Trial Outcomes & Findings for Efficacy and Safety of Tideglusib in Congenital Myotonic Dystrophy (NCT NCT03692312)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

56 participants

Primary outcome timeframe

Baseline and week 20

Results posted on

2025-10-08

Participant Flow

Children and adolescents (≥6 - ≤16 years) with a diagnosis of genetically confirmed congenital type 1 myotonic dystrophy. Subjects were to have a Clinical Global Impression-Severity score of ≥4 at Screening and V2, be ambulatory and able to complete the 10m walk/run test. Planned randomization of 56 subjects closed at 53 subjects due to fewer than expected discontinuations. A participant assigned to placebo was found to have some tideglusib levels and was included in analysis sets for tideglusib

Participant milestones

Participant milestones
Measure	Tideglusib Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Overall Study STARTED	27	26
Overall Study COMPLETED	25	25
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Efficacy and Safety of Tideglusib in Congenital Myotonic Dystrophy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tideglusib n=28 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Total n=53 Participants Total of all reporting groups
Age, Continuous	11.0 years STANDARD_DEVIATION 3.32 • n=5 Participants	11.0 years STANDARD_DEVIATION 3.61 • n=7 Participants	11.0 years STANDARD_DEVIATION 3.43 • n=5 Participants
Age, Customized Median	10 years n=5 Participants	11 years n=7 Participants	10 years n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	9 Participants n=7 Participants	18 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	16 Participants n=7 Participants	35 Participants n=5 Participants
Race/Ethnicity, Customized Ethic origin n (%) · Hispanic or Latino	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Race/Ethnicity, Customized Ethic origin n (%) · Not Hispanic or latino	25 Participants n=5 Participants	20 Participants n=7 Participants	45 Participants n=5 Participants
Race/Ethnicity, Customized Race n (%) · Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race n (%) · American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race n (%) · Asian	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Race n (%) · White	27 Participants n=5 Participants	18 Participants n=7 Participants	45 Participants n=5 Participants
Race/Ethnicity, Customized Race n (%) · Other	0 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and week 20

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=25 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=26 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Change in Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS)	-1.65 score on a scale Standard Error 0.620	-3.40 score on a scale Standard Error 0.618	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tideglusib n=26 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=26 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Change in Clinical Global Impression- Improvement Scale (CGI-I) Scores	3.11 score on a scale Standard Error 0.190	2.77 score on a scale Standard Error 0.189	—

SECONDARY outcome

Timeframe: Baseline and week 20

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=25 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Change in Top 3 Caregiver Concerns Visual Analogue Scale (VAS) Score	-1.74 score on a scale Standard Error 0.780	-6.47 score on a scale Standard Error 0.780	—

SECONDARY outcome

Timeframe: Baseline and week 20

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=25 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Caregiver Completed Congenital DM1 Rating Scale (CC-CDM1-RS)	-0.18 score on a scale Standard Error 0.770	-3.36 score on a scale Standard Error 0.782	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tideglusib n=25 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Clinical Global Impression - Severity Scale (CGI-S)	-0.20 score on a scale Standard Error 0.076	-0.12 score on a scale Standard Error 0.076	—

SECONDARY outcome

Timeframe: 20 weeks

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=25 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
10-meter Walk-run Test	-0.54 Seconds Standard Error 0.393	-0.19 Seconds Standard Error 0.391	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tideglusib n=28 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Total number of TEAEs	20 Participants	19 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Total number of serious TEAEs	1 Participants	0 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Total number of serious TEAEs related to treatment	0 Participants	0 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Total number of subjects with TEAEs leading to discontinuation from the study	1 Participants	0 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Total number of subjects with treatment-related TEAEs leading to discontinuation from the study	1 Participants	0 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Total number of subjects with TEAEs leading to death	0 Participants	0 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Severity: Mild	13 Participants	15 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Severity: Moderate	7 Participants	4 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Severity: Severe	0 Participants	0 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Unrelated to active treatment	18 Participants	17 Participants	—
Number of Adverse Events (AEs), Including Serious Adverse Events (SAEs), Between Screening to End of Study. Related to active treatment	2 Participants	2 Participants	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=28 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Number of Abnormal Findings in Objective Assessments (e.g. Laboratory Values, ECGs, Vital Signs and Bone Mineral Density) Between Screening and End of Study. Alanine aminotransferase increased	1 Participants	0 Participants	—
Number of Abnormal Findings in Objective Assessments (e.g. Laboratory Values, ECGs, Vital Signs and Bone Mineral Density) Between Screening and End of Study. Haemoglobin decreased	1 Participants	0 Participants	—
Number of Abnormal Findings in Objective Assessments (e.g. Laboratory Values, ECGs, Vital Signs and Bone Mineral Density) Between Screening and End of Study. Transaminases increased	1 Participants	0 Participants	—
Number of Abnormal Findings in Objective Assessments (e.g. Laboratory Values, ECGs, Vital Signs and Bone Mineral Density) Between Screening and End of Study. Weight decreased	0 Participants	2 Participants	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=20 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=19 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
CDM1-RS Independent Central Rater Score (CDM1-RS)	-2.26 score on a scale Standard Error 0.533	-2.55 score on a scale Standard Error 0.547	—

