts of Activity) | Weekly total number of 3 minute bouts of activity (observed value at week 12) | 0.938 3 minute bouts of activity per hour | Standard Deviation 0.5268 |
| Cohort 2 | Actigraphy (3-minute Bouts of Activity) | Weekly total number of 3 minute bouts of activity (change from baseline at week 12) | -0.284 3 minute bouts of activity per hour | Standard Deviation 0.1805 |
Comparison: Change from baseline to week 12 in the weekly total number of 3 minute bouts of activity per hour wear timep-value: 0.185795% CI: [-0.33, 0.066]Mixed Models Analysis
Comparison: Change from baseline to week 12 in the weekly total number of 3 minute bouts of activity per hour wear timep-value: 0.005495% CI: [-0.549, -0.102]Mixed Models Analysis
Secondary
Actigraphy (Steps)
Actigraphy is a non-invasive method of monitoring physical activity via an actigraph device. The actigraph device was worn on the waist during waking hours, according to the device's instruction manual.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Actigraphy (Steps) | Weekly total number of steps (observed value at week 12) | 556.387 steps per hour wear time | Standard Deviation 255.6433 |
| Cohort 1 | Actigraphy (Steps) | Weekly total number of steps (change from baseline at week 12) | -51.427 steps per hour wear time | Standard Deviation 198.9754 |
| Cohort 2 | Actigraphy (Steps) | Weekly total number of steps (observed value at week 12) | 352.518 steps per hour wear time | Standard Deviation 263.1992 |
| Cohort 2 | Actigraphy (Steps) | Weekly total number of steps (change from baseline at week 12) | -53.802 steps per hour wear time | Standard Deviation 89.0843 |
Secondary
Area Under the Plasma Concentration vs. Time Curve of Tideglusib
Pharmacokinetic samples were collected to determine area under the plasma concentration vs. time curve from 0 to 12 h and area under the plasma concentration vs. time curve from 0 to 24 h of tideglusib
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration vs. Time Curve of Tideglusib | Area under the plasma concentration vs. time curve from 0 to 12 h (AUC0-12) | 3054.27 ng/mL.h | Standard Deviation 1418.3 |
| Cohort 1 | Area Under the Plasma Concentration vs. Time Curve of Tideglusib | Area under the plasma concentration vs. time curve from 0 to 24 h (AUC0-24) | 3208.8 ng/mL.h | Standard Deviation 1459.03 |
| Cohort 2 | Area Under the Plasma Concentration vs. Time Curve of Tideglusib | Area under the plasma concentration vs. time curve from 0 to 12 h (AUC0-12) | 1214.88 ng/mL.h | Standard Deviation 390.81 |
| Cohort 2 | Area Under the Plasma Concentration vs. Time Curve of Tideglusib | Area under the plasma concentration vs. time curve from 0 to 24 h (AUC0-24) | 1302.42 ng/mL.h | Standard Deviation 396.96 |
Secondary
Biomarker - Lymphocyte GSK3β Levels and Activity
Total levels of GSK3β protein was determined via x-MAP technology in a Luminex 200 platform using the AKT Pathway Total Multispecies 7-Plex Panel from ThermoFisher Scientific.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Biomarker - Lymphocyte GSK3β Levels and Activity | 1.42 microgram per microliter | Standard Deviation 0.81 |
| Cohort 2 | Biomarker - Lymphocyte GSK3β Levels and Activity | 1.95 microgram per microliter | Standard Deviation 0.79 |
Secondary
Blood Pharmacokinetics of Tideglusib
Pharmacokinetic samples were collected to determine time of the maximum plasma concentration and terminal elimination half-life of tideglusib
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Blood Pharmacokinetics of Tideglusib | Terminal elimination half-life (T1/2) | 1.82 h | Standard Deviation 0.64 |
| Cohort 1 | Blood Pharmacokinetics of Tideglusib | Time of the maximum plasma concentration (Tmax) | 0.79 h | Standard Deviation 0.27 |
| Cohort 2 | Blood Pharmacokinetics of Tideglusib | Terminal elimination half-life (T1/2) | 2.68 h | Standard Deviation 1.7 |
