Efficacy and Safety of Tideglusib in Congenital Myotonic Dystrophy

The Clinician-Completed Congenital DM1 Scale is an 11-item rating scale completed by the clinician that scores the symptom severity of domains that are clinically relevant in Congenital DM1. The severity of the clinician's concern in each domain is scored by using a 5-point Likert Scale. Scores range from 0 = Not present to 4 = Very severe.

Time frame: Baseline and week 20

The 10-meter walk/run test is a performance measure used to assess walking speed in seconds over a short distance. It can be used as an assessment of functional mobility.

Time frame: 20 weeks

The Caregiver-Completed Congenital DM1 Scale is a caregiver assessment of the subject on symptoms that may occur in individuals with CDM1. There are a total of 11 clinically relevant symptoms that the caregiver is asked to rate the severity of. The symptoms are rated on a score from 0 to 4 based on overall severity where 0 = symptom not present or is no longer present during the relevant time frame, and 4 = very severe, symptom causes pronounced and consistent impairment and is highly disruptive with regard to daily life. A total CC-CDM1-RS score for each subject was calculated as the sum of the scores where 0 = min and 44 = max. A higher score represents a worse outcome.

Time frame: Baseline and week 20

Change from baseline to end of treatment in the independent central rater CDM1-RS total score. CDM1 Rating Scale is an 11-item rating scale completed by the clinician to score the symptom severity that are clinically relevant in CDM1. The severity of the clinician's concern in each domain is scored by using a 5-point Likert Scale. Scores range from 0 = Not present to 4 = Very severe.

Time frame: Baseline to week 20

Population: A subject (randomized to tideglusib) withdrew consent on Day 12 of randomized treatment and was excluded from the intent-to-treat analysis, full and per-protocol analysis sets as they did not have a post-baseline efficacy assessment.

The CGI-I requires the clinician to rate how much the subject's illness has changed (improved, worsened or stayed the same) relative to a baseline state on a seven point scale. A 7-point Likert type scale is used with ratings of 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: Baseline and week 20

Population: A subject (randomized to tideglusib) withdrew consent on Day 12 of randomized treatment and was excluded from the intent-to-treat analysis, full and per-protocol analysis sets as they did not have a post-baseline efficacy assessment.

The clinician administered CGI-I rates how much the subject's illness has improved or worsened relative to a baseline state. A 7-point Likert type scale is used with ratings of 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: Baseline and week 20

Population: A subject (randomized to tideglusib) withdrew consent on Day 12 of randomized treatment and was excluded from the intent-to-treat analysis, full and per-protocol analysis sets as they did not have a post-baseline efficacy assessment.

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. Caregivers were asked to rate three causes for concern by drawing a vertical mark on a 10 cm long VAS 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: Baseline and week 20

The Clinical Global Impression - Severity Scale (CGI-S) is a 7-point 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. Subjects are 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.

Time frame: Baseline and week 20

CGI-S is a 7-point Likert type scale. An independent central rater rated the CGI-S scales for both the in-clinic and telehealth interviews. Subjects are 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.

Time frame: Baseline and week 20

Population: A subject (randomized to tideglusib) withdrew consent on Day 12 of randomized treatment and was excluded from the intent-to-treat analysis, full and per-protocol analysis sets as they did not have a post-baseline efficacy assessment.

Abnormal laboratory findings (e.g. hematology, liver function, biochemistry, urinalysis) or other abnormal assessments (e.g. ECGs, vital signs) that are judged by the Investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE. The Investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.

Time frame: Between Screening to End of Study, up to 28 weeks

Population: A participant assigned to placebo was found to have some tideglusib levels (due to inadvertent exposure between siblings in opposing arms), and was therefore, included in the safety analysis and full analysis sets for tideglusib.

Adverse events may be volunteered spontaneously by the subject, or discovered as a result of general, non-leading questioning by physician.

Time frame: Between Screening to End of Study, up to 28 weeks

Population: A participant assigned to placebo was found to have some tideglusib levels (due to inadvertent exposure between siblings in opposing arms), and was therefore, included in the safety analysis and full analysis sets for tideglusib.