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Tideglusib n=25 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=23 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
CGI-I Independent Central Rater Score (CGI-I)	2.74 score on a scale Standard Error 0.227	2.65 score on a scale Standard Error 0.234	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=21 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=19 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Independent Rater Clinical Global Impression - Severity Scale (CGI-S)	-0.15 score on a scale Standard Error 0.080	-0.21 score on a scale Standard Error 0.093	—

POST_HOC outcome

Timeframe: Baseline and week 20

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=24 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=24 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
MDRI Analysis	0.8 score on a scale Standard Error 0.31	-0.1 score on a scale Standard Error 0.25	—

POST_HOC outcome

Timeframe: 20 weeks

Analysis of Ratio to Baseline in Creatine Phosphokinase

Outcome measures

Outcome measures
Measure	Tideglusib n=24 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=24 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo Matching placebo, orally, once daily Placebo: Matching placebo formulation
Creatine Phosphokinase	0.81 Ratio to Baseline Interval 0.68 to 0.97	1.05 Ratio to Baseline Interval 0.89 to 1.26	—

POST_HOC outcome

Timeframe: 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. 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.

Outcome measures

Outcome measures
Measure	Tideglusib n=10 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=12 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo n=23 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation
Mean Group Difference in 10 Meter Walk/ Run	9.1 Seconds Interval 6.9 to 16.1	8.7 Seconds Interval 6.5 to 12.2	8.5 Seconds Interval 3.9 to 18.7

POST_HOC outcome

Timeframe: 20 weeks

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=10 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=12 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo n=23 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation
Mean Change From Baseline Group Difference in 10 Meter Walk/ Run	0.4 Seconds Standard Deviation 1.7	-1.5 Seconds Standard Deviation 2.2	-0.1 Seconds Standard Deviation 1.8

POST_HOC outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tideglusib n=9 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=9 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo n=19 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation
Mean Group Difference in Peabody Picture Vocabulary Test (PPVT)	109 score on a scale Interval 35.0 to 185.0	134 score on a scale Interval 53.0 to 192.0	130 score on a scale Interval 51.0 to 191.0

POST_HOC outcome

Timeframe: Baseline to week 20

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=9 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=9 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo n=19 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation
Mean Change From Baseline Group Difference in Peabody Picture Vocabulary Test (PPVT)	3 score on a scale Standard Deviation 14	6 score on a scale Standard Deviation 17	-2 score on a scale Standard Deviation 10

POST_HOC outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Tideglusib n=11 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=12 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo n=23 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation
Mean Group Difference in Creatine Phosphokinase	147 IU/L Interval 77.0 to 273.0	195 IU/L Interval 42.0 to 460.0	299 IU/L Interval 57.0 to 987.0

POST_HOC outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Tideglusib n=11 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=12 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo n=23 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation
Mean Change From Baseline Group Difference in Creatine Phosphokinase	-17 UI/L Standard Deviation 27	-65 UI/L Standard Deviation 147	30 UI/L Standard Deviation 138

POST_HOC outcome

Timeframe: Baseline and week 20

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.

Outcome measures

Outcome measures
Measure	Tideglusib n=11 Participants Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=12 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation	Placebo n=23 Participants Matching placebo, orally, once daily Placebo: Matching placebo formulation
Mean Group Difference in MDRI	0.8 score on a scale Interval -1.0 to 3.0	0.9 score on a scale Interval -2.0 to 4.0	-0.2 score on a scale Interval -2.0 to 3.0

Adverse Events

Tideglusib

Serious events: 1 serious events

Other events: 20 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tideglusib n=28 participants at risk Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 participants at risk Matching placebo, orally, once daily Placebo: Matching placebo formulation
Surgical and medical procedures Scoliosis Surgery	3.6% 1/28 • Number of events 1 • Consent to end of study, up to 28 weeks 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.	0.00% 0/25 • Consent to end of study, up to 28 weeks 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.

