A Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Tideglusib Versus Placebo for the Treatment of Children and Adolescents With Congenital Myotonic Dystrophy (REACH CDM)
Phase: PHASE2
Conditions: Congenital Myotonic Dystrophy
Sponsor: AMO Pharma Limited

Study Protocol 
Official Title: 
A Randomized, Double-Blind Study to Evaluate the Efficacy and 
Safety of Tideglusib Versus Placebo for the Treatment of Children 
and Adolescents with Congenital Myotonic Dystrophy (REACH 
CDM) 
NCT Number:  
NCT03692312 
Document Date: 
02 February 2023 
 

Investigational Medicinal 
Product: Tideglusib 
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Protocol No: AMO-02-MD-2-003 
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Protocol Number: 
AMO-02-MD-2-003 
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02 FEB 2023 
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A Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Tideglusib 
Versus Placebo for the Treatment of Children and Adolescents with Congenital Myotonic 
Dystrophy (REACH CDM) 
 
EudraCT No: 2016-004623-23 
IND No: 130,741 
Version No: Version 9.0 Final 
Date of Protocol: 02 February, 2023 
 
Sponsor: 
AMO Pharma Ltd. 
Braeburn, 
Grove Road, 
Godalming, 
Surrey, 
GU7 1RE, 
United Kingdom. 
 
 
 
 
 
 
 
 
Confidentiality Statement: 
This protocol contains information which is the property of AMO Pharma and therefore is 
provided to you in confidence for review by you, your staff, an applicable ethics 
committee/institutional review board and regulatory authorities. It is understood that this 
information will not be disclosed to others without the written approval from AMO Pharma 
This study will be conducted in compliance with Good Clinical Practice (GCP), the 
principles of the Declaration of Helsinki (with amendments), and in accordance with local 
legal and regulatory requirements. 

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1. PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
A Randomized, Double-Blind Study to Evaluate the 
Efficacy and Safety of Tideglusib versus Placebo for 
the Treatment of Children and Adolescents with 
Congenital Myotonic Dystrophy (REACH CDM) 
 
 
PROTOCOL NO. 
AMO-02-MD-2-003 
 
 
COORDINATING 
INVESTIGATOR 
 
 
 
SPONSOR 
AMO Pharma Ltd. 
 
 
INVESTIGATIONAL 
MEDICINAL PRODUCT 
Tideglusib 
 
PHASE OF DEVELOPMENT 
2/3 
 
 
INDICATION 
Congenital Myotonic Dystrophy (Congenital DM1) 
 
 
STUDY DESIGN 
This is a randomized, double-blind study of weight 
adjusted 1000 mg tideglusib versus placebo across a 
treatment period. The subjects are children 
between the ages of 6 to 16 years with Congenital 
Myotonic Dystrophy (Congenital DM1). 

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Approximately 56 children were planned to be 
randomized into the study, assuming a dropout rate 
of 10-13%. After a blinded sample size re-estimation 
(SSRE), the protocol was amended to allow 
enrollment of between 56 and 66 children 
randomized into the study, if feasible. 
 
 
 
 
 
The study will have 5 distinct phases: 
• Screening 
 Subjects will be 
screened to ensure adherence to eligibility 
criteria. 
• 
• Double-blind dose 
run-in (
 
 
 
Subjects randomized at 
 (Baseline) to the 
weight adjusted 1000 mg dose level will take 
tideglusib at a weight adjusted 400 mg dose level 
from weeks 
, then they will take tideglusib at 
a weight adjusted 600 mg dose level from weeks 
 and thereafter they will take tideglusib at a 
weight adjusted 1000 mg dose level from weeks 
. Subjects randomized at 
 (Baseline) to 
placebo will remain on that treatment for weeks 
 
• Double-blind 
maintenance 
(Weeks 
. 
Subjects will continue on the fixed  dose  of  
1000 mg weight adjusted tideglusib or placebo, 
which they have been previously randomized to 
for 
 
• Follow-up Period (Weeks 
 for those 
subjects not participating in the extension study 
AMO-02-MD-2-004 
- 
Adverse events will be elicited at 
 
 and 
 (
 post end of 
treatment visit via telephone by a member of 
the study team 
). 

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An in 
 
- 
-clinic follow-up visit will occur 2 
after end of treatment 
 
 
Due to the global COVID-19 (Coronavirus Disease 
2019) pandemic and the potential for resurgences of 
COVID-19, for the purposes of this protocol, ‘in- 
clinic’ visits, when pertaining to Visits
 Visi
 
(Weeks 
, may be conducted via a combination 
of telehealth and home healthcare providers in the 
event COVID-19 related reasons, e.g. institutional 
restrictions, 
travel 
restrictions, 
quarantine 
or 
shielding, prevent subjects from being seen in-person 
at the investigator site. Home healthcare visits will 
not be conducted if the subject or a member of the 
family present in the home has, or is suspected to 
have, COVID-19. 
 
Data Safety Monitoring Committee 
An independent Data Safety Monitoring Committee 
(DSMC) consisting of clinical and other experts will 
be established by the Sponsor to review safety 
findings during the study and to help ensure the well- 
being of enrollees. 
 
 
STUDY OBJECTIVES 
Primary Objective: 
• To evaluate the efficacy, from baseline to end of 
treatment, of weight adjusted 1000 mg tideglusib 
compared to placebo in children and adolescents 
with Congenital DM1 as measured by the 
Clinician-Completed Congenital DM1 Rating 
Scale (CDM1-RS) 
 
 
Secondary Objectives: 
• To evaluate the safety and tolerability of weight 
adjusted 1000 mg tideglusib compared to placebo 
in children and adolescents with Congenital DM1 

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• To evaluate the efficacy, from baseline to end of 
treatment, of weight adjusted 1000 mg tideglusib 
compared to placebo in children and adolescents 
with Congenital DM1 as measured by clinician- 
completed rating scales, caregiver-completed 
rating 
scales, 
functional 
assessments, 
and 
biomarker/physiological assessments 
• To evaluate the blood pharmacokinetics of 
tideglusib and its main metabolite (NP04113) 
after repeat dosing in children and adolescents 
with Congenital DM1 
• To evaluate the consistency of telehealth data and 
in-clinic data for the CDM1-RS and CGI rating 
scales 
 
STUDY ENDPOINTS 
Primary Efficacy Endpoint: 
• Clinician-Completed Congenital DM1 Rating 
Scale (CDM1-RS) 
 
Key Secondary Efficacy Endpoint: 
• Clinical Global Impression- Improvement 
Scale (CGI-I)* 
 
Secondary Efficacy Endpoints: 
• Top 3 Caregiver Concerns VAS score 
• Caregiver Completed Congenital DM1 Rating 
Scale (CC-CDM1-RS) 
• Clinical Global Impression - Severity Scale 
(CGI-S) 
• Clinician-Completed Congenital DM1 Rating 
Scale (CDM1-RS) - Independent Central 
Rater Score 
• Clinical Global Impression- Severity Scale 
(CGI-S) – Independent Central Rater Score 
 
 
* Sometimes referred to as the CGI-C 

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• Clinical Global Impression- Improvement 
Scale (CGI-I) - Independent Central Rater 
Score 
• 10-meter walk-run test (preferred speed and 
fastest speed) 
 
 
Exploratory Endpoints: 
• DXA Scan measurement of total body 
lean/muscle mass 
• Measurement of lip strength (via lip force 
meter) 
• Congenital 
and 
Childhood 
Myotonic 
Dystrophy Health Index (CC-MDHI) Parent 
Proxy Instrument 
• Autism Behavior Inventory- Clinician (ABI- 
C) 
• 
 
and Adaptive Behavior Composite standard 
scores of the Vineland Adaptive Behavior 
Scale – 
 
• Quantitative myometric measure of hand grip 
strength 
• NIH Toolbox Cognition Battery: Dimensional 
Change Card Sort Test 
• NIH Toolbox Cognition Battery: Picture 
Sequence Memory Test 
• Peabody Picture Vocabulary Test (PPVT) 
• 
levels 
• 
 
sample 
• 
 
 
• Serial blood pharmacokinetics of tideglusib 
 
Safety Endpoints: 

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• The incidence of Adverse events (AEs), 
including serious adverse events (SAEs), 
between Screening and end of treatment. The 
incidence will also be assessed during a 
 
 follow-up period after discontinuation 
of the study drug for those subjects not 
participating in the extension study AMO-02- 
MD-2-004. 
• The incidence of abnormal findings in 
objective assessments (e.g. laboratory values, 
ECGs, vital signs and bone mineral density) 
between Screening and end of treatment. The 
incidence of abnormal findings in objective 
assessments will also be assessed during a 
 
follow-up period after discontinuation 
of the study drug for those subjects not 
participating in the extension study AMO-02- 
MD-2-004. 
SUBJECT POPULATION 
Diagnosis and main criteria for inclusion: 
Inclusion Criteria: 
The subject will not be considered eligible for the 
study without meeting all of the criteria below: 
1. Subjects under study must be children or adolescents 
with a diagnosis of Congenital DM1. For the 
purposes of this study, the following definitions 
apply. 
In addition to the genetic confirmation of DM1, one 
or more of the following clinically relevant (e.g. 
requiring medical intervention) signs or symptoms 
was evident within the first month after birth: 
o Hypotonia 
o Generalized weakness 
o Respiratory insufficiency 
o Feeding difficulties 
o Clubfoot or another musculoskeletal deformity 

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2. Diagnosis must be genetically confirmed 
3. Subjects must be male or female children and 
adolescents aged ≥6 years and ≤16 years at 
Screening 
4. Subjects must have a Clinical Global Impression – 
Severity (CGI-S) score of 4 or greater at Screening 
and start of Run-in 
 
5. Subjects must be ambulatory and able to complete 
the 10-meter walk-run test (orthotics/splints allowed, 
forearm crutches are not allowed) 
6. Written, voluntary informed consent must be 
obtained before any study related procedures are 
conducted. Where a parent or LAR provides 
consent, there must also be assent from the subject 
(as required by local regulations) 
7. Subject’s caregiver must be willing and able to 
support participation for duration of study 
8. Subject must be willing and able to comply with the 
required food intake restrictions as outlined per 
protocol 
 
 
Exclusion Criteria: 
Subjects are excluded from the study if any of the 
following exclusion criteria are met: 
1. Non-ambulatory (full time) wheel chair use 
2. Body mass index (BMI) less than 13.5 kg/m² or 
greater than 40 kg/m² 
3. Receiving other medications/therapies not stable (i.e. 
changed) within 4 weeks prior to Screening. For 
each enrollee, every effort should be made to 
maintain stable regimens (i.e. dose, as applicable, 
and frequency) of allowed concomitant medications 
(e.g. concomitant mexiletine or stimulants) and 
allowed non-medicine based therapies (e.g. 
occupational or physiotherapy) throughout the 

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course of the study, from the time of commencement 
of Screening until the last study assessment. 
4. Use within 4 weeks prior to Baseline 
) of strong 
CYP3A4 inhibitors. Examples include 
clarithromycin, telithromycin, ketoconazole, 
itraconazole, posaconazole, nefazodone, idinavir and 
ritonavir 
5. Concurrent use of drugs metabolized by CYP3A4 
with a narrow therapeutic window e.g. warfarin and 
digitoxin 
6. Medical illness or other concern which would cause 
the investigator to conclude that the subject will not 
be able to perform the study procedures or 
assessments or would confound interpretation of data 
obtained during assessment 
7. Current enrollment in a clinical trial of an 
investigational drug or enrollment in a clinical trial 
of an investigational drug in the last 6 months 
8. Gastrointestinal disease which, in the opinion of the 
investigator, may interfere with the absorption, 
distribution, metabolism or excretion of the study 
medication and impact the interpretability of the 
study results 
9. Current clinically significant (as determined by the 
investigator) neurological, cardiovascular, renal, 
hepatic, endocrine or respiratory disease that may 
impact the interpretability of the study results 
10. Clinically significant heart disease (in the opinion of 
the investigator) or current evidence of second or 
third degree heart block, atrial flutter, atrial 
fibrillation, ventricular arrhythmias, or requires 
medication for treatment of a cardiac arrhythmia 
11. Implantation of a cardiac pacemaker within the 12 
months preceding Screening 
12. Average QTcF value of >450 msec at Screening or at 
Run-In 
** (may repeat to confirm) 

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25. A history of significant drug allergy (such as Steven- 
Johnson syndrome, anaphylaxis) 
26. A history of alcohol or substance use disorders 
27. Current malignancy or any history of malignancy 
except for surgically cured skin cancer or 
pilomatricoma (benign tumor of the hair follicle that 
is associated with Congenital DM1) 
28. Severe arthritis or other medical condition (besides 
Congenital DM1) that would significantly impact 
ambulation or completion of myometric assessments 
29. Hypersensitivity to tideglusib or any components of 
its formulation including allergy to strawberry 
30. Unable to swallow liquids or may have trouble 
swallowing liquids (in the opinion of the 
investigator), unless medication to be administered 
via gastrostomy tube 
31. Judged clinically to be at risk of suicide (suicidal 
ideation, severe depression, or other factors) over the 
last three months, as assessed by the Investigator. 
 
**As  the  central  ECG  report  for  
  will  not  be 
available prior to the subject commencing run-in, 
eligibility related to ECGs (exclusion criteria 12 and 
13) will be based on the investigator’s calculation of 
the mean QTcF value of all ECGs taken at 
 and 
their initial review of the ECG tracings at 
 If there 
is a conflict between the investigator’s initial 
assessment of the ECG and the central ECG report, 
whereby the subject would no longer be eligible for 
the study, the subject will be withdrawn from the 
study at or before 
, prior to randomization into the 
double-blind treatment period. 
***Acceptable contraception is considered to be 
using one of the following birth control methods and 
should be in place for the duration of the study and 
for 30 or 90 days after last dose of IMP, respectively 
for female and male subjects: 

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• Combined 
or 
progestogen-only 
hormonal 
contraception 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
• vasectomised partner 
• sexual abstinence, defined as true abstinence. True 
Abstinence: When this is in line with the preferred 
and usual lifestyle of the subjects [periodic 
abstinence 
(such 
as 
calendar, 
ovulation, 
symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of 
contraception] 
• Male or female condom with or without 
spermicide1 
• Cap, diaphragm or sponge with spermicide1 
1A combination of male condom with either cap, 
diaphragm or sponge with spermicide (double barrier 
methods) are also considered acceptable birth control 
methods 
 
TIDEGLUSIB 
Unit-dose packets of ‘tideglusib 
 for oral 
FORMULATION/DOSE 
suspension’ and/or ‘tideglusib 
 
 for oral 
suspension’ will be constituted 
. 
Dosing will be weight adjusted at tideglusib 400 mg, 
600 mg or 1000 mg dose levels, 
 
 
. For 
blinding    purposes,    each    active    dose    has    a 
corresponding matching placebo presentation i.e. 
‘placebo for tideglusib 
 for oral suspension’ or 
‘placebo for tideglusib 
 for oral suspension’ 
which will be dosed to those randomized to placebo 
and as required to blind at the 400 mg, 600 mg and 
1000 mg dosing phases. 