| Cohort 2 | Blood Pharmacokinetics of Tideglusib | Time of the maximum plasma concentration (Tmax) | 0.65 h | Standard Deviation 0.29 |
Secondary
Clinical Global Impressions- Improvement (CGI-I)
The CGI-I requires the clinician to rate how much the subject's illness has improved or worsened relative to a baseline state. A seven point Likert type scale is used from 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Clinical Global Impressions- Improvement (CGI-I) | 3.1 Scores on a scale | Standard Deviation 0.83 |
| Cohort 2 | Clinical Global Impressions- Improvement (CGI-I) | 3.0 Scores on a scale | Standard Deviation 1.07 |
Comparison: Observed value at week 12 in Clinical Global Impression Global Improvement Scale (CGI-I)p-value: 0.00395% CI: [2.6, 3.7]Mixed Models Analysis
Comparison: Observed value at week 12 in Clinical Global Impression Global Improvement Scale (CGI-I)p-value: 0.000995% CI: [2.4, 3.6]Mixed Models Analysis
Secondary
Clinical Global Impressions- Severity (CGI-S)
The CGI-S is a 7-point Likert type scale that requires the clinician to rate the severity of the subject's illness at the time of assessment, relative to the clinician's past experience with subjects who have the same diagnosis. Considering total clinical experience, a subject is assessed on severity of illness at the time of rating 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. Change in CGI-S was observed in only 1 subject. Consequently statistical analysis was not conducted.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Clinical Global Impressions- Severity (CGI-S) | Observed value at week 12 | 4.8 Values on a scale | Standard Deviation 1.16 |
| Cohort 1 | Clinical Global Impressions- Severity (CGI-S) | Change from baseline at week 12 | -0.1 Values on a scale | Standard Deviation 0.35 |
| Cohort 2 | Clinical Global Impressions- Severity (CGI-S) | Observed value at week 12 | 4.9 Values on a scale | Standard Deviation 0.83 |
| Cohort 2 | Clinical Global Impressions- Severity (CGI-S) | Change from baseline at week 12 | 0.0 Values on a scale | Standard Deviation 0 |
Secondary
Clinician-completed Domain Specific Cause for Concern Visual Analogue Scale (VAS): Myotonic Dystrophy
The Clinician-completed Domain Specific Causes for Concern is a Visual Analogue Scale completed by the clinician that scores the severity of concerns of domains that are clinically relevant in myotonic dystrophy. The severity of the clinician's concern is scored by using a 10 cm visual analogue scale (VAS), with anchors of not at all severe at the left end (0 cm) and very severe at the right end (10 cm). The clinician is asked to make a vertical line indicating his/her level of concern in each domain, using a time frame of the past week for reference. A score is to be determined by measuring the number of centimeters on the 10 cm VAS line from the anchor point on the left side of the line. A total VAS score for each subject was calculated as the sum of the scores for the 17 domains (minimum = 0, maximum = 170 cm). A higher score represents a worse outcome.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Clinician-completed Domain Specific Cause for Concern Visual Analogue Scale (VAS): Myotonic Dystrophy | VAS total score (observed value at week 12) | 51.19 Score on a scale | Standard Deviation 8.798 |
| Cohort 1 | Clinician-completed Domain Specific Cause for Concern Visual Analogue Scale (VAS): Myotonic Dystrophy | VAS total score (change from baseline at week 12) | -5.80 Score on a scale | Standard Deviation 4.855 |
| Cohort 2 | Clinician-completed Domain Specific Cause for Concern Visual Analogue Scale (VAS): Myotonic Dystrophy | VAS total score (observed value at week 12) | 59.28 Score on a scale | Standard Deviation 17.45 |