Other adverse events

Additional Information

Dr. Mike Snape, Chief Scientific Officer

AMO Pharma Ltd.

Phone: +44 (0) 7775915639

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator has the right to publish study results from his/her specific site. However, any publication that includes AMO Pharma confidential information cannot be submitted for publication without AMO Pharma's prior written approval.
Publication restrictions are in place

Restriction type: OTHER

Measure	Tideglusib n=28 participants at risk Weight adjusted tideglusib, orally, once daily Tideglusib for oral suspension, weight-adjusted at 400 mg for 2 weeks, then up-titrated to a weight-adjusted 600 mg for 2 weeks, after which 1000 mg was administered for the remainder of the treatment period, once daily	Placebo n=25 participants at risk Matching placebo, orally, once daily Placebo: Matching placebo formulation
Infections and infestations Nasopharyngytitis	10.7% 3/28 • Number of events 4 • Consent to end of study, up to 28 weeks 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.	12.0% 3/25 • Number of events 3 • Consent to end of study, up to 28 weeks 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.
Infections and infestations Upper respiratory tract infection	10.7% 3/28 • Number of events 4 • Consent to end of study, up to 28 weeks 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.	8.0% 2/25 • Number of events 2 • Consent to end of study, up to 28 weeks 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.
Infections and infestations COVID-19	7.1% 2/28 • Number of events 2 • Consent to end of study, up to 28 weeks 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.	4.0% 1/25 • Number of events 1 • Consent to end of study, up to 28 weeks 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.
Respiratory, thoracic and mediastinal disorders Cough	14.3% 4/28 • Number of events 4 • Consent to end of study, up to 28 weeks 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.	0.00% 0/25 • Consent to end of study, up to 28 weeks 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.
Respiratory, thoracic and mediastinal disorders Rhinorrhea	10.7% 3/28 • Number of events 3 • Consent to end of study, up to 28 weeks 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.	4.0% 1/25 • Number of events 1 • Consent to end of study, up to 28 weeks 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.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/28 • Consent to end of study, up to 28 weeks 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.	8.0% 2/25 • Number of events 2 • Consent to end of study, up to 28 weeks 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.
Gastrointestinal disorders Vomiting	10.7% 3/28 • Number of events 3 • Consent to end of study, up to 28 weeks 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.	8.0% 2/25 • Number of events 2 • Consent to end of study, up to 28 weeks 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.
Gastrointestinal disorders Diarrhea	7.1% 2/28 • Number of events 5 • Consent to end of study, up to 28 weeks 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.	20.0% 5/25 • Number of events 6 • Consent to end of study, up to 28 weeks 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.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/28 • Consent to end of study, up to 28 weeks 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.	8.0% 2/25 • Number of events 2 • Consent to end of study, up to 28 weeks 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.
Injury, poisoning and procedural complications Fall	7.1% 2/28 • Number of events 2 • Consent to end of study, up to 28 weeks 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.	0.00% 0/25 • Consent to end of study, up to 28 weeks 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.
Injury, poisoning and procedural complications Skin abrasion	7.1% 2/28 • Number of events 2 • Consent to end of study, up to 28 weeks 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.	0.00% 0/25 • Consent to end of study, up to 28 weeks 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.
General disorders Vaccination site pain	7.1% 2/28 • Number of events 3 • Consent to end of study, up to 28 weeks 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.	4.0% 1/25 • Number of events 1 • Consent to end of study, up to 28 weeks 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.
Investigations Weight decreased	0.00% 0/28 • Consent to end of study, up to 28 weeks 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.	8.0% 2/25 • Number of events 2 • Consent to end of study, up to 28 weeks 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.
Musculoskeletal and connective tissue disorders Back pain	7.1% 2/28 • Number of events 2 • Consent to end of study, up to 28 weeks 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.	4.0% 1/25 • Number of events 1 • Consent to end of study, up to 28 weeks 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.
Nervous system disorders Headache	10.7% 3/28 • Number of events 3 • Consent to end of study, up to 28 weeks 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.	0.00% 0/25 • Consent to end of study, up to 28 weeks 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.