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Regardless of the dose a subject has been assigned to, 
study medication will always  be 
 
   This  can be  a  
 packet 
combination, 
an 
 
 
 
packet 
combination, or an 
 
 
 packet 
combination depending on which treatment group the 
subject has been assigned to and which dose they are 
taking, e.g. during 
 
 
 
ROUTE OF ADMINISTRATION 
Oral 
 
 
DURATION/FREQUENCY 
OF 
TREATMENT 
Taken once daily at approximately 
 
, by oral route. 
 
 
. Administration by 
gastrostomy tube is also permissible, provided the 
 are followed. 
Participation for individual subjects will consist of a 
 run-in phase. Subjects 
will be randomized to either weight adjusted 1000 mg 
tideglusib, or matched placebo, once daily for
weeks. Subjects randomized to weight adjusted  
1000 mg tideglusib will receive the 400 mg weight 
adjusted dose level of tideglusib for 
 and 
then will advance to the 600 mg weight adjusted dose 
level for the next 
. Thereafter, these 
subjects will take tideglusib at the weight adjusted 
1000 mg dose level for the remaining 
 
 
 
EFFICACY ASSESSMENTS 
The study will evaluate efficacy from four different 
perspectives (also referred to as efficacy domains): 
clinician-completed assessments, caregiver- 
completed assessments, functional assessments (i.e. 
assessments that require in-clinic performance by the 
enrollee), and biomarker/physiological assessments. 

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Vineland 
 
The efficacy domains will include the measures 
described below. 
• Clinician-completed assessments: 
o Clinician-Completed Congenital DM1 Rating 
Scale (CDM1-RS) 
o Clinical Global Impressions (Severity and 
Improvement) scale 
o Clinician-Completed Congenital DM1 Rating 
Scale (CDM1-RS) Independent Central Rater 
Score 
o Clinical Global Impressions (Severity and 
Improvement) scale Independent Central 
Rater Score 
o Autism Behavior Scale- Clinician (ABI-C) 
o 
Adaptive Behavior Scale - 
 
• Caregiver-completed assessments: 
o Top 3 Caregiver Concerns VAS 
o Caregiver Completed Congenital DM1 Rating 
Scale (CC-CDM1-RS) 
o Congenital 
and 
Childhood 
Myotonic 
Dystrophy Health Index (CC-MDHI) Parent 
Proxy Instrument 
• Functional assessments: 
o 10-meter walk-run test (preferred speed and 
fastest speed) 
o Quantitative myometric measure of hand grip 
strength 
o Measurement of lip strength via lip force 
meter 
o NIH Toolbox Cognition Battery: Dimensional 
Change Card Sort Test 
o NIH Toolbox Cognition Battery: Picture 
Sequence Memory Test 
o Peabody Picture Vocabulary Test (PPVT) 

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• Biomarker/physiological assessments: 
o Dual-energy X-ray absorptiometry (DXA) 
whole body scan of lean muscle mass 
o 
levels and activity 
o 
analysis 
o 
 
 
 
SAFETY ASSESSMENTS 
This study will compare the incidence of adverse 
events (AE), including serious adverse events 
(SAE), between Screening and end of treatment with 
weight adjusted 1000 mg tideglusib versus placebo, 
for 
. The incidence of abnormal findings in 
objective assessments (e.g. clinical laboratory 
values, urinalysis, physical examination findings, 
vital signs, weight, ECG and bone mineral density) 
during the course of the study will also be assessed. 
The incidence will also be assessed during a 
 
follow-up period after discontinuation of the study 
drug for those subjects not participating in the 
extension study AMO-02-MD-2-004. 
 
 
PHARMACOKINETIC 
ASSESSMENTS 
Pharmacokinetic blood samples will be collected for 
measurement of tideglusib and its primary 
metabolite, NP04113. PK samples will be collected 
at Visits  and 
 (corresponding to Weeks and 
). 
 samples will be collected at Week 
). 
The time of administration of study medication will 
not be adjusted from the time the subject normally 
takes their dose of study medication. It will be noted 
in the CRF whether the subject dosed at home or in 
the clinic. 
If the subject normally takes their dose of study 
medication where they would be in the clinic 
between 
 post dose, then ideally 
 
 

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 These associations may be statistically tested 
using correlation coefficients and general linear 
models, if appropriate. 
 
 
STATISTICAL ANALYSIS 
Details of all planned analyses will be specified in a 
separate statistical analysis plan (SAP) which will be 
finalized prior to hard-lock of the study database. 
The SAP will contain details of all the analyses 
including specifications for all tables, listings and 
figures. All statistical programming will be 
performed using SAS software. 
Estimated Sample Size: 
No clinical trial data are available on the CDM1-RS 
instrument. Twenty-five subjects per group will 
generate 70% power to detect the effect size of 0.6 
at the 0.1 two-sided significance level. This sample 
size will also be sufficient to generate 80% power to 
detect the effect size of 0.82 at the 0.05 two-sided 
significance level. Accounting for a 10%-13% drop- 
out rate, approximately 28 subjects per group will be 
enrolled. A blinded sample size re-estimation 
(SSRE), based on the observed variance in the 
primary outcome measure, was performed once 33% 
of subjects had been enrolled and had completed 
. The effect size assumptions were partially 
based on the Clinician VAS (
 
 total score changes from baseline 
to end of study (6 points on drug vs. 1 point on 
placebo with the common standard deviation of 5.8). 
Based on these and other data, 29 and 22 subjects 
per group will be sufficient to generate 90% and 
80% power at the 0.05 two-sided significance level. 
Based on these calculations, a suggested sample size 
of approximately 56 patients total was deemed to be 

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adequate to detect the treatment effect or at least a 
consistent trend. 
Based on the blinded SSRE, the planned sample size 
is sufficient to detect the treatment difference 
between active and control arms based on the 
primary endpoint with at least 80% power at the 
0.05 two sided significance level. However, the 
variability of the key secondary endpoint was 
slightly greater than that originally assumed. 
Respectively, it was recommended, if operationally 
feasible, to increase the total sample size to a 
maximum of 66 subjects. 
Statistical Methods for Safety: 
Analysis of safety will be performed based on the 
Safety Analysis Set (SAS). See section 11.2 for 
definition. All AEs will be coded using the MedDRA 
dictionary and will be summarized by treatment. 
Other safety data, including laboratory, vital signs 
and ECG values including change from baseline will 
be summarized. 
Statistical Methods for Efficacy: 
Primary and key secondary analyses of efficacy will 
be based on the Intent to Treat (ITT) population. 
Other efficacy analyses will be performed based on 
the Full Analysis Set (FAS). See section 11.2 for 
definitions. 
The primary efficacy endpoint will be calculated at 
each time point as a total score based on 11 domain 
ratings. Changes from Baseline 
 to post- 
treatment visits will be summarized by treatment 
group at each study visit. For the CGI-I the observed 
values will be summarized. 
Change from baseline to end of treatment will be 
analysed using general linear model. Improvement 
during the 
run-in period may be included as 
a covariate. The statistical significance of changes 

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from baseline over time may also be assessed using 
the linear mixed effects repeated measures model. 
Due to COVID-19 related restrictions some of the 
data at certain visits may be collected using a 
telehealth approach while other data may be 
collected during in-clinic visits. To evaluate the 
consistency of telehealth data and in-clinic data for 
the CDM1-RS and CGI rating scales and to 
minimize the potential bias, Baseline (
, Week  
(
) and Week 
) visits will be performed 
using both in-clinic and telehealth data collection 
approaches. Analysis to evaluate the consistency of 
these two methods of data collection will be 
performed. 
According to the recommendations in the FDA 
Guidance “Statistical Considerations for Clinical 
Trials During the COVID-19 Public Health 
Emergency”, sensitivity analyses will be performed 
in addition to the primary analysis (FDA, 2020). The 
sensitivity analyses will include combined use of 
telehealth and in-clinic data; the impact of using 
telehealth data on outcomes will be evaluated. 
The exploratory endpoint analysis will be outlined in 
the SAP. The details of the analysis methods will be 
determined after exploratory endpoint data review. 
 
 
NUMBER OF STUDY CENTERS 
Up to 14 sites in the US, UK, Canada, Australia, and 
New Zealand 
 
 
ESTIMATED FIRST SUBJECT 
SCREENED 
Q1 2021 
 
ESTIMATED LAST SUBJECT 
LAST VISIT 
Q4 2022 

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Visit25 
Screening 
Run-in 
Baseline 
h 
Interim 
h 
Interim 
h 
Interim 
h,22 
Interim 
h 
Interim 
h, 22 
Interim 
h 
Interim 
i 
End of 
Treatm 
ent i, 23 
AE Follow up 
[Follow 
-up]h ,24 
 
post 
EOT24 
 
post 
EOT24 
 
 
 
 
 
 
 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-I Via 
Telehealth10 
Vineland Adaptive 
Behavior Scale 
Clinician-Completed 
Congenital DM1 
Rating Scale (CD 
M1-RS) In Clinic 
Clinician-Completed 
Congenital DM1 
Rating Scale (CDM1- 
RS) via Telehealth11 
Independent Central 
Rating of the CGI-S12 
Independent Central 
Rating of the CGI-I12 
Independent Central 
Rating of the 
Clinician-Completed 
Congenital DM1 
Rating Scale (CDM1- 
RS)12 
Caregiver Top 3 
Concerns VAS 
CC-MDHI Parent 
Proxy Instrument 
Caregiver- 
Completed 
Congenital DM1 
Rating Scale (CC- 
CDM1-RS) 

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End of 
AE Follow up 
 
Visit25 
 
 
Week 
NIH Dimensional 
Change Card Sort 
Test 
NIH Picture 
Sequence Memory 
Test 
Peabody Picture 
Vocabulary Test 
 
Sample13 
Sample for PK 
analysis14 
 
 
 
 
Muscle RNA Sample 
(optional)17 
Sample18 
Dosing and/or 
Dispensing19 
Screening 
 
 
 
Run-in 
 
 
 
 
Baseline 
h 
 
 
 
 
Interim 
h 
 
 
 
 
 
Interim 
h 
 
 
 
 
 
Interim 
h,22 
 
 
 
 
Interim 
h 
 
 
 
 
 
Interim 
h, 22 
 
 
 
 
Interim 
h 
 
 
 
 
 
Interim 
i 
 
 
 
 
 
Treatm 
ent i, 23 
 
 
 
 
post 
EOT24 
 
 
 
 
post 
EOT24 
 
 
 
[Follow 
-up]h ,24 
 
 
 
Randomization 
Subject Diary 
Issue/Review20 
Adverse Events21 
Concomitant 
Medication 
 
 

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2. TABLE OF CONTENTS, FIGURES AND LISTINGS 
1. 
PROTOCOL SYNOPSIS ....................................................................................... 2 
2. 
TABLE OF CONTENTS, FIGURES AND LISTINGS ...................................... 28 
3. 
LIST OF ABBREVIATIONS .............................................................................. 33 
4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE ......................... 36 
5. 
BACKGROUND INFORMATION ..................................................................... 39 
5.1 
Myotonic dystrophy ............................................................................................. 39 
5.2 
Tideglusib ............................................................................................................. 40 
5.3 
Pre-clinical Research ............................................................................................ 41 
5.4 
Clinical Experience .............................................................................................. 48 
5.5 
Rationale for this Study ........................................................................................ 58 
6. 
STUDY OBJECTIVES AND PURPOSE ............................................................ 62 
6.1 
Primary Objective ................................................................................................ 62 
6.2 
Secondary Objectives ........................................................................................... 62 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ....................................... 62 
7.1 
Subject Numbers .................................................................................................. 62 
7.2 
Inclusion Criteria .................................................................................................. 63 
7.3 
Exclusion Criteria ................................................................................................. 64 
7.4 
Withdrawal Criteria .............................................................................................. 66 
8. 
STUDY DESIGN ................................................................................................. 67 
8.1 
Study Endpoints to be assessed: ........................................................................... 67 
8.2 
Study Design ........................................................................................................ 69 
8.3 
COVID-19 Impact to Study Design ..................................................................... 70 
8.4 
DSMC .................................................................................................................. 72 
9. 
STUDY MEDICATION AND ADMINISTRATION ......................................... 72 
9.1 
Study Medication ................................................................................................. 72 
9.2 
Allocation to Treatment ....................................................................................... 75 
9.3 
Study Treatment and Administration ................................................................... 76 
9.4 
Duration of Subject Participation ......................................................................... 78 
9.5 
Laboratory Alerts, Stopping Rules and Discontinuation Criteria ........................ 79 

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9.6 
Treatment Accountability and Compliance Checks ............................................. 82 
9.7 
Treatment Blinding Code ..................................................................................... 83 
9.8 
Unblinding the Treatment Assignment ................................................................ 83 
9.9 
Permitted concomitant medication/ non- pharmacological therapies .................. 83 
9.10 
Prohibited concomitant medications .................................................................... 84 
10. 
STUDY SCHEDULE ........................................................................................... 84 
10.1 
Efficacy Assessments ........................................................................................... 84 
10.1.1 Clinician-Completed Assessments ....................................................................... 84 
10.1.1.1 Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS) ...................... 84 
10.1.1.2 Clinical Global Impressions (Severity and Improvement) ................................... 86 
10.1.1.3 Autism Behavior Inventory - Clinician (ABI-C) ................................................. 87 
10.1.1.4 Vineland Adaptive Behavior Scales- 
 