| Cohort 2 | Clinician-completed Domain Specific Cause for Concern Visual Analogue Scale (VAS): Myotonic Dystrophy | VAS total score (change from baseline at week 12) | -3.38 Score on a scale | Standard Deviation 2.726 |
Comparison: Change from baseline at week 12 in the clinician-completed domain specific causes for concern VAS total score (cm)p-value: <0.000195% CI: [-8.35, -3.47]Mixed Models Analysis
Comparison: Change from baseline at week 12 in the clinician-completed domain specific causes for concern VAS total score (cm)p-value: 0.011695% CI: [-5.71, -0.83]Mixed Models Analysis
Secondary
Computerised Handgrip Myometer Measure of Grip Strength and Muscle Relaxation Time
Handgrip myometry is used as a measure of myotonia and muscle strength for the dominant hand
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Computerised Handgrip Myometer Measure of Grip Strength and Muscle Relaxation Time | Observed value (at week 12) | 14.0899 kg | Standard Deviation 7.71583 |
| Cohort 1 | Computerised Handgrip Myometer Measure of Grip Strength and Muscle Relaxation Time | Change from baseline (at week 12) | 1.0098 kg | Standard Deviation 3.09422 |
| Cohort 2 | Computerised Handgrip Myometer Measure of Grip Strength and Muscle Relaxation Time | Change from baseline (at week 12) | -1.4893 kg | Standard Deviation 2.89328 |
| Cohort 2 | Computerised Handgrip Myometer Measure of Grip Strength and Muscle Relaxation Time | Observed value (at week 12) | 14.1334 kg | Standard Deviation 6.86499 |
Comparison: Change from baseline to week 12 in grip strength (kg)p-value: 0.373295% CI: [-1.1526, 2.973]Mixed Models Analysis
Comparison: Change from baseline to week 12 in grip strength (kg)p-value: 0.178295% CI: [-3.4525, 0.6731]Mixed Models Analysis
Secondary
Dual-energy X-ray Absorptiometry (DXA)
DXA utilises two low energy X-ray beams, with different energy levels, which are aimed at the subject's bones. The DXA scan is more typically used to measure bone mineral density, however it can also be used to measure total lean muscle mass
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Dual-energy X-ray Absorptiometry (DXA) | Arms (observed value at week 12) | 3102.9 gram | Standard Deviation 898.69 |
| Cohort 1 | Dual-energy X-ray Absorptiometry (DXA) | Arms (change from baseline at week 12) | -252.8 gram | Standard Deviation 1038.49 |
| Cohort 1 | Dual-energy X-ray Absorptiometry (DXA) | Legs (observed value at week 12) | 11767.0 gram | Standard Deviation 2980.78 |
| Cohort 1 | Dual-energy X-ray Absorptiometry (DXA) | Legs (change from baseline at week 12) | -62.5 gram | Standard Deviation 646.22 |
| Cohort 1 | Dual-energy X-ray Absorptiometry (DXA) | Total (observed value at week 12) | 38267.6 gram | Standard Deviation 8274.58 |
| Cohort 1 | Dual-energy X-ray Absorptiometry (DXA) | Total (change from baseline at week 12) | 411.6 gram | Standard Deviation 2040.84 |
| Cohort 2 | Dual-energy X-ray Absorptiometry (DXA) | Total (observed value at week 12) | 37740.4 gram | Standard Deviation 8481.27 |
| Cohort 2 | Dual-energy X-ray Absorptiometry (DXA) | Arms (observed value at week 12) | 4098.5 gram | Standard Deviation 1313.53 |
| Cohort 2 | Dual-energy X-ray Absorptiometry (DXA) | Legs (change from baseline at week 12) | 95.0 gram | Standard Deviation 299.82 |
| Cohort 2 | Dual-energy X-ray Absorptiometry (DXA) | Arms (change from baseline at week 12) | 35.9 gram | Standard Deviation 357.09 |
| Cohort 2 | Dual-energy X-ray Absorptiometry (DXA) | Total (change from baseline at week 12) | 391.9 gram | Standard Deviation 763.01 |
| Cohort 2 | Dual-energy X-ray Absorptiometry (DXA) | Legs (observed value at week 12) | 12262.8 gram | Standard Deviation 3225.63 |
Comparison: Changes from baseline to week 12 in the DXA scan total lean muscle mass (g)p-value: 195% CI: [-1270, 2178.5]ANCOVA