Analysis of Ratio to Baseline in Creatine Phosphokinase

Time frame: 20 weeks

A multi-domain responder index (MDRI) analysis was performed by combining 5 endpoints to objectively assess movement, muscle integrity and strength, cognitive skills and adaptive behavior. For each of the 5 endpoints, subjects were scored +1 point if their change exceeded or was equal to the threshold in a beneficial direction, -1 point if their change exceeded or was equal to the threshold in a detrimental direction and 0 points otherwise. The sum of these 5 scores were added together to provide an MDRI score between -5 and 5, where a higher score indicates greater overall improvement.

Time frame: Baseline and week 20

Post-hoc analyses comparing the mean change from baseline from clinical responses of subjects with tideglusib exposures above the 50th percentile (who achieved the desired target exposure) with those subjects who showed lower exposure levels, and with the placebo group. The 10-meter walk/run test is a performance measure used to assess walking speed in seconds over a short distance. It can be used as an assessment of functional mobility.

Time frame: 20 weeks

Post-hoc analyses comparing the mean change from baseline in clinical responses of subjects with tideglusib exposures above the 50th percentile (who achieved the desired target exposure) with those subjects who showed lower exposure levels, and with the placebo group. Concentration of Creatine Phosphokinase (UI/L).

Time frame: 20 weeks

Post-hoc analyses comparing the mean change from baseline clinical responses of subjects with tideglusib exposures above the 50th percentile (who achieved the desired target exposure) with those subjects who showed lower exposure levels, and with the placebo group. The PPVT-4 scale is a norm-referenced instrument for measuring the receptive (hearing) vocabulary. It contains training items and 228 test items, each consisting of four full-color pictures as response options on a page. Each test produces a raw score and a standard score. The raw score counts the number of correct responses. Raw scores are reported here as standardized scores are considered less appropriate for a pediatric population with cognitive deficits. Higher scores mean a better performance/receptive vocabulary. The lowest possible raw score is 0, the maximum raw score depends on the number of items administered so theoretically, the highest score possible on this test would be 228.

Time frame: Baseline to week 20

Post-hoc analyses comparing the mean clinical responses of subjects with tideglusib exposures above the 50th percentile (who achieved the desired target exposure) with those subjects who showed lower exposure levels, and with the placebo group. The 10-meter walk/run test is a performance measure used to assess walking speed in seconds over a short distance. It can be used as an assessment of functional mobility.

Time frame: 20 weeks

Post-hoc analyses comparing the mean clinical responses of subjects with tideglusib exposures above the 50th percentile (who achieved the desired target exposure) with those subjects who showed lower exposure levels, and with the placebo group. Concentration of Creatine Phosphokinase (UI/L).

Time frame: 20 weeks

Post-hoc analyses comparing the mean clinical responses of subjects above and below the 50th percentile of tideglusib exposure levels with the placebo group. A multi-domain responder index (MDRI) analysis was performed by combining 5 objective endpoints. For each of the 5 endpoints, subjects were scored +1 point if their change exceeded or was equal to the threshold in a beneficial direction, -1 point if their change exceeded or was equal to the threshold in a detrimental direction and 0 points otherwise. The sum of these 5 scores were added together to provide an MDRI score between -5 and 5, where a higher score indicates greater overall improvement.

Time frame: Baseline and week 20

Post-hoc analyses comparing the mean clinical responses of subjects with tideglusib exposures above the 50th percentile (who achieved the desired target exposure) with those subjects who showed lower exposure levels, and with the placebo group. The PPVT-4 scale is a norm-referenced instrument for measuring the receptive (hearing) vocabulary. It contains training items and 228 test items, each consisting of four full-color pictures as response options on a page. Each test produces a raw score and a standard score. The raw score counts the number of correct responses. Raw scores are reported here as standardized scores are considered less appropriate for a pediatric population with cognitive deficits. Higher scores mean a better performance/receptive vocabulary. The lowest possible raw score is 0, the maximum raw score depends on the number of items administered so theoretically, the highest score possible on this test would be 228.

Time frame: Baseline and week 20