88 
(Vineland- 
10.1.2 Caregiver-Completed Assessments ...................................................................... 88 
10.1.2.1 Congenital and Childhood Myotonic Dystrophy Health Index (CC-MDHI) Parent- 
Proxy Instrument ................................................................................................................ 88 
10.1.2.2 Top 3 Caregiver Concerns Visual Analogue Scale (VAS) .................................. 89 
10.1.2.3 Caregiver-Completed Congenital DM1 Rating Scale (CC-CDM1-RS) .............. 89 
10.1.2.4 Caregiver Myotonic Dystrophy Type 1 Status ..................................................... 90 
10.1.3 Functional Assessments ....................................................................................... 90 
10.1.3.1 10-Meter walk-run test (preferred speed and fastest speed) ................................. 90 
10.1.3.2 Quantitative myometric measure of hand grip strength ....................................... 91 
10.1.3.3 Measurement of lip strength via lip force meter .................................................. 91 
10.1.3.4 NIH Toolbox Cognition Battery: Dimensional Change Card Sort Test .............. 92 
10.1.3.5 NIH Toolbox Cognition Battery: Picture Sequence Memory Test ...................... 92 
10.1.3.6 Peabody Picture Vocabulary Test (PPVT) ........................................................... 93 
10.1.4 Biomarker/Physiological Assessments ................................................................ 93 
10.1.4.1 Dual-energy X-ray absorptiometry (DXA) whole body scan of  lean  muscle 
mass 
93 
10.1.4.2 
and activity ............................................................. 94 
10.2 
Safety Assessments .............................................................................................. 94 
 

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10.2.1 Medical/Surgical and Medication history ............................................................ 94 
10.2.2 Physical Examination ........................................................................................... 95 
10.2.3 Height ................................................................................................................... 95 
10.2.4 Weight .................................................................................................................. 96 
10.2.5 Adverse Event collection ..................................................................................... 96 
10.2.6 Vital signs ............................................................................................................. 96 
10.2.7 Clinical Laboratory Evaluations ........................................................................... 97 
10.2.8 ECG ...................................................................................................................... 98 
10.3 
Pharmacokinetic Assessments............................................................................ 100 
10.4 
Other Assessments ............................................................................................. 102 
10.4.1 Diary ................................................................................................................... 102 
10.4.2 
Sample ................................................................................................ 102 
10.4.3 
Samples ............................................................... 102 
10.4.3.1
Sample ................................................................. 102 
10.4.3.2
Sample ........................................................................... 103 
10.4.3.3 
Testing Sample .................................................................... 103 
10.5 
Adverse Events ................................................................................................... 104 
10.5.1 Definitions .......................................................................................................... 104 
10.5.2 Severity Categorization ...................................................................................... 106 
10.5.3 Assessment of Causality .................................................................................... 106 
10.5.4 Outcome Categorization ..................................................................................... 106 
10.5.5 Symptoms of Disease Under Study .................................................................... 107 
10.5.6 Clinical Laboratory Evaluations ......................................................................... 107 
10.5.7 Abuse, Misuse, Overdose or Medication Error .................................................. 107 
10.5.8 Serious Adverse Event Reporting ...................................................................... 108 
10.5.9 Time Period, Frequency, and Method of Detecting AEs and SAEs .................. 109 
11. 
STATISTICAL CONSIDERATIONS ............................................................... 110 
11.1 
Estimated Sample Size ....................................................................................... 111 
11.2 
Study Populations ............................................................................................... 112 
11.3 
Demographic and Baseline Characteristics ........................................................ 112 

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11.4 
Statistical Methods for Safety ............................................................................ 112 
11.5 
Statistical Methods for Efficacy ......................................................................... 113 
11.6 
Missing data ....................................................................................................... 115 
11.7 
Statistical Methods for Pharmacokinetics .......................................................... 116 
12. 
END OF THE STUDY ...................................................................................... 116 
13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT ........................... 116 
13.1 
Independent Ethics Committee/Institutional Review Board and Relevant 
Authorities........................................................................................................................ 116 
13.2 
Ethical Conduct of the Study ............................................................................. 116 
13.3 
Informed Consent and/or Assent ........................................................................ 116 
14. 
STUDY AND DATA MANAGEMENT ........................................................... 117 
14.1 
Protocol Amendments ........................................................................................ 117 
14.2 
Monitoring .......................................................................................................... 117 
14.3 
Quality Assurance .............................................................................................. 117 
14.4 
Data Recording ................................................................................................... 117 
14.4.1 Data to be Considered as Source Data ............................................................... 117 
14.5 
CRF .................................................................................................................... 118 
14.6 
Confidentiality .................................................................................................... 118 
14.7 
Retention of Study Data ..................................................................................... 118 
14.8 
Communication and Publication of Results ....................................................... 119 
14.9 
Indemnification .................................................................................................. 119 
15. 
REFERENCES ................................................................................................... 121 
16. 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ..................... 127 
17. 
APPENDICES .................................................................................................... 130 
APPENDIX A: Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS) ........ 130 
APPENDIX B: Clinical Global Impressions (Severity and Improvement) ..................... 136 
APPENDIX C: Autism Behavior Inventory- Clinician (ABI-C) ..................................... 141 
APPENDIX D: Congenital and Childhood Myotonic Dystrophy Health Index (CC-MDHI) 
Parent Proxy Instrument .................................................................................................. 148 
APPENDIX E: Caregiver Top 3 Concerns Visual Analog Scale (VAS)......................... 154 

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APPENDIX F: Caregiver Completed Congenital DM1 Rating Scale (CC-CDM1-RS) .156 
APPENDIX G: 
 ................................................................... 161 
 
TABLE OF FIGURES 
Figure 1: Toxic events caused by mutant CUG repeats in DM1 cells and possible therapeutic 
approaches for their correction. ..................................................................................................... 43 
Figure 2: Reversal of myodifferentiation deficits of myoblasts isolated from N = 3 infant 
Congenital DM1 patients ............................................................................................................... 45 
Figure 3 CSF levels of beta-site APP cleaving enzyme-1 (BACE1) and phosphorylated tau 
(p181tau) in subjects with AD ....................................................................................................... 57 
Figure 4: Study Design .................................................................................................................. 70 
Figure 5 Dose 
.................................................................................................................. 79 
 
TABLE OF TABLES 
Table 1: Standard Schedule of Events ........................................................................................... 20 
Table 2: Schedule of Events Where a Visit Needs To Be Conducted Via Telehealth and Home 
Healthcare Due to COVID-191 .......................................................................................................................................................... 25 
Table 3: Overview of Frequent Adverse Events Observed in Healthy Volunteer Studies ............ 51 
Table 4: Summary of TEAE Reported in More Than One Case in NP031112-08B03 Clinical 
Trial 
52 
Table 5: ALT Summary from study NP031112-08B03 ................................................................. 55 
Table 6: ALT Summary from study NP031112-08B02 ................................................................. 56 
Table 7: ALT Summary from study NP031112-10B04 ................................................................. 56 
Table 8: Dose Cartons .................................................................................................................... 75 
Table 9: 
 .................................................................................................................... 78 

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3. LIST OF ABBREVIATIONS 
ABI-C 
AD 
ADME 
ADR 
AE 
ALCOAC 
ALT 
ANCOVA 
ASD 
AST 
AUC 
BMI 
BP 
BRIEF-2 
CC-MDHI 
CC-CDM1-RS 
CDM1-RS 
Congenital DM1 
COVID-19 
CGI 
CGI-I 
CGI-S 
Cmin 
Cmax 
CNS 
CPK 
CRF 
CRO 
CSF 
CTG/CUG 
CTIMP 
CYP 
DCCS 
DM-1 
DM-2 
DNA 
DSMC 
DSM-IV 
DXA 
EC 
ECG 
eCRF 
EOT 
Autism Behavior Inventory- Clinician 
Alzheimer’s Disease 
Absorption, Distribution, Metabolism and Excretion 
Adverse Drug Reaction 
Adverse Event 
Attributable, Legible, Contemporaneous, Original, Accurate, Complete 
Alanine amino transferase 
Analysis of Covariance 
Autism Spectrum Disorder 
Aspartate amino transferase 
Area Under the Curve 
Body Mass Index 
Blood Pressure 
Behavior Rating Inventory of Executive Function-Second Edition 
Congenital and Childhood Myotonic Dystrophy Health Index 
Caregiver-Completed Congenital DM1 Rating Scale 
Clinician-Completed Congenital DM1 Rating Scale 
Congenital Myotonic Dystrophy 
Coronavirus Disease 2019 
Clinical Global Impression 
Clinical Global Impression- Improvement Scale 
Clinical Global Impression- Severity Scale 
Minimum Serum/Plasma Concentration 
Maximum Serum/Plasma Concentration 
Central Nervous System 
Creatinine Phosphokinase 
Case Report Form 
Contract Research Organization 
Cerebrospinal Fluid 
Cytosine, Thymine/Uracil, Guanine nucleotides 
Clinical Trial of an Investigational Medicinal Product 
Cytochrome P450 enzymes 
Dimensional Change Card Sort Test 
Type 1 Myotonic Dystrophy 
Type 2 Myotonic Dystrophy 
Deoxyribonucleic acid 
Data Safety Monitoring Committee 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
Dual-energy X-ray absorptiometry 
Ethics Committee 
Electrocardiogram 
Electronic Case Report Form 
End-of-Treatment 

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FAS 
FDA 
GCP 
GGT 
GLM 
GSK 
HAV 
HCV 
IB 
ICH 
IEC 
IgM 
IMP 
IND 
INR 
IRB 
IRT 
ITT 
IUD 
IUS 
IVR 
LAR 
LFT 
MBNL1 
MD 
MRI 
NCE 
NIH 
PK 
PKAS 
PPS 
PPVT 
PSMT 
PSP 
PT 
PV 
QTcB 
QTcF 
RNA 
SAE 
SAF 
SAP 
SAS 
SD 
SE 
Full Analysis Set 
Food and Drug Administration 
Good Clinical Practice 
Gamma-Glutamyl Transferase 
General Linear Model 
Glycogen Synthase Kinase 
Hepatitis A Virus 
Hepatitis C Virus 
Investigator’s Brochure 
International Council on Harmonization 
Independent Ethics Committee 
Immunoglobulin M 
Investigational Medicinal Product 
Investigational New Drug 
International Normalized Ratio 
Institutional Review Board 
Interactive Response Technology 
Intent to Treat 
Intrauterine Device 
Intrauterine Hormone-Releasing System 
Interactive Voice Recognition 
Legally Authorized Representative 
Liver Function Tests 
Muscle Blind Like Splicing Regulator 1 
Multiple Dose 
Magnetic Resonance Imaging 
New Chemical Entity 
National Institute of Health 
Pharmacokinetics 
Pharmacokinetics Analysis Set 
Per-Protocol Set 
Peabody Picture Vocabulary Test 
Picture Sequence Memory Test 
Progressive Supranuclear Palsy 
Prothombin Time 
Pharmacovigilance 
Corrected QT- Bazett’s Formula 
Corrected QT- Fridericia’s Formula 
Ribonucleic Acid 
Serious Adverse Event 
Safety Analysis Set 
Statistical Analysis Plan 
Statistical Analysis System 
Standard Deviation 
Standard Error 

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SERCA1 
SOP 
SUSAR 
T1/2 
TEAE 
Tmax 
TSH 
UK 
ULN 
US 
VAS 
Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 
Standard Operating Procedure 
Suspected Unexpected Serious Adverse Reaction 
Half-life 
Treatment-Emergent Adverse Event 
Time to Maximum Concentration 
Thyroid Stimulating Hormone 
United Kingdom 
Upper Limit of Normal 
United States 
Visual Analog Scale 

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4. INVESTIGATORS AND ADMINISTRATIVE STRUCTURE 
 
 
Coordinating Investigator 
 
 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
 
 
 
Contract Research Organization / Monitors 
 
 
 
 
 
 
 
 
.
 
 
 
 

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5. 
BACKGROUND INFORMATION 
5.1 
Myotonic dystrophy 
Myotonic dystrophy is a monogenetic disorder caused by non-coding expansion repeats in 
the DMPK gene (myotonic dystrophy type 1 or adult onset DM1 or Steinert disease), which 
is located on chromosome 19, or the CNBP gene (myotonic dystrophy type 2 or DM2), 
which is located on chromosome 3. There are no symptomatic or disease-modifying 
treatments approved for the treatment of individuals with myotonic dystrophy. 
DM1 may be present at birth (Congenital Myotonic Dystrophy), appear during childhood 
(Childhood Myotonic Dystrophy) or during adulthood (Classic Adult onset Myotonic 
Dystrophy and Late onset Myotonic Dystrophy). 
Congenital Myotonic Dystrophy (Congenital DM1) is a life threatening disorder, with a 
mortality rate of 25 percent by age 1.5 years and 50 percent by age 30 years (Reardon et 
al., 1993). This study reported that 50 percent of subjects were unable to walk unaided 
with 4 percent of subjects requiring wheelchairs. Less than a quarter of Congenital DM1 
patients were able to attend mainstream schooling due to intellectual disability, 15 percent 
were still fecally incontinent at 5 years of age and in patients who lived to 20 years of age, 
79 percent were unemployed. Complementary data were reported by Ekström et al., 
(2009), who noted learning disabilities in 95 and 89 percent of Congenital and Childhood 
DM1 patients, respectively. Ekström et al., (2008) also reported that 68 percent and 50 
percent, respectively, of individuals with Congenital and Childhood DM1 had an Autism 
Spectrum Disorder (ASD). 
Current practice distinguishes between congenital, infantile, juvenile, adult, and late onset 
forms (Dogan et al., 2016) of DM1. The condition is a multi-system disorder that affects 
muscle, brain, the heart, and liver amongst other organs. When DM1 has an onset in early 
adulthood, presentation is primarily characterized by a progressive distal weakness of the 
hands and arms, myotonia and excessive daytime sleepiness (Heatwole et al., 2012). Adult 
onset DM1 is associated with increased mortality, with mean survival age reported to be in 
the range of 55.4 years (Mathieu et al., 1999) to 60 years (de Die-Smulders et al., 1998). 
Congenital DM1 is distinct from all other forms of DM1 in both time of onset, severity of 
disease, and genetic presentation. 
• The expansion repeat size in individuals with Congenital DM1 is typically 
significantly larger than individuals with juvenile- or adult onset forms of DM1 
(Ekström et al., 2008). 
• The congenital onset form of DM1 is by definition diagnosable at birth due to the 
presence of characteristic clinical signs that are not present in DM1 with onset at 
other ages (Genevieve et al., 2015). 