Comparison: Changes from baseline to week 12 in the DXA scan total lean muscle mass (g)p-value: 0.312595% CI: [-289.5, 1198.5]ANCOVA
Secondary
Nine Hole Peg Test (NHPT)
Measure of fine manual dexterity. Time to taken to complete the NHPT (dominant hand) is recorded.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Nine Hole Peg Test (NHPT) | Observed value at week 12 | 23.590 seconds | Standard Deviation 8.2592 |
| Cohort 1 | Nine Hole Peg Test (NHPT) | Change from baseline at week 12 | -2.168 seconds | Standard Deviation 3.9007 |
| Cohort 2 | Nine Hole Peg Test (NHPT) | Observed value at week 12 | 24.760 seconds | Standard Deviation 3.8275 |
| Cohort 2 | Nine Hole Peg Test (NHPT) | Change from baseline at week 12 | -0.950 seconds | Standard Deviation 1.708 |
Comparison: Change from baseline to week 12 in the time taken (seconds) to complete the nine hole peg test for the dominant armp-value: 0.011195% CI: [-3.731, -0.593]Mixed Models Analysis
Comparison: Change from baseline to week 12 in the time taken (seconds) to complete the nine hole peg test for the dominant armp-value: 0.208895% CI: [-2.525, 0.614]Mixed Models Analysis
Secondary
Ohio State University (OSU) Autism Clinical Global Impression (CGI)
The OSU Autism CGI scale contains separate subscales for symptom severity and for global improvement. These are rated in a similar way to the National Institute of Mental Health (NIMH) CGI Severity scale, but it is focused on autism spectrum symptoms. OSU Autism CGI-severity and OSU Autism CGI-improvement scores use a seven point Likert rating scale from 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Ohio State University (OSU) Autism Clinical Global Impression (CGI) | OSU autism CGI-Severity (observed value at week 12) | 1.9 Units on a scale | Standard Deviation 0.99 |
| Cohort 1 | Ohio State University (OSU) Autism Clinical Global Impression (CGI) | OSU autism CGI-Severity (change from baseline at week 12) | -0.1 Units on a scale | Standard Deviation 0.35 |
| Cohort 1 | Ohio State University (OSU) Autism Clinical Global Impression (CGI) | OSU autism CGI-Improvement (observed value at week 12) | 3.4 Units on a scale | Standard Deviation 0.74 |
| Cohort 2 | Ohio State University (OSU) Autism Clinical Global Impression (CGI) | OSU autism CGI-Severity (observed value at week 12) | 2.3 Units on a scale | Standard Deviation 1.83 |
| Cohort 2 | Ohio State University (OSU) Autism Clinical Global Impression (CGI) | OSU autism CGI-Severity (change from baseline at week 12) | 0 Units on a scale | Standard Deviation 0 |
| Cohort 2 | Ohio State University (OSU) Autism Clinical Global Impression (CGI) | OSU autism CGI-Improvement (observed value at week 12) | 4 Units on a scale | Standard Deviation 0 |
Comparison: Observed value at week 12 in OSU global improvement scale for autism (OSU CGI-I)p-value: 0.001195% CI: [3, 3.7]Mixed Models Analysis
Comparison: Observed value at week 12 in OSU global improvement scale for autism (OSU CGI-I)p-value: 195% CI: [3.6, 4.4]Mixed Models Analysis
Secondary
Ohio State University (OSU) Autism Rating Scale (OARS)
The OARS-4 contains the autism signs and symptoms in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. These were to be rated with the degree of impairment the subject experiences for the given symptom. The symptoms were to be elicited in a semi-structured interview with the subject's primary caregiver. The assessor was to take both frequency/duration and degree of impairment into account and how much the item interferes with relationships, learning, and/or activities of daily living. The scores for this assessment were from 0 (Never or Rarely; Not a Problem) to 3 (Very Often; A Severe Problem): a score for each symptom of social impairment, communication impairment and restricted patterns were averaged to provide a total impairment score. A higher score represents a worse outcome (minimum = 0, maximum 3).