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• In particular, the CNS features of Congenital DM1 are much more severe than 
juvenile or adult onset forms. Almost all individuals with Congenital DM1 have 
intellectual disability, which is not the case with juvenile DM1 (Ekström et al., 
2008). 
• Also, characteristic neuromuscular and skeletomuscular features, described below, 
are evident at birth in Congenital DM1. 
• Congenital DM1 can be distinguished at the molecular and histological level. 
Congenital DM1 is associated with RNA splicing variants that are not present in the 
adult onset form (Thomas et al., 2017). The presentation of muscle cell types in 
Congenital DM1 is different to that in juvenile and adult onset DM1 (Nakamori et 
al., 2017). 
Congenital DM1 may be a disorder in which muscle fibers fail to develop at the 
microscopic level, being therefore a developmental disorder. Adult onset DM1 can be 
considered a degenerative disorder of muscle, whose histopathological features may appear 
in adulthood in Congenital DM1. The genomic lesions in Congenital DM1 and Adult-onset 
DM1 may differ in respect somatic instability. 
The hallmark clinical stigmata of neonates with Congenital DM1 include hypotonia, 
generalized weakness, respiratory insufficiency, feeding difficulties, and clubfoot or 
another musculoskeletal deformity. As infancy and young childhood progress, Congenital 
DM1 is associated with pronounced and unremitting oral facial weakness including 
diminished lip strength, respiratory difficulties, characteristic facies, often profound 
intellectual disability and behavioral disorders akin to ASD (Johnson et al., 2016). These 
features are not central to Adult-onset DM1 which is associated with signs and symptoms 
that arise later in life, and in which fatigue, daytime sleepiness and milder cognitive deficits 
are associated with distal and proximal muscle weakness as well as myotonia. 
As described previously, Congenital DM1 is associated with significant morbidity and 
mortality; life expectancy is significantly shortened with 25 percent of affected patients 
deceased by 18 months and less than 50 percent surviving to 30 years of age. Life- 
expectancy may be decreased in Adult-onset DM1 but to a lesser degree. 
 
 
5.2 
Tideglusib 
Tideglusib (4-benzyl-2-naphtalen-1-yl-1,2,4-thiadiazolidine-3,5-dione) is a new chemical 
entity (NCE) from the thiadiazolidindiones chemical family. It is an irreversible inhibitor 
of Glycogen synthase kinase 3 beta (GSK-3 β). 
Tideglusib is a brain penetrant and can be orally administered. The IMP is ‘tideglusib for 
oral suspension’. It
 

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GSK-3 is a serine/threonine protein kinase enzyme that recently emerged as a key target in 
drug discovery. GSK-3 has two isoforms – GSK-3α and GSK-3β. GSK-3β is implicated 
in neuromuscular and neurodevelopmental disorders. GSK-3β is highly expressed in 
muscle cells as well as in brain cells (Woodgett, 1990), is important in central nervous 
system (CNS) ontology (Beurel et al., 2012) and is a key signaling element in activity 
dependent synaptic plasticity (Rui et al., 2013). 
Signaling downstream of the insulin receptor is disrupted in DM1, given the significant 
splicing mis-regulation of the insulin receptor itself. Prior therapeutic trials (Heatwole, et 
al., 2011) have focused on upregulating the insulin signal itself. The current approach 
targets the disrupted signaling downstream of the insulin receptor, at the GSK-3β site. 
Jones et al., reported in 2012 that GSK-3β mediates muscle pathology in myotonic 
dystrophy based on increased GSK-3β activity in DM1 expressing cell lines, muscle biopsy 
samples from DM1 expressing transgenic mice and DM1 patient tissue samples. 
Tideglusib has also been shown to interact directly with an RNA construct containing the 
DMPK gene CUG repeat formed as a hairpin. Administration of tideglusib is also 
associated with fragmentation of the mutant DMPK gene RNA in Congenital DM1 patient 
tissue and reduction of DMPK gene RNA foci in muscle from the HSALR mouse (Wang et 
al 2019). Further, tideglusib reverses deficits in myodifferentiation of Congenital DM1 
myoblasts in vitro. Tideglusib also significantly attenuates abnormalities in total levels 
and splice variants of key effectors such as BIN1 and SERCA1 in Congenital DM1 tissue 
in vitro and the HSALR transgenic mouse model of DM1 (
 
 
Refer to the current Investigator Brochure for additional information on tideglusib. 
Given the above, the research intended by the Sponsor seeks to investigate the efficacy and 
safety of tideglusib in children and adolescents ages 6-16 years, affected by Congenital 
DM1. 
 
 
5.3 
Pre-clinical Research 
A comprehensive ICH-compliant pre-clinical program has been conducted with tideglusib. 
Summary information is described in this section with additional information on the non- 
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: 
 
 
Adverse Event 
Active 
N=
 
Placebo 
N= 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3
 

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ADVERSE 
EVENT 
 
 
TOTAL 
 
 
 
 
 
 
 
n 
% 
n 
% 
N 
% 
n 
% 
N 
% 
n 
% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4: 
- 
 

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Table 5: 
 
 
 
 
 
 
 
 
 
 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
 
 
 
 
 
 
 
 

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5.5 
Rationale for this Study 
There are currently no approved pharmacological treatments for individuals with DM1. 
Moreover, Congenital DM1 is a rare disease with a high mortality rate and as such has a 
significant unmet need for the development of pharmacological treatments. As described 
in Section 5.3, there is both pre-clinical and in-vitro clinical evidence to suggest that 
inhibition of GSK-3 could have the potential to reverse myotonia and improve muscle 
weakness in patients with Congenital DM1. Similarly, there is affirming preclinical 
evidence from neurodevelopmental models that suggest that tideglusib may have the 
potential to improve the associated neurocognitive and neuropsychiatric symptoms 
associated with DM1. This will be the first randomized, double-blind, placebo-controlled 
study of a GSK-3 inhibitor in children and adolescents with Congenital DM1. The 
following factors are taken into account: 
 
Dose: 
The dose of tideglusib that will be utilized in this study is within the dose range, and the 
weight-adjustment dosing strategy, that was implemented in the aforementioned Canadian 
TIDE study in children and adolescents with ASD. The doses for the TIDE study and for 
this study were selected based upon preclinical efficacy pharmacology studies as well as 
the safety data from prior clinical studies. 
 
 
 
 
 
 
 
 
 

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Clinical studies in adults have shown that chronic administration of an  oral  dose of  
1000 mg tideglusib for six months or greater is generally safe and well tolerated. 
In the recently completed AMO-02-MD-2-001 study, the study drug was well tolerated 
with all 16 subjects enrolled completing the study, and no early discontinuations or dose 
adjustments required. There were no SAEs or suspected unexpected serious adverse 
reactions (SUSARs) reported during the study and no serious AEs related to drug. There 
were no systematic irregularities in objective assessments (e.g. vital signs, ECGs, 
laboratory assessments). 
 
. 
 
 
Pharmacokinetics: 
 
 
 
 
 
 
 

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Duration: 
Based on data from a natural history study of this population and in consideration of the 
type of improvements anticipated to be measured, a duration of 
weeks of treatment has 
been selected to investigate the effects of tideglusib on existing signs and symptoms. The 
effects of tideglusib and analogues on transgenic mouse models of myotonic dystrophy and 
on abnormal differentiation of Congenital DM1 muscle tissue in vitro revealed rapid onset 
following acute dosing. The time course over which tideglusib or any other 
pharmacological agent may demonstrate efficacy in ameliorating the symptoms of 
Congenital DM1 has not yet been established. 

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6. STUDY OBJECTIVES AND PURPOSE 
6.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy, from baseline to end of 
treatment, of weight adjusted 1000 mg tideglusib compared to placebo in children and 
adolescents with Congenital DM1 as measured by the Clinician-Completed Congenital 
DM1 Rating Scale (CDM1-RS). 
6.2 Secondary Objectives 
Secondary Objectives of this study are: 
• To evaluate the safety and tolerability of weight adjusted 1000 mg tideglusib compared 
to placebo in children and adolescents with Congenital DM1 
• To evaluate the efficacy, from baseline to end of treatment, of weight adjusted 1000 mg 
tideglusib compared to placebo in children and adolescents with Congenital DM1 as 
measured by clinician-completed, caregiver-completed rating scales, functional 
assessments, and biomarker/physiological assessments 
• To evaluate the blood pharmacokinetics of tideglusib and its main metabolite 
(NP04113) after repeat dosing in children and adolescents with Congenital DM1 
• To evaluate the consistency of telehealth data and in-clinic data for the CDM1-RS and 
CGI rating scales 
 
7. SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 Subject Numbers 
Approximately 56 children were planned to be randomized into the study, assuming a 
dropout rate of 10-13%. After a blinded sample size re-estimation (SSRE), the protocol 
was amended to allow enrollment of between 56 and 66 children randomized into the study, 
if feasible. 
 
 
Randomization will occur in a 1:1 manner such that each treatment group will have 
approximately 28 subjects (assuming a 10-13% drop-out rate) contributing data to the 
primary efficacy analysis. Randomization will be stratified by age at the time of screening. 
 
 
 
Subjects that withdraw due to COVID-19 related reasons e.g. institutional restrictions, 
travel restrictions, subject in quarantine, or subject shielding, after receiving randomized 

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treatment  may  be  replaced. 
Subjects that withdraw from the study after receiving 
randomized treatment for non-COVID-19 related reasons will not be replaced. 
Subject eligibility will not be re-assessed after the 
is for the purposes of analysis. 
run-in period; the run-in period 
 
 
7.2 Inclusion Criteria 
The subject will not be considered eligible for the study without meeting all of the criteria 
below: 
1. Subjects under study must be children or adolescents with a diagnosis of DM1. For the 
purposes of this study, the following definitions apply. 
In addition to the genetic confirmation of DM1, one or more of the following clinically 
relevant (e.g. requiring medical intervention) signs or symptoms was evident within the 
first month after birth: 
• Hypotonia 
• Generalized weakness 
• Respiratory insufficiency 
• Feeding difficulties 
• Clubfoot or another musculoskeletal deformity 
2. Diagnosis must be genetically confirmed 
3. Subjects must be male or female children and adolescents aged ≥6 years and ≤16 years 
at Screening 
4. Subjects 
greater at 
a Clinical G 
and start of 
ression – Severity (CGI-S) score of 4 or 
) 
5. Subjects must be ambulatory and able to complete the 10-meter walk-run test 
(orthotics/splints allowed, forearm crutches are not allowed) 
6. Written, voluntary informed consent must be obtained before any study related 
procedures are conducted. Where a parent or LAR provides consent, there must also 
be assent from the subject (as required by local regulations) 
7. Subject’s caregiver must be willing and able to support participation for duration of 
study 
8. Subject must be willing and able to comply with the required food intake restrictions 
as outlined per protocol 
must have 
 
lobal Im
 

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7.3 Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Non-ambulatory (full time) wheel chair use 
2. Body mass index (BMI) less than 13.5 kg/m² or greater than 40 kg/m² 
3. Receiving other medications/therapies not stable (i.e. changed) within 4 weeks prior to 
Screening. For each enrollee, every effort should be made to maintain stable regimens 
(i.e. dose, as applicable, and frequency) of allowed concomitant medications (e.g. 
concomitant mexiletine or stimulants) and allowed non-medicine based therapies (e.g. 
occupational or physiotherapy) throughout the course of the study, from the time of 
commencement of Screening until the last study assessment 
4. Use within 4 weeks prior to Baseline (
) of strong CYP3A4 inhibitors. Examples 
include clarithromycin, telithromycin, ketoconazole, itraconazole, posaconazole, 
nefazodone, idinavir and ritonavir 
5. Concurrent use of drugs metabolized by CYP3A4 with a narrow therapeutic window 
e.g. warfarin and digitoxin 
6. Medical illness or other concern which would cause the investigator to conclude that 
the subject will not be able to perform the study procedures or assessments or would 
confound interpretation of data obtained during assessment 
7. Current enrollment in a clinical trial of an investigational drug or enrollment in a 
clinical trial of an investigational drug in the last 6 months 
8. Gastrointestinal disease which, in the opinion of the investigator, may interfere with 
the absorption, distribution, metabolism or excretion of the study medication and 
impact the interpretability of the study results 
9. Current clinically significant (as determined by the investigator) neurological, 
cardiovascular, renal, hepatic, endocrine or respiratory disease that may impact the 
interpretability of the study results 
10. Clinically significant heart disease (in the opinion of the investigator) or current 
evidence of second or third degree heart block, atrial flutter, atrial fibrillation, 
ventricular arrhythmias, or requires medication for treatment of a cardiac arrhythmia 
11. Implantation of a cardiac pacemaker within the 12 months preceding Screening 
12. Average QTcF value of >450 msec at 
confirm) 
or at 
** (may repeat to 
13. Clinically significant abnormalities in safety laboratory tests, vital signs or ECG, as 
determined by the investigator, at 
or 
, (
)**, as applicable (may 
repeat to confirm) 

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Total biliru
 
Serologic 
 
 
14. Females 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 
15. Males, engaged in sexual relations with a female of child-bearing potential, not using 
an acceptable contraceptive*** method if not surgically sterile 
16. Kidney disease requiring ongoing treatment 
17. A history of chronic liver disease with current out of range values for ALT, clinically 
relevant hepatic steatosis or other clinical manifestations of liver disease 
18. ALT value > 2X the upper limit of the normal reference range at 
 (may 
repeat to confirm) 
19. 
 bin value greater than the upper limit of the normal reference range at 
(unless due to Gilbert’s syndrome) (may repeat to confirm). For subjects 
with a well known/well documented diagnosis of Gilbert’s syndrome a total bilirubin 
value greater than 2 x the upper limit of the normal reference range at 
repeat to confirm) 
(may 
20. HbA1c values greater than 6% or 42.0 mmol/mol at 
21. TSH values outside of the normal reference range at 
22. Serum creatinine >1.7 mg/dL (>150 micro 
(according to Cockcroft-Gault formula) at 
(may repeat to confirm) 
(may repeat to confirm) 
creatinine clearance ≤ 60 mL/min 
(may repeat to confirm) 
23. Clinical history of hepatitis or previous or current positive serological evidence for 
Hepatitis B or C 
24. 24. 
al evidence of Hepatitis A at 
or in the 
preceding 
 
25. A history of significant drug allergy (such as Steven-Johnson syndrome, anaphylaxis) 
26. A history of alcohol or substance use disorders 
27. Current malignancy or any history of malignancy except for surgically cured skin 
cancer or pilomatricoma (benign tumor of the hair follicle that is associated with 
Congenital DM1) 
28. Severe arthritis or other medical condition (besides Congenital DM1) that would 
significantly impact ambulation or completion of myometric assessments 
29. Hypersensitivity to tideglusib or any components of its formulation including allergy 
to strawberry 
30. Unable to swallow liquids or may have trouble swallowing liquids (in the opinion of 
the investigator), unless medication to be administered by gastrostomy tube 
31. Judged clinically to be at risk of suicide (suicidal ideation, severe depression, or other 
factors) over the last three months, as assessed by the investigator. 
mole/L or 
 
 

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**As the central ECG report for 
 will not be available prior to the subject commencing 
run-in, eligibility related to ECGs (exclusion criteria 12 and 13) will be based on the 
investigator’s calculation of the mean QTcF value of all ECGs taken at 
 and their initial 
review of the ECG tracings at 
  If there is a conflict between the investigator’s initial 
assessment of the ECG and the central ECG report, whereby the subject would no longer 
be eligible for the study, the subject will be withdrawn from the study at or before 
, prior 
to randomization into the double-blind treatment period. 
***Acceptable contraception is considered to be using one of the following birth control 
methods and should be in place for the duration of the study and for 30 or 90 days after last 
dose of IMP, respectively for female and male subjects: 
• Combined or progestogen-only hormonal contraception 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
• vasectomised partner 
• sexual abstinence, defined as true abstinence. True Abstinence: When this is in line 
with the preferred and usual lifestyle of the subjects [periodic abstinence (such as 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception] 
• Male or female condom with or without spermicide1, 
• Cap, diaphragm or sponge with spermicide1, 
1A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods) are also considered acceptable birth control 
methods 
 
7.4 Withdrawal Criteria 
A subject should be withdrawn from treatment if they meet the discontinuation criteria in 
section 9.5. If a subject is discontinued at any time after Run-in 
, the investigator will 
make every effort to see the subject and complete the EOT visit as soon as possible (ideally 
within 72 hours) after being discontinued from IMP treatment and then attend the follow- 
up visit, 
 after final dose. 
Subjects may withdraw from the study at any time without stating a reason and without 
prejudice to further treatment. The Investigator may withdraw a subject from the study 
and discontinue study treatment and assessments at any time. 

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Early discontinuation of any subject who has given informed consent to participate will be 
recorded including the reason for discontinuation. The primary reason for a subject 
withdrawing prematurely will be selected from the following standard categories of early 
discontinuations: 
• Failed to meet enrollment criteria. 
• Adverse Event: Clinical events occurred or laboratory results are reported that in the 
medical judgment of the investigator are grounds for discontinuation in the best 
interests of the subject. 
• Withdrawal of Consent: The subject desired to withdraw from further participation 
in the study. The subject is not obliged to provide any reason for withdrawal of consent, 
but where a reason is given this will be recorded on the CRF. 
• Protocol Violation: The subject failed to adhere to the protocol requirements, at the 
investigator’s discretion e.g. the subject requires initiating a medication from the 
prohibited medications list or is consistently noncompliant with the pre- and post-dose 
food restrictions 
• Pregnancy: The subject has either a positive urine or serum pregnancy test during the 
study. 
• Lost to Follow-Up: The subject stopped coming for visits and study personnel were 
unable to contact the subject or caregiver. Every effort should be made to re-contact 
the subject prior to declaring a subject as lost to follow-up, which must be at least 3 
documented attempts. The 3rd must be in writing and confirmed to have been received 
(e.g. registered post). 
• Other: The subject was terminated for a reason other than those listed above, such as 
theft or loss of study drugs or termination of study by Sponsor. 
 
8. STUDY DESIGN 
8.1 Study Endpoints to be assessed: 
 
Primary Efficacy Endpoint: 
• Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS) 
 
Key Secondary Efficacy Endpoint: 
• Clinical Global Impression - Improvement Scale (CGI-I)* 
 
 
 
* Sometimes referred to as the CGI-C 

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In the event a combined telehealth and home healthcare visit is required, or unscheduled 
visits as outlined in section 9.5, the following endpoints and procedures may be impacted, 
as follows: 
• Clinician completed assessments (i.e. CDM1-RS, CGI-I, CGI-S, Vineland 
Adaptive Behavior Scale and ABI-C) will be completed via telehealth 
• Caregiver-completed assessments (i.e. Top 3 Caregiver Concerns VAS, CC-MDHI 
and CC-CDM1-RS) will be completed remotely in the subject’s home 
• 10-meter walk-run test: will not be collected as it is unable to be completed safely 
in a subject’s home 
• Lip strength assessment will not be able to be completed as specialized 
physiotherapists are unavailable for home healthcare visits 
• Grip strength assessment will not be able to be completed as specialized 
physiotherapists are unavailable for home healthcare visits 
• NIH toolbox assessments (i.e. Dimensional Change Card Sort Test and Picture 
Sequence Memory Test) and the Peabody Picture Vocabulary Test (PPVT) will not 
be completed as telehealth administration is non-standard administration for these 
tests. Sensitivity analyses on the primary, key secondary and one secondary 
endpoint to support telehealth administration are intended to be performed, and 
therefore additional sensitivity analyses for these exploratory tests will not be 
performed. 
• DXA scan: will need to be completed locally or may be unable to be completed 
samples will be unable to be processed outside of a clinical 
laboratory, and therefore will not be collected 
• Physical examinations will not be able to be completed outside of the clinic setting. 
If a subject is unable to complete Week
 in-clinic, a physical exam will be 
completed locally. 
• Vital signs, height and weight will be collected remotely in the subject’s home 
using an AMO approved home healthcare vendor 
• Safety laboratory and urinalysis samples will be collected remotely in the subject’s 
home using an AMO approved home healthcare vendor 
• Pregnancy testing will be completed via a serum sample collected by an AMO 
approved home healthcare vendor 
• The standard 12-lead ECG will be replaced with a 6-lead ECG using equipment 
provided by the central ECG vendor and completed in the subject’s home using an 
AMO approved home healthcare vendor 

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• PK samples will be unable to be processed outside of a clinical laboratory setting, 
and therefore will not be collected 
• The diary review will need to be completed remotely by the study staff 
• 
 will be unable to be processed outside of a 
clinical laboratory, and therefore will not be collected 
• 
 will not be able to be collected or processed outside 
of the clinic setting 
• Adverse event collection, concomitant medication review will be completed by 
telehealth or telephone 
• IMP will need to be shipped from the investigator site to the subject’s home and 
unused IMP returned via arranged shipment to the investigator site 
 
Home healthcare visits will not be conducted if local restrictions prohibit it or if the subject 
or a member of the family present in the home has, or is suspected to have, COVID-19, 
and those assessments will not be completed. The details of telehealth and in-clinic data 
assessment are outlined in the SAP. 
 
 
8.4 DSMC 
An independent Data Safety Monitoring Committee (DSMC) consisting of clinical and 
other experts will be established by the Sponsor to review safety findings during the study 
and to help ensure subject safety. The DSMC will form a Charter prior to their first data 
review; that Charter will include a description of the Committee, the Members and their 
responsibilities, timing of the reviews, and considerations for any statistical items (e.g. data 
displays) that may be required for the data reviews. 
The DSMC will meet quarterly to review safety and tolerability data for the total study 
population. The DSMC review will be unblinded. The DSMC will make a 
recommendation to either proceed with the protocol with no modification or may suggest 
changes to the protocol. Based on the results of their data reviews, the DSMC will submit 
its recommendations in written form to the Sponsor who is responsible for responding to 
the recommendations of the DSMC and to take appropriate action. 
 
 
9. STUDY MEDICATION AND ADMINISTRATION 
9.1 Study Medication 
Investigational Medicinal Product (IMP): Tideglusib for oral suspension 

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The unit-dose packets (active and matching placebo) must be 
, 
 
 
 
Chemical Name: 4-benzyl-2-naphthalen-1-yl-1,2,4-thiadiazolidine-3,5-dione 
wder blend presented in individual 
were developed for this study, namely ‘tideglusib 
or placebo for 
oral suspension’ and ‘tideglusib 
or placebo for oral suspension’ 
. 
The IMP was developed to be dosed orally following 
 
 The formulation contains an 
 
 
 
 
 
A matching placebo powder blend formulation was developed according to protocol and 
study design. Placebo products are prepared for each strength. The products are filled dose- 
proportionally in identical unit-dose packets at the same total powder blend weight as the 
corresponding 
 active strength products. It is comprised of the same 
qualitative composition as the active product except that tideglusib 
 
 
 
 
Tideglusib dosing will be weight-adjusted at 400 mg, 600 mg, or 1000 mg dose levels, with 
each subject randomized to tideglusib starting at a weight-adjusted 400 mg dose level for 
 weeks, then up 
to a weight-adjusted 600 mg dose level for the next  weeks until 
they reach the final dose level of weight-adjusted 1000 mg tideglusib. Weight-adjusted 
dosing for 400 mg, 600 mg or 1000 mg dose levels of tideglusib result in target 
 
 respectively. 
Subjects weighing
 Run-in (
) will not need to make weight adjustments for 
their randomized dose of IMP and 
 
 
Subjects weighing 
 Run-in (
 will need to make a weight adjustment to the 
dose of IMP they have been randomized to 
 
 The
 
 
 APPENDIX G: 
 
The IMP is a po
 

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’ 
. The IMP (packets and cartons) label text will comply with all applicable 
regulatory requirements. For information on which cartons constitute which doses refer to 
Table 8. 
The caregiver/ LAR will be given clear instructions that all unused packets should be 
returned at each visit and they will be provided with new medication at the subsequent 
visit. If IMP is not returned at a visit, the caregiver/LAR must be informed to only use 
packets from the new cartons and return both sets of IMP at the next visit. 
If Visits 
Weeks 
) are conducted via a combination of telehealth and home 
healthcare providers due to COVID-19 related reasons, shipment of the IMP from the 
investigator site directly to the subject’s home will be arranged. Unused IMP may also be 
returned from the subject’s home to the investigator site via arranged shipment. 
 
Table 8: Dose Cartons 
 
Dose 
Cartons of Medication Dispensed per 
 
timeframe 
400 mg 
 
 
600 mg 
 
 
1000 mg 
 
 
Placebo 
 
 
 
9.2 Allocation to Treatment 
Subject numbers are assigned to subjects as consent is obtained for them to participate in 
the study. Within each site (numbered uniquely within a protocol), the subject number is 
assigned to subjects according to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to the IMP allocated 
to the subject. This will be allocated at Baseline, Week 
 once Run-In is completed. 

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 should be discarded. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
The date and time of dosing should be recorded in the subject diary along with confirmation 
that the dose was administered without issue or a description of any issues (e.g. incomplete 
dose). 
Weight measurement at Run-In 
 will be used to determine the weight based dosing 
and will be kept throughout the study, even if the subject’s weight changes. 

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i. 
Withdraw from Study 
The subject/caregiver should be contacted to discontinue their study medication 
immediately and to be withdrawn from the study, if any of the stopping rules for individual 
subjects described below are met. 
 
Stopping Rules for Individual Subjects 
If a subject meets one or more of the following criteria, they should be immediately 
discontinued from the study 
 
 
 
 
 
The subject will be instructed to return to the clinic for a follow-up assessment ideally 
within 72 hours, and at that time, repeat laboratory work will be obtained 
 
), a physical 
examination will be conducted, and the protocol-defined study assessments for end-of- 
treatment will be completed. If possible, 
 PK sample will be obtained. 
 
 
ii. 
Dose Adjustment 
If a subject has either an 
 
 
 
 
 
 
 
As the study is double-blind, to maintain the blind, regardless of the dose of study 
medication the subject has been assigned to, all subjects will be given new medication as 
follows: 
 

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If a subject has 
 
 
 
 
 
Ideally, this procedure should not take more 
 
 
 
 
• If the 
 
The 
safety analyses) to the 
 
assigned for statistica 
group where they have 
 
 
iii. 
Subject/Caregiver contacted by Investigator for further evaluation 
If a subject has 
 
 
 
 
 
 (see withdraw 
from study above). 
If no, the subject/caregiver should be instructed to call the investigator immediately if they 
experience any of these symptoms before the next scheduled clinic visit. The investigator 
should at the minimum arrange for collection of clinical labs 
 
 ideally within 
 from the subject, and 
if these clinical labs are collected during an in-clinic visit should also conduct a brief 
physical examination, collect vital signs, collect 
 PK sample when possible, and 
check for any AEs or changes to concomitant medications. The investigator should also 
assess the need for continued follow-up before the next appointment, as appropriate. 
 
 
will b
t
 
l purposes (both for efficacy and 
 

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If clinical laboratory tests are obtained with a home healthcare visit, a member of the study 
team should telephone the subject and/or caregiver to assess if there have been any AEs 
and collect any new or changed medications. This should be assessed again at the next in- 
clinic appointment to ensure accurate collection of information. 
 
Management of Diarrhea 
In case of 
 
 
 
 
 
 
 
 
9.6 Treatment Accountability and Compliance Checks 
In accordance with regulatory requirements, the Investigator or designated site staff must 
document the amount of IMP dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to the Sponsor (or 
representative) when applicable. Product accountability records must be maintained 
throughout the course of the study. 
Every effort should be made to collect cartons and unused packets of IMP from the subjects 
at each visit to allow for accountability and for compliance to be checked. It is essential 
that subjects and caregivers are given information not to use medication from the previous 
visit if they do not return all medication. 
At each in-clinic visit, the subject diary will be reviewed and compared to the 
accountability evidence to further ascertain compliance and ensure dose times are recorded 
for all dose administrations, including if dosing is done in-clinic. 
Diary review may be completed remotely, if required due to a COVID-19 related reason. 
Unused packets of IMP will be returned to the investigator site at the next in-clinic visit, 
or if the situation requires, unused packets may be returned directly from the subject’s 
home to the investigator site via arranged shipment. 
At the end of the study, all unused IMP will be returned to the Sponsor’s designee or 
destroyed by the site according to the Sponsor’s instructions once it has been inventoried 
and the monitor has reviewed drug accountability records. 

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9.7 Treatment Blinding Code 
An IRT will be employed in the study to manage the randomization of subjects, tracking 
and confirmation of shipments and returns, IMP supply management, inventory 
management and supply ordering, IMP expiration tracking, and emergency un-blinding of 
the IMP. 
The IRT vendor will provide a user manual and training to each site with detailed 
instruction on the use of the IRT. 
 