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Ohio State University (OSU) Autism Rating Scale (OARS) | Total impairment mean (observed value at week 12) | 0.239 Units on a scale | Standard Deviation 0.3178 |
| Cohort 1 | Ohio State University (OSU) Autism Rating Scale (OARS) | Total impairment mean (change from baseline at week 12) | -0.054 Units on a scale | Standard Deviation 0.0782 |
| Cohort 2 | Ohio State University (OSU) Autism Rating Scale (OARS) | Total impairment mean (observed value at week 12) | 0.303 Units on a scale | Standard Deviation 0.4946 |
| Cohort 2 | Ohio State University (OSU) Autism Rating Scale (OARS) | Total impairment mean (change from baseline at week 12) | -0.010 Units on a scale | Standard Deviation 0.0283 |
Comparison: Change from baseline to week 12 in the OSU Autism Rating Scale - DSM-IV (OARS-4) total impairment meanp-value: 0.006895% CI: [-0.092, -0.017]Mixed Models Analysis
Comparison: Change from baseline to week 12 in the OSU Autism Rating Scale - DSM-IV (OARS-4) total impairment meanp-value: 0.60995% CI: [-0.047, 0.028]Mixed Models Analysis
Secondary
Peabody Picture Vocabulary Test (PPVT)
The PPVT-4 scale is a norm-referenced instrument for measuring the receptive (hearing) vocabulary of children and adults. It contains training items and 228 test items, each consisting of four full-colour pictures as response options on a page. For each item, the examiner says a word, and the examinee responds by selecting the picture that best illustrates that word's meaning. Each administration of the test produces a raw score (number of test items answered correctly), which can be converted to a standard score (using age-based norms) with a mean of 100 and a standard deviation of 15. Higher scores mean a better performance/receptive vocabulary.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Peabody Picture Vocabulary Test (PPVT) | Age-based standard score (observed value at week 12) | 63.8 Units on a scale | Standard Deviation 15.81 |
| Cohort 1 | Peabody Picture Vocabulary Test (PPVT) | Age-based standard score (change from baseline at week 12) | -0.1 Units on a scale | Standard Deviation 7.97 |
| Cohort 2 | Peabody Picture Vocabulary Test (PPVT) | Age-based standard score (observed value at week 12) | 79.8 Units on a scale | Standard Deviation 22.23 |
| Cohort 2 | Peabody Picture Vocabulary Test (PPVT) | Age-based standard score (change from baseline at week 12) | -1.1 Units on a scale | Standard Deviation 5.57 |
Comparison: Change from baseline to week 12 in the peabody picture vocabulary test age-based standard scorep-value: 0.663195% CI: [-6.5, 4.3]ANCOVA
Comparison: Change from baseline to week 12 in the peabody picture vocabulary test age-based standard scorep-value: 0.954695% CI: [-5.5, 5.2]ANCOVA
Secondary
Plasma Concentration of Tideglusib
Pharmacokinetic samples were collected to determine Tideglusib plasma concentration
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Plasma Concentration of Tideglusib | Maximum plasma concentration (Cmax) | 1041.25 ng/mL | Standard Deviation 361.44 |
| Cohort 1 | Plasma Concentration of Tideglusib | Minimum plasma concentration (Cmin) | 8.63 ng/mL | Standard Deviation 5.68 |
| Cohort 1 | Plasma Concentration of Tideglusib | Steady-state concentration (CSS) | 133.7 ng/mL | Standard Deviation 60.79 |
| Cohort 2 | Plasma Concentration of Tideglusib | Maximum plasma concentration (Cmax) | 496.94 ng/mL | Standard Deviation 104.88 |
| Cohort 2 | Plasma Concentration of Tideglusib | Minimum plasma concentration (Cmin) | 5.14 ng/mL | Standard Deviation 4.06 |
| Cohort 2 | Plasma Concentration of Tideglusib | Steady-state concentration (CSS) | 54.27 ng/mL | Standard Deviation 16.54 |
Secondary
Respiratory Forced Vital Capacity (FVC)
FVC is a measure of lung function (the total amount of air exhaled during a Forced Expiratory Volume is measured using a spirometer)