 
9.8 Unblinding the Treatment Assignment 
The treatment assignment must not be broken during the study except in emergency 
situations where the identification of the subject treatment code is required for further 
treatment of the subject. The investigator should contact the medical monitor as soon as 
possible after the investigator has been unblinded if the medical monitor was not contacted 
prior to unblinding of treatment code. 
In the event that the treatment assignment is broken, the date, the signature of the person 
who broke the code, and the reason for breaking the code are recorded in the IRT and the 
source documents. Upon breaking the blind, the subject is withdrawn from the study, but 
should be followed up for safety purposes. Any code breaks that occur must be reported to 
the CRO and Sponsor. 
Code break IRT access is held by the investigator and pharmacist/designated person at the 
site and by the medical monitor, or designee, for the study. 
 
 
9.9 Permitted concomitant medication/ non- pharmacological therapies 
All concomitant medications and non-pharmacological therapies (e.g. physiotherapy, 
occupational therapy, speech therapy, yoga) taken or implemented during the study will be 
recorded in the CRF with indication, dose information, frequency and dates of 
administration as applicable. The Investigator should inquire at each clinic visit whether 
there have been changes in any permitted concomitant medications or non-medical 
therapies or interventions, including those in the school setting (e.g. speech therapy). 
With regard to any permitted medication (e.g. concomitant mexiletine or stimulants) or 
therapy (e.g. occupational or physiotherapy) that the subject was taking on entry to the 
study, every effort should be made to continue at the same dose (as applicable) and 
frequency throughout the study. 

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9.10 
Prohibited concomitant medications 
Strong CYP3A4 inhibitors e.g. clarithyromycin, telithromycin, ketoconazole, itarconazole, 
posaconazole, nefazadone, indinavir, ritonavir are not permitted during this study. 
Drugs metabolized by CYP3A4 with a narrow therapeutic window e.g. warfarin and 
digitoxin, are not permitted during the study. 
Treatment with any other IMP is not permitted during this study or within 6 months prior 
to Screening. 
 
10. STUDY SCHEDULE 
Refer to Table 1 for a schedule of events where the subject is able to attend the investigator 
site in person. 
Refer to Table 2 for an adjusted schedule of events in the event that a subject is unable to 
attend the investigator site in person due to a COVID-19 related reason. If a subject is in 
quarantine due to COVID-19, home-health care visits/assessments will not be completed. 
 
 
10.1 
Efficacy Assessments 
All assessments will be performed by the investigator or appropriately delegated and 
trained personnel. 
The study will evaluate efficacy from four different perspectives (also referred to as 
efficacy domains): clinician-completed assessments, caregiver-completed assessments, 
functional assessments (i.e. assessments that require in-clinic performance by the enrollee), 
and biomarker/physiological assessments. The efficacy domains will include the measures 
described below: 
 
 
10.1.1 Clinician-Completed Assessments 
10.1.1.1 
Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS) 
 
The Clinician-completed Congenital DM1 Rating Scale is an 11-item rating scale 
completed by the clinician to score the symptom severity of the following domains that are 
clinically relevant in Congenital DM1: 
If the subject is taking 
 
 
. 

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• Limitations with mobility or walking 
• Problems with hands or arms 
• Signs of Fatigue 
• Signs of Pain 
• Gastrointestinal issues 
• Communication difficulties 
• Impaired sleep or daytime sleepiness 
• Difficulty thinking 
• Myotonia 
• Breathing difficulties 
• Choking or swallowing issues 
This list of domains is informed by the Congenital and Childhood Myotonic Dystrophy 
Health Index (CC-MDHI) (Johnson et al., 2016). The CC-MDHI is a rating scale 
developed from a Natural History Study of the symptoms and impact of Congenital DM1 
(Johnson et al., 2016). The CC-MDHI is a 168-item Likert scale that covers multiple 
aspects of the specific phenotype of Congenital DM1, intended for completion by the 
caregiver of the subject. The CDM1-RS is being developed in collaboration with the 
authors of the CC-MDHI. This new outcome measure utilizes domains informed by those 
reported for the CC-MDHI; the scale covers much of the breadth of the clinical phenotype 
of 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. The clinician is asked to rate 
the severity of each symptom, using a time frame of the past week including the day of the 
assessment for reference. 
A standard interview and examination form will be provided to the sites to assist the rater 
making assessments and in eliciting commentary from the subject or their caregiver across 
each of the core domains of the affected individual’s Congenital DM1, and also on 
associated symptoms. Every effort will be made to ensure that the same rater also observes 
the subject at each visit to the clinic or telehealth visit. 
At Baseline (
), Week
) and Week 
) the CDM1-RS will be rated twice for 
consistency evaluation purposes. One rating will be from an interview completed in-clinic 
and an another from an interview completed via telehealth within the 
 period before 
the in-clinic visit. Both the in-clinic and telehealth interviews will be video recorded. 

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In addition to the investigator ratings of the CDM1-RS, an independent central rater will 
also rate the CDM1-RS for both the in-clinic and telehealth interviews recorded at Baseline 
), Week  
 and Week 
 
The CDM1-RS will be completed according to the schedule of events and will be assessed 
via telehealth instead of an in-clinic interview if required due to a COVID-19 related 
reason. 
A copy is included in APPENDIX A: Clinician-Completed Congenital DM1 Rating Scale 
(CDM1-RS). 
 
 
10.1.1.2 
Clinical Global Impressions (Severity and Improvement) 
The clinician administered Clinical Global Impression - Severity (CGI-S) and - 
Improvement (CGI-I) scale (Guy, 1976) will be performed in accordance with the schedule 
of events. The CGI rating scale permits a global evaluation of the subject’s improvement 
over time and will be administered as detailed in the schedule of events. 
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. 
The CGI-I, sometimes referred to as the CGI-C, requires the clinician to rate how much 
the subject’s illness has changed (improved, worsened or stayed the same) relative to a 
baseline state (Amer Psychiatric Pub Inc, 2000). A seven 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. 
The CGI-I at Baseline 
) should be rated against the subject’s clinical presentation at 
Run-in  
). For subsequent  CGI-I ratings completed from 
  onwards, the 
assessment should be compared against the subject’s clinical presentation at Baseline (
. 
In this study, score levels for the CGI-S and CGI-I are calibrated to standard scoring 
anchors which are specific to the Congenital DM1 phenotype. A standard interview and 
examination form will be provided to the sites as a guide to the rater in evaluating the 
subject and in eliciting commentary from the subject or their caregiver across each of the 
core domains of the affected individual’s Congenital DM1 and also on associated 
symptoms. Every effort will be made to have the same rater also observe the subject at 
each visit to the clinic or telehealth visit. 

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10.1.1.4 Vineland Adaptive Behavior Scales- 
– 
(Vineland
) 
The Vineland Adaptive Behavior Scales – 
 (Vineland –
 measures personal 
and social skills needed for everyday living. It provides a targeted assessment of adaptive 
behavior via a semi-structured parent or caregiver interview. 
 
a
 
 
 
 
 
 
 
 Test 
administration can be accomplished on a portable device such as an iPad or given via 
paper/pencil. The Vineland-
 includes suggested interview questions as 
well as item-level probe questions. 
 
 The 
 version 
of the Vineland
 
 can generally be completed within 20 minutes, ideally 
completed by a clinician with at least two years of experience working with individuals 
with ASD. The 
 version will be utilized in this study. 
The Vineland
 will be administered according to the schedule events and will be assessed 
via telehealth if required due to a COVID-19 related reason. 
 
 
10.1.2 Caregiver-Completed Assessments 
10.1.2.1 Congenital and Childhood Myotonic Dystrophy Health Index (CC-
MDHI) Parent-Proxy Instrument 
The Congenital and Childhood Myotonic Dystrophy Health Index (CC-MDHI) surveys the 
overall quality of life in relation to the subject’s myotonic dystrophy symptoms. The CC- 
MDHI is a rating scale developed from a Natural History Study of the symptoms and 
impact of Congenital DM1 (Johnson et al., 2016). The CC-MDHI Parent Proxy is a 19 
question, 128-item Likert scale that covers multiple aspects of the specific phenotype of 
Congenital DM1, intended for completion by the caregiver of the subject. Each item offers 
6 levels of severity ranging from “he/she doesn’t experience this” to “it affects his/her life 
severely”. 
The CC-MDHI will be administered according the schedule events and will be completed 
remotely in the subject’s home if required due to a COVID-19 related reason. 
A copy of the CC-MDHI Parent Proxy can be found in APPENDIX D: Congenital and 
Childhood Myotonic Dystrophy Health Index (CC-MDHI) Parent Proxy Instrument. 
 

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10.1.2.2 
Top 3 Caregiver Concerns Visual Analogue Scale (VAS) 
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 will be 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 and “very severe” at the 
right end. Ideally, the caregiver should choose one item that relates to muscle function 
(such as problems with walking, drinking from a straw, or grip), one item that relates to 
cognitive abilities (such as problems with thinking, planning or concentration), and one 
item that relates to performing activities of daily living (for example, problems or 
difficulties brushing teeth, getting dressed or helping with household chores). The 3 
concerns related to the subject’s myotonic dystrophy will be chosen and rated at baseline. 
These 3 signs and symptoms will be rated again according to the schedule of events using 
the same scales and will be completed remotely in the subject’s home if required due to a 
COVID-19 related reason. 
A copy of the Top 3 concerns VAS is included in APPENDIX E: Caregiver Top 3 Concerns 
Visual Analog Scale (VAS). 
 
 
10.1.2.3 Caregiver-Completed Congenital DM1 Rating Scale (CC- CDM1-
RS) 
This scale provides a caregiver assessment of the subject on symptoms that may occur in 
individuals with CDM1. There are a total of 11 symptoms that the caregiver is asked to 
rate: 
 
• Limitations with mobility or walking 
• Problems with hands or arms 
• Signs of fatigue 
• Signs of pain 
• Gastrointestinal issues 
• Communication difficulties 
• Impaired sleep or daytime sleepiness 
• Difficulty thinking 
• Myotonia 

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• Breathing difficulties 
• Choking or swallowing issues 
 
These symptoms are rated on a score from 0 to 4 based on overall severity (e.g. severity of 
symptoms, frequency of symptoms, context in which it occurs and functional impact), 
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. 
When rating each symptom, the caregiver will be asked to consider how the symptom 
influences how the subject feels and how it impacts his/her ability to perform everyday 
functions. Caregivers ratings should also incorporate important observations that they 
make of the subject, with regard to his/her symptoms. For example, caregivers should 
consider the subject's behaviors and verbalizations (what he/she says), as well as the 
symptoms that the caregiver can actually see. When making their ratings, the caregiver is 
asked to consider a time frame of the past week including the day of the assessment for 
reference. 
The CC-CDM1-RS will be administered according to the schedule of events and will be 
completed remotely in the subject’s home if required due to a COVID-19 related reason. 
A copy of the CC-CDM1-RS is included in APPENDIX F: Caregiver Completed 
Congenital DM1 Rating Scale (CC-CDM1-RS). 
 
10.1.2.4 
Caregiver Myotonic Dystrophy Type 1 Status 
Study staff will ask the caregiver for some optional basic information about themselves 
which will be recorded in the CRF. The information includes: 
• Relationship of the caregiver to the subject (e.g. mother, father, sibling, other) 
• If the caregiver has a diagnosis of DM1 
• Which subtype of DM1 the caregiver has, if applicable 
 
 
10.1.3 Functional Assessments 
10.1.3.1 
10-Meter walk-run test (preferred speed and fastest speed) 
The 10-meter walk/run test is a performance measure used to assess walking speed in 
meters per second over a short distance. It can be used as an assessment of functional 
mobility. The test will be conducted according to the schedule of events and will be 
performed at the subject’s preferred walking speed and then at the fastest speed possible. 

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For each speed, the test should be repeated until 3 valid measures are obtained. No more 
than 6 trials per speed should be conducted, with 10-15 seconds of rest between trials to 
avoid fatigue. If needed, the rest period can be longer, until the subject has recovered. 
The subject walks without assistance for 12 meters while the time taken to walk from meter 
1 to meter 11 is recorded. The electronic timing system starts and stops when the subject 
crosses the 1 and 11-meter line, respectively. Assistive devices such as orthotics/splints are 
allowed, forearm crutches or walkers are not allowed. Use of assistive devices must be 
documented and kept consistent for that subject throughout the study. 
For the fastest speed possible, the assessor will document whether the subject was able to 
run, walk fast or walk for each assessment. Whether the subject is running is defined as 
both feet being off the floor at the same time. If the subject is not able/willing to perform 
the fastest speed possible for all 3 valid assessments, this will also be recorded. 
The 10-meter walk/run will not be collected remotely (i.e. if an in-clinic visit is not possible 
due to a COVID-19 related reason) as it is unable to be completed safely in a home 
environment. 
 
 
10.1.3.2 Quantitative myometric measure of hand grip strength 
Handgrip myometry is used as a measure of myotonia and muscle strength and has been 
validated as a reliable measure in patients with DM1 (Moxley et al., 2007). 
The force of concentration will be measured using the Jamar Handgrip Dynamometer and 
will be measured in kilograms (Kg). 
Handgrip strength will be tested bilaterally, first on the right and then followed by the left 
hand. The subject will be asked to squeeze the Jamar Handgrip dynamometer for 3-5 
seconds to allow for maximal muscle contraction, after which the subject will release their 
grip and relax their hand. This will be repeated until 3 valid measures are obtained. A 
maximal 6 trials per hand will be attempted, with a 5 to 10 second rest given between trials 
to avoid fatigue. 
Handgrip strength will not be collected remotely (i.e. if an in-clinic visit is not possible due 
to a COVID-19 related reason) as specialized physiotherapists are unavailable for home 
healthcare visits. 
 
 
10.1.3.3 Measurement of lip strength via lip force meter 
Lip strength will be measured using a mouthguard adaptation for the digital force meter. 
Subject s will insert the mouthguard between their incisors and their lips and hold as force 
is applied for 10 seconds with increasing force until the mouthguard is dropped. 

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Measurements will be repeated until 3 valid times are obtained. No more than 6 trials will 
be conducted, with at least 10-15 seconds rest in between trials to avoid fatigue. If needed, 
the rest period can be longer. 
Lip strength will not be collected remotely (i.e. if an in-clinic visit is not possible due to a 
COVID-19 related reason) as specialized physiotherapists are unavailable for home 
healthcare visits. 
 
 
10.1.3.4 NIH Toolbox Cognition Battery: Dimensional Change Card Sort 
Test 
The NIH Toolbox Cognition Battery: Dimensional Change Card Sort Test (DCCS) is a 
measure of cognitive flexibility and attention in individuals aged 3 years and older. Two 
target pictures are presented that vary along two dimensions (e.g., shape and color). 
Subjects are asked to match a series of bivalent test pictures (e.g., yellow balls and blue 
trucks) to the target pictures, first according to one dimension (e.g., color) and then, after 
a number of trials, according to the other dimension (e.g., shape). The relevant dimension 
for sorting is indicated by a cue word (e.g., “shape” or “color”) that appears on the screen 
for all subjects and that, for young children ages 3-11 years, is also spoken by a prerecorded 
audio file. 
The NIH Toolbox Cognition Battery: Dimensional Change Card Sort Test is unable to be 
collected remotely as telehealth administration is non-standard administration and may 
alter the integrity of the data collected. Sensitivity analyses on the primary, key secondary 
and one secondary endpoint to support telehealth administration are intended to be 
performed, therefore additional sensitivity analyses for this exploratory test will not be 
performed. 
 
 
10.1.3.5 NIH Toolbox Cognition Battery: Picture Sequence Memory Test 
The NIH Toolbox Cognition Battery: Picture Sequence Memory Test (PSMT) is a measure 
developed for the assessment of episodic memory for ages 3-85 years. It involves recalling 
increasingly lengthy series of illustrated objects and activities that are presented in a 
particular order on the iPad screen, with corresponding audio-recorded phrases. The 
sequence of pictures appears one at a time in the center of the computer screen in a fixed 
order. As each picture appears, a recording briefly describes its content. This continues 
until all pictures in a sequence have been displayed and placed in their proper positions. 
Once all the pictures in the sequence are displayed, the pictures then are placed in a random 
spatial array at the center of the screen. The subjects are asked to recall the sequence of 
pictures demonstrated over two learning trials; sequence length varies from 6-18 pictures, 

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depending on age. Subjects are given credit for each adjacent pair of pictures they correctly 
place. The test takes approximately seven minutes to administer. 
The NIH Toolbox Cognition Battery: Picture Sequence Memory Test is unable to be 
collected remotely as telehealth administration is non-standard administration and may 
alter the integrity of the data collected. Sensitivity analyses on the primary, key secondary 
and one secondary endpoint to support telehealth administration are intended to be 
performed, therefore additional sensitivity analyses for this exploratory test will not be 
performed. 
 
 
10.1.3.6 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-color 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 as well as a standard score, derived 
from the number of responses attempted and the number of correct responses. The percent 
of correct responses is also reported. 
The PPVT will be performed according to the schedule of events. 
The PPVT is unable to be collected remotely as telehealth administration is non-standard 
administration and telehealth administration is not included in the normative group. 
Sensitivity analyses on the primary, key secondary and one secondary endpoint to support 
telehealth administration are intended to be performed, therefore additional sensitivity 
analyses for this exploratory test will not be performed. 
 
 
10.1.4 Biomarker/Physiological Assessments 
10.1.4.1 Dual-energy X-ray absorptiometry (DXA) whole body scan of lean 
muscle mass 
DXA (previously DEXA) utilizes two low energy X-ray beams, with different energy 
levels, which are aimed at the subject’s bones. The DXA scan measures bone mineral 
density, lean muscle mass, fat content, and total body composition. The amount of radiation 
used in a DXA scan is very low. 
The primary assessment of interest in this study, from an efficacy perspective, is lean 
muscle mass. Subjects will have their lean muscle mass determined by a whole body DXA 
scan and the following parameters recorded in grams; arms, legs and total. Bone mineral 

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• Any surgical procedures that have occurred during 1 year before the Screening Visit 
(
) and any history of having an implanted cardiac pacemaker 
• History of use of mechanical ventilation, gastronomy tube or cough assist devices 
 
10.2.2 Physical Examination 
A full physical examination will be conducted. This will be completed by a delegated 
physician. 
A full physical examination is composed of a review of the following body systems: 
• General appearance 
• Skin 
• Head, eyes, ears, nose and throat 
• Respiratory 
• Cardiovascular 
• Abdomen (including liver and kidneys) 
• Musculoskeletal 
• Neurological 
Any abnormalities that are identified at the Screening Visit (
) will be documented in the 
subject’s source and on the medical/surgical history CRF page. Any changes occurring 
after the Screening Visit will be captured as AEs on the AE CRF page, as determined by 
the Investigator. 
If an improvement/resolution of a physical examination finding documented in the 
subject’s medical history occurs during the study, it should be recorded in the source 
document. If there is resolution of a physical examination finding previously noted as an 
AE, then the event resolution and stop date should be recorded on the AE CRF page. 
Physical examinations will not be completed if an in-clinic visit is not feasible due to a 
COVID-19 related reason. If a subject is unable to attend Week 
 as an in-clinic 
visit, a physical examination will be obtained locally by a physician. 
 
 
10.2.3 Height 
A calibrated stadiometer should be used to measure height. Height should be measured in 
centimetres without shoes with the subject standing on a flat surface and with their chin 
parallel to the floor. The body should be straight but not rigid. The subject’s height should 
be recorded to the nearest 0.5cm. 

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Height will be collected remotely in the subject’s home using an AMO approved home 
healthcare vendor, if required due to a COVID-19 related reason. 
 
 
10.2.4 Weight 
The same calibrated scale should be used for all weight measurements for a subject. Weight 
should be measured in kilograms without shoes and recorded to the nearest 0.1 kg. Bulky 
items should be removed whenever possible to ensure the most accurate weight is recorded. 
All orthotics should be removed prior to weight measurement. 
Weight will be collected remotely in the subject’s home using an AMO approved home 
healthcare vendor, if required due to a COVID-19 related reason. 
 
 
10.2.5 Adverse Event collection 
Subjects will be questioned in a non-leading way to determine if AEs have occurred since 
the last visit e.g. “Have you had any health problems since your last visit?” AEs and SAEs 
will be collected from the time of informed consent. 
At Week 
 or Week 
, a member of the study team should telephone the subject 
and/or caregiver to assess if there have been any AEs and collect any new or changed 
medications. This should be assessed again at the next in-clinic appointment to ensure 
accurate collection of information. 
Adverse events will be elicited at 
 hours 
) and
 hours (
) post the end of 
treatment visit (
 via telephone by a member of the study team. 
Standard (i.e. non-leading) questions should be used but the clinician should bear in mind 
that the purpose of AE questioning is to elicit events specifically related to study drug 
dependency, abuse or withdrawal. However, all reported adverse events should be reported 
in the eCRF. 
Adverse events will be collected by telehealth or telephone if required due to a COVID-19 
related reason. 
Refer to section 10.5 for additional details of AE collection and reporting. 
 
 
10.2.6 Vital signs 
Vital signs will include the following measures: temperature, pulse, systolic and diastolic 
blood pressure and respiratory rate. Blood pressure and pulse will be determined after the 
subject has been in the sitting position for 5 minutes. 

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The biochemistry analysis will include 
 
 
 
 
Blood pressure should be determined by cuff (using the same method, the same arm, and 
in the same position throughout the study). A BP cuff appropriate for the subject’s arm 
length and girth should be used for all BP measurements. The cuff should be approximately 
two-thirds the length/width of the subject’s arm (from elbow to shoulder). The cuff should 
be calibrated and ideally the same cuff should be used on a subject throughout the study. 
All BP measurements should be performed by the same study site personnel (if possible) 
throughout the study. 
Any vital signs which in the opinion of the investigator are deemed to be clinically 
significant are to be recorded as an AE. Any clinically significant abnormalities at the 
follow-up visit should be followed up and repeated until they have returned to baseline or 
are, in the opinion of the investigator, no longer clinically significant. 
Vital signs will be collected remotely in the subject’s home using an AMO approved home 
healthcare vendor, if required due to a COVID-19 related reason. 
 
 
10.2.7 Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed according to the study laboratory’s normal 
procedures. Reference ranges will be supplied by the study laboratory and will be used to 
assess the laboratory data for clinical significance and out of range changes. 
Safety laboratory and urinalysis samples will be collected remotely in the subject’s home 
using an AMO approved home healthcare vendor for unscheduled visits as required or if 
required due to a COVID-19 related reason. 
 
 
Biochemistry 
A biochemistry sample will be collected as outlined in the schedule of events. Biochemistry 
blood samples can be drawn with the subject in either a fasting or non-fasting state. 
However, if a sample needs to be repeated, the subsequent sample should be drawn from 
the subject in the same fasting/non-fasting state. 
At the Screening 
 a virology panel (may be collected separately from the biochemistry 
sample in some regions) will analysed to determine if there is serological evidence of 
Hepatitis A at 
or in the past 
 or an active Hepatitis B or C infection 
(Anti-HAV IgM, anti-HBc IgM, Hep B surface antigen, HCV). If an initial positive result 

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A full blood count with differential should be collected as outlined in the schedule of 
events. This should include 
 
(
 
 
)
 
is obtained indicating an active Hepatitis C infection, the result will need to be confirmed 
and an additional blood sample may be collected from the subject. 
 
 
 
At Screening 
 and EOT 
), a 
obtained. 
panel 
 should be 
Additionally, at Screening 
 and EOT 
, 
 should also be obtained. 
 
Hematology 
 
 
A 
 will be collected as outlined in the schedule of events. The 
actual 
 and the 
 will be reported from this 
sample. 
 
Urinalysis 
Urinalysis will be performed by dipstick and documented in source documents as outlined 
in the schedule of events. Abnormal results should be investigated further by sending to 
the study central laboratory. 
 
Pregnancy Test 
Serum pregnancy test for female subjects of child bearing potential at Screening will be 
performed. At subsequent visits, a urine pregnancy test is sufficient if acceptable and 
preferable according to local practice. If a female subject of child bearing potential is seen 
at home for a visit, due to a COVID-19 related reason or an unscheduled visit requiring a 
pregnancy test, by a home health care professional, the central laboratory will perform a 
serum pregnancy test using the biochemistry sample. 
 
 
10.2.8 ECG 
All ECGs will be performed using equipment provided by the central ECG provider and 
all ECGs performed will be transmitted electronically to the central ECG provider for 
 

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Actual PK blood sample collection date and time will be recorded. 
 
 
 
 
 
 at Week 
) should also be recorded. At Week 
  
 
PK sample should be recorded. In addition, at Week 
 
 should also be 
recorded. 
 
 
A single PK sample may also be collected at an unscheduled visit if in the opinion of the 
investigator this would provide useful information. 
Population pharmacokinetic modelling will be used to analyze the data. If PK parameters 
cannot be estimated using the study data only, prior information on parameter distributions 
from a previously reported pharmacokinetic model of tideglusib will be used. In order to 
determine whether there are associations between pharmacokinetic parameters and 
efficacy measures, change from baseline in efficacy measures over the course of the study 
may be correlated with model-predicted PK parameters estimated for each subject. These 
associations may be statistically tested using correlation coefficients and general linear 
models, if appropriate. 
Instructions for the collection, handling, storage, processing and shipment of the 
pharmacokinetic samples will be provided in a separate laboratory manual. 
PK samples cannot be processed outside of a clinical laboratory setting. Therefore, these 
sample will not be collected if an in-clinic visit is not feasible due to a COVID-19 related 
reason. 
With the exception of Week 
), 
 
 
 
 
(
 

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 These samples will not be utilized for 
anything other than the tests described within this protocol. 
collection, handling, storage, processing and shipment of the 
sample will be provided in a separate laboratory manual. 
and 
and 
 samples cannot be processed outside of a clinical laboratory, 
therefore will not be collected if an in-clinic visit is not feasible due to a COVID-19 related 
reason. 
 
 
10.4.3.2 
At Baseline (
) and end of treatment visits (
 an optional 
be performed. 
 
may 
 
 
If the subject has had a 
 
 
 Baseline 
 sample. 
 
 
 
 
 
 
 
 
Instructions for the collection, handling, storage, processing and shipment of 
samples will be provided in a separate laboratory manual. 
 samples cannot be collected or processed outside of the clinic setting 
therefore these samples will not be collected if an in-clinic visit is not feasible due to a 
COVID-19 related reason. 
10.4.3.3 
Testing Sample 
A blood sample will be taken for 
 testing at the timepoint described in the 
schedule of events. Testing 
 include both 
 testing as well as 
 testing. 
 
The
 
 
 
Instructions for the
 
 

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e collection, handling, storage, processing and shipment of the 
testing samples will be provided in a separate laboratory manual. 
 
 
10.5 
Adverse Events 
Adverse events may be volunteered spontaneously by the subject, or discovered as a result 
of general, non-leading questioning. All adverse events should be recorded in the CRF and 
source document. 
 
10.5.1 Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Abnormal laboratory findings should be reviewed by a delegated physician to determine 
whether they are clinically significant. Clinically significant abnormal laboratories should 
be reported as an AE. Where possible an underlying diagnosis should be reported as the 
AE. 
 
Adverse Drug Reaction (ADR) 
All events considered to be untoward and unintended responses to a medicinal product 
related to any dose should be considered adverse drug reactions. The definition covers also 
medication errors and uses outside what is foreseen in the protocol, including misuse and 
abuse of the product. The phrase “responses to a medicinal product” means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
 
Serious Adverse Event (SAE) 
An adverse event that at any dose: 
• Results in death 
Instructions for th 
 

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• Is life-threatening (i.e. the subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it was more 
severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization (see 
explanation below) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is considered to be an important medical event 
 
Based upon medical and scientific judgment, important medical events that may not be 
immediately life-threatening, or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above may be considered a serious adverse event. 
Hospitalizations are defined as initial or prolonged admissions that include an overnight 
stay. Hospitalization or prolonged hospitalization for technical, practical or social reasons, 
in the absence of an adverse event is not an SAE. 
 
Pregnancy 
Pregnancy itself is not considered an AE. However, any pregnancy complication, 
spontaneous or elective abortion (for medical reasons), still birth, neonatal death, or 
congenital anomaly will be recorded in both the clinical and safety database. 
If the investigator becomes aware of a pregnancy in a female subject, or in a female partner 
of a male subject in this study, every effort will be made to follow the pregnancy until 
termination or delivery. 
In the event of pregnancy (either in a female subject or a female partner of a male subject 
in the study), it will be reported on a pregnancy form, and reported as per the information 
in section 10.5.8. This report will be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects or congenital abnormalities. The outcome will be documented in the CRF if 
feasible. In the case of a female subject, the subject must be withdrawn from the study. 
 
Unexpected Adverse Drug Reaction 
An adverse reaction, the nature or severity of which is not consistent with applicable 
product information (e.g., Investigators Brochure for an unapproved IMP). 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 

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A serious AE that is suspected to be related to the administered medicinal product and the 
nature or severity of which is not consistent with applicable product information. 
Reports which add significant information on the specificity, increase of occurrence, or 
severity of a known, already documented serious adverse reaction constitute unexpected 
events. 
 