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Respiratory Forced Vital Capacity (FVC) | Observed value (at week 12) | 2.1509 litres | Standard Deviation 0.93362 |
| Cohort 1 | Respiratory Forced Vital Capacity (FVC) | Change from baseline (at week 12) | -0.0179 litres | Standard Deviation 0.32603 |
| Cohort 2 | Respiratory Forced Vital Capacity (FVC) | Observed value (at week 12) | 2.4220 litres | Standard Deviation 1.15969 |
| Cohort 2 | Respiratory Forced Vital Capacity (FVC) | Change from baseline (at week 12) | 0.0118 litres | Standard Deviation 0.36746 |
Comparison: Change from baseline to week 12 in FVC (litres)p-value: 0.888695% CI: [-0.3368, 0.2941]Mixed Models Analysis
Comparison: Change from baseline to week 12 in FVC (litres)p-value: 0.920495% CI: [-0.3003, 0.3307]Mixed Models Analysis
Secondary
Top 3 Concerns Visual Analogue Scale (VAS) Score
The Top 3 concerns VAS allows caregivers to identify their main three causes of concern, related to the subject's myotonic dystrophy, rather than these being pre-specified within a scale and then rating how these concerns have changed at specific time-points during the study. Subjects, where possible, and caregivers were asked to rate three causes for concern by drawing a vertical mark on a 10 cm long visual analogue scale with anchors of not at all severe at the left end (0 cm) and very severe at the right end (10 cm). A score for each concern was to be determined by measuring the number of centimeters on the 10 cm VAS line from the anchor point on the left side of the line. A total VAS score for each subject was calculated as the sum of the scores for the 3 concerns (minimum = 0 cm, maximum = 30 cm). A higher score represents a worse outcome.
Time frame: 12 weeks
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Top 3 Concerns Visual Analogue Scale (VAS) Score | Subject Top 3 Concerns VAS total score (observed value at week 12) | 15.66 Score on a scale | Standard Deviation 6.331 |
| Cohort 1 | Top 3 Concerns Visual Analogue Scale (VAS) Score | Subject Top 3 Concerns VAS total score (change from baseline at week 12) | -1.76 Score on a scale | Standard Deviation 3.455 |
| Cohort 1 | Top 3 Concerns Visual Analogue Scale (VAS) Score | Caregiver Top 3 Concerns VAS total score (observed value at week 12) | 18.84 Score on a scale | Standard Deviation 3.583 |
| Cohort 1 | Top 3 Concerns Visual Analogue Scale (VAS) Score | Caregiver Top 3 Concerns VAS total score (change from baseline at week 12) | -2.39 Score on a scale | Standard Deviation 2.669 |
| Cohort 2 | Top 3 Concerns Visual Analogue Scale (VAS) Score | Caregiver Top 3 Concerns VAS total score (change from baseline at week 12) | -1.98 Score on a scale | Standard Deviation 2.001 |
| Cohort 2 | Top 3 Concerns Visual Analogue Scale (VAS) Score | Subject Top 3 Concerns VAS total score (observed value at week 12) | 15.29 Score on a scale | Standard Deviation 5.641 |
| Cohort 2 | Top 3 Concerns Visual Analogue Scale (VAS) Score | Caregiver Top 3 Concerns VAS total score (observed value at week 12) | 16.58 Score on a scale | Standard Deviation 6.151 |
| Cohort 2 | Top 3 Concerns Visual Analogue Scale (VAS) Score | Subject Top 3 Concerns VAS total score (change from baseline at week 12) | -2.00 Score on a scale | Standard Deviation 2.598 |
Comparison: Change from baseline to week 12 in the subject top three concerns VAS total score (cm)p-value: 0.072895% CI: [-3.71, 0.18]Mixed Models Analysis
Comparison: Change from baseline to week 12 in the subject top three concerns VAS total score (cm)p-value: 0.045695% CI: [-3.94, -0.04]Mixed Models Analysis
Comparison: Change from baseline to week 12 in the caregiver top three concerns VAS total score (cm)p-value: 0.005895% CI: [-4.03, -0.8]Mixed Models Analysis
Comparison: Change from baseline to week 12 in the caregiver top three concerns VAS total score (cm)p-value: 0.020895% CI: [-3.56, -0.34]Mixed Models Analysis