 
10.5.2 Severity Categorization 
The severity (intensity) of each AE will be classified as: 
• Mild (Grade 1) 
Awareness of sign or symptom, but easily tolerated; no 
interference with activity 
• Moderate (Grade 2) 
Sign or symptom causes discomfort, some interference with 
activity 
• Severe (Grade 3) 
Sign or symptom of sufficient intensity to prevent activity 
• Potentially Life Threatening (Grade 4) 
Requires 
emergent 
care 
or 
hospitalization 
Examples of gradation for AEs can be found in the FDA Guidance for Industry “Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials” (FDA, 2005). 
A change in severity should be captured as a new AE. 
 
 
10.5.3 Assessment of Causality 
 
A study physician must assess the relationship to the IMP for each AE. The likely 
relationship of each AE to the IMP will be assessed according to the definitions below: 
• Unrelated 
• Related 
 
10.5.4 Outcome Categorization 
All AEs should have an outcome recorded, which should be updated if it changes during 
the reporting and follow-up period (defined in section 10.5.9). The possible outcomes 
should be: 
• Fatal 
• Recovered/Resolved 

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• Recovering/Resolving 
• Recovered/Resolved with sequalae 
• Not recovered/not resolved 
For fatal outcomes, every effort should be made to ensure source documentation (e.g. 
autopsy report, death certificate) to confirm the cause of death will be available to be 
reviewed by the independent DSMC. 
 
 
10.5.5 Symptoms of Disease Under Study 
Symptoms of the disease under study (e.g. problems with ambulation, fine motor 
difficulties, fatigue, speech difficulties, and gastrointestinal issues) present before study 
entry should be recorded in the CRF. These symptoms should not be classed as AEs as 
long as changes are within the normal day to day fluctuation or expected progression of 
the disease; however, significant worsening of the symptoms, in the opinion of the 
investigator, should be recorded as an AE. 
 
 
10.5.6 Clinical Laboratory Evaluations 
Abnormal laboratory findings (e.g. 
) 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, 
as defined in Section 10.5.1. 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study and significantly worsen following the start of the study will be 
reported as AEs or SAEs. 
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. 
Subjects with any TEAE laboratory abnormality (
) will be 
followed up until recovery or stabilization of the condition. 
 
 
10.5.7 Abuse, Misuse, Overdose or Medication Error 
Subjects should not exceed the maximum daily doses or take any two doses within an 8- 
hour interval. There is no specific antidote to tideglusib. In the event of an overdose, 
appropriate supportive measures should be employed as clinically indicated and the 
Medical Monitor must be informed immediately. The investigator should determine 

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appropriate supportive assessments which may include a thorough assessment for potential 
hepatotoxicity, including assessment of serum chemistries, with particular attention to ALT 
and bilirubin levels, after the cessation of drug. Repeat examinations should be conducted 
as clinically indicated. 
 
 
10.5.8 Serious Adverse Event Reporting 
Once an Investigator or delegate becomes aware that an SAE or pregnancy has occurred in 
a study subject, she/he will report the information to the Sponsor’s appointed agent within 
24 hours of awareness by completing the SAE or Pregnancy form and e-mailing (or faxing 
if e-mail is not possible) this and any available supporting documentation to the details 
below: 
 
Pharmacovigilance 
(PV) Provider: 
 
SAE email contact: 
 
SAE Fax number: 
 
 
SAE Telephone 
contact: 
 
 
 
 
The SAE/Pregnancy form will always be completed as thoroughly as possible with all 
available details of the event, and signed by the Investigator (or authorized designee). If 
the Investigator does not have all information regarding an SAE or Pregnancy, he/she will 
not wait to receive additional information before notifying the PV Provider / Medical 
Monitor of the event and completing the form. The form will be updated when additional 
information is received. 
The Investigator will always provide an assessment of causality at the time of the initial 
report as described in Section 10.5.3 of this protocol. 

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The PV provider will contact the Investigator should it be necessary to clarify any of the 
event information. The Investigator should provide follow-up information for the event to 
the PV provider as soon as it becomes available. 
Any event that in the opinion of the Principal Investigator may be of immediate or potential 
concern for the subject’s health or well-being will be reported to the Medical Monitor with 
parallel notification to the PV Provider. 
SAEs that are ongoing at the Week 
follow-up visit (
 will be followed until 
resolution or stabilization of subject condition, whichever occurs first. In such cases, 
follow-up SAE forms will be completed at the Week 
 follow-up visit 
 and on 
resolution or stabilisation, whichever occurs first. 
SAEs occurring to a subject after the subject has completed the clinical trial and for which 
a reasonable possibility of a causal relationship is assessed by the investigator, should be 
reported by the investigator to the Sponsor if the investigator becomes aware of them 
regardless of the time that has elapsed (post-trial events). 
All SAE and AE data will be reviewed by the independent DSMC at scheduled meetings. 
AMO Pharma Ltd is required to expedite to worldwide regulatory authorities, reports of 
Serious Adverse Events, Serious Adverse Drug reactions or Suspected Unexpected Serious 
Adverse Reactions (SUSARs) in line with the relevant legislation of the applicable 
Regulatory Authorities. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. In 
accordance with 21 CFR 312.32 of the United States Code of Federal Regulations, the 
European Commission Directive 2001/20/EC, and C.05.014 of the Canadian Food and 
Drug Regulations, AMO Pharma Ltd or delegate will notify the relevant Institutional 
Review Board, Ethics Committees, and Research Ethics Board in concerned Regulatory 
Authorities of applicable SUSARs as individual notifications or through a periodic line 
listing. 
AMO Pharma Ltd or delegate will submit to the Regulatory Authorities all safety updates 
and periodic reports, as required by applicable regulatory requirements. 
 
 
10.5.9 Time Period, Frequency, and Method of Detecting AEs and SAEs 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start 
of the study (i.e., before on-study informed consent is obtained) that do not result in the 
exclusion of the subject from participating in the study, should be recorded as 
Medical/Surgical History. 

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All SAE’s and AEs occurring after informed consent and on or before the final visit must 
be reported. All AEs must be recorded irrespective of whether they are considered drug 
related. 
At each visit/assessment in the period defined above, AEs will be evaluated by the 
Investigator and recorded. 
Any AEs already documented at a previous assessment and designated as ongoing, should 
be reviewed at subsequent visits. If these have resolved, this should be documented. 
 
 
11. STATISTICAL CONSIDERATIONS 
The details of all planned analyses will be specified in a separate statistical analysis plan 
(SAP) which will be finalized prior to hard-lock of the study database. The SAP will 
contain details of all the analyses including specifications for all tables, listings and figures. 
All statistical programming will be performed using SAS software. 
A blinded sample size re-estimation (SSRE), based on the observed variance in the primary 
outcome measure, will occur when approximately 33% of subjects are enrolled and have 
completed 
 The variability of key secondary and secondary endpoints may 
be assessed as well, if feasible. This SSRE was executed as planned. 
Primary and key secondary analyses of efficacy will be based on the Intent To Treat (ITT) 
population and the summary of safety based upon the Safety Analysis Set (see definitions 
below in section 11.2). Other efficacy analyses will be based on the Full Analysis Set. 
Statistical significance will be assessed at the 0.05 two-sided level, unless specified 
otherwise. 
In general, statistical analyses will be performed using methods which account for known 
potential confounding data (e.g. sites/geographic locations, baseline characteristics, 
 
Changes in efficacy variables from Baseline 
 to post-treatment visits (or observed 
values for some variables such as CGI-I) will be summarized and compared between the 
weight adjusted tideglusib 1000 mg dose and placebo at each study visit. The primary 
comparison will be performed for changes from baseline to end of treatment. The model 
details and data displays will be described in the SAP. 
Additionally, the changes from baseline over time will be compared using linear mixed 
effects repeated measures modelling. 
For all analyses, the effects of the weight adjusted tideglusib 1000 mg dose versus placebo 
will be estimated at the end of treatment and presented along with associated 95% two- 
sided confidence intervals and p-values. The comparisons may also be performed at other 

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time points; however the p-values should be reviewed with caution due to potential 
multiplicity issue (high probability of chance-alone outcomes). 
Subjects 
 and who discontinue 
the study will be classified as screening failures. Subjects 
 but who discontinue the study before taking a dose of tideglusib will be classified 
as run-in failures. 
 
 
11.1 
Estimated Sample Size 
 
One of the study goals is to identify consistent efficacy trends in the primary and key 
secondary endpoints. Twenty-five subjects per group will generate 70% power to detect 
the effect size of 0.6 at the 0.1 two-sided significance level. This sample size will also be 
sufficient to generate 80% power to detect the effect size of 0.82 at the 0.05 two-sided 
significance level. Accounting for a 10%-13% drop-out rate, approximately 28 subjects 
per group were initially planned. No data are available on the CDM1-RS instrument. Based 
on the preliminary data observed in the AMO-02-MD-2-001 study, the assumed effect sizes 
look reasonable. The effect size assumptions are partially based on the Clinician VAS total 
score changes from baseline to end of study (6 points on drug vs. 1 point on placebo with 
the common standard deviation of 5.8). Based on these and other data, 29 and 22 subjects 
per group will be sufficient to generate 90% and 80% power at the 0.05 two-sided 
significance level. Based on these calculations, the suggested sample size of 56 patients 
total was considered adequate to detect the treatment effect or at least a consistent trend. 
A blinded SSRE, based on the observed variance in the primary outcome measure, was 
performed during the conduct of the study. Based on the blinded SSRE, the planned 
sample size is sufficient to detect the treatment difference between active and control 
arms based on the primary endpoint with at least 80% power at the 0.05 two sided 
significance level. However, the variability of the key secondary endpoint was slightly 
greater than that originally assumed. Respectively, it was recommended, if operationally 
feasible, to increase the total sample size to a maximum of 66 subjects. 
However, based on the blinded SSRE, the pooled standard deviation of change from 
baseline for the primary endpoint was 2.64. Assuming this standard deviation and as long 
as the difference in the primary endpoint mean change from baseline to EOT between drug 
and control is at least 2.2, the power to detect treatment differences will be 82% if 
n=25/group. 
 
 
The details of the SSRE and summary of scenarios and outcomes are outlined in the SAP. 
 
 
 

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11.2 
Study Populations 
 
Assignment of subjects to analysis populations will be agreed prior to database lock and 
unblinding. 
 
The Intent to Treat Set (ITT) will include all randomized subjects. Subjects will be included 
in the analysis set according to their randomized treatment assignment regardless of actual 
treatment received. The ITT is the primary population for the analysis of efficacy data. 
 
The Safety Analysis Set (SAF) will include all randomised subjects who took at least one 
dose of IMP. The SAF will be used for all summaries of safety data. 
 
The Full Analysis Set (FAS) will include all randomised subjects in the SAF for whom any 
efficacy data were collected post randomisation. Subjects will be included in the analysis 
set according to the treatment they actually received. 
 
The Per Protocol Set (PPS) will include all subjects in the FAS who did not have any major 
protocol violations. Definitions of major and minor protocol violations will be included in 
the SAP prior to data lock and unblinding. Subjects excluded from the PPS will be 
determined prior to data unblinding. If no subjects are excluded from the PPS, the PPS will 
not be required. The PPS will be used for secondary analyses of efficacy data. 
 
The Pharmacokinetic Analysis Set (PKAS) will consist of all subjects for whom PK 
samples that were taken were analyzable and for whom the corresponding dosing 
information prior to sample collection and sample collection information is available. 
Listings of study data will be based on all subjects who were randomised into the study. 
 
 
11.3 
Demographic and Baseline Characteristics 
Summaries of demographic and baseline characteristics (including medical history, 
Congenital DM1 history, prior treatments) will be provided by treatment group and overall 
for the SAF. 
 
 
11.4 
Statistical Methods for Safety 
All safety summaries and analyses will be performed using the SAF. 
All AEs will be coded using the MedDRA dictionary and will be summarized by treatment 
using frequencies and percentages as appropriate. 

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Other safety data, including laboratory, vital signs and ECG values including change from 
baseline will be summarized. Changes in safety parameters from Baseline (
 over time 
will be described by treatment dose, and shift tables at time points of interest will be 
generated. Changes from the start of the 
 run-in period 
) to 
Baseline 
) will also be produced as indicative of the effect of two weeks of 
 
 
 
 
11.5 
Statistical Methods for Efficacy 
Primary analysis of efficacy will be based on the ITT population. Additional analysis will 
be performed based on FAS. 
The primary efficacy endpoint (CDM1-RS) will be calculated at each time point as a total 
score based on 11 domain ratings. Changes in efficacy variables from the start of the 
 
 run-in 
to Baseline 
for each subject will be summarized and will 
be considered as indicative of the effect of two weeks of 
. Changes from 
Baseline 
 to post-treatment visits will be summarized by treatment group (weight 
adjusted tideglusib 1000 mg versus Placebo) at each study visit. For the CGI-I the observed 
values will be summarized. 
Change from baseline to end of treatment will be analysed using general linear model with 
terms for treatment group, baseline and treatment group by baseline interaction (observed 
values will be analysed for the CGI-I). 
 
 
The statistical significance of changes from baseline over time may also be assessed using 
the linear mixed effects repeated measures model with fixed effect terms for treatment 
group, follow-up visit and treatment group by follow-up visit interaction. Subject will be 
included as a random effect and baseline as a covariate. 
 
 If covariates/interactions in any model are 
not statistically significant at the 0.05/0.1 two-sided levels, respectively, they will be 
excluded from the model. The details will be specified in the SAP. 
The key secondary efficacy endpoint for analysis is: 
• CGI-I at the end of treatment 
 
The secondary efficacy endpoints for analysis are: 
• The change from baseline in the Top 3 Caregiver Concerns VAS total score to end of 
treatment 
• The change from baseline in the CC-CDM1-RS total score to end of treatment 

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• The change from baseline in CGI-S to end of treatment 
• The change from baseline in the CDM1-RS independent central rater total score to end 
of treatment 
• The change from baseline in CGI-S independent central rater score to end of treatment 
• CGI-I independent central rater score at the end of treatment 
• The change from baseline in 10 Meter Walk/Run (preferred speed and fastest speed) to 
end of treatment 
 
Due to COVID-19 related restrictions some of the data at certain visits may be collected 
using a telehealth approach while other data may be collected during in-clinic visits. To 
evaluate the consistency of telehealth data and in-clinic data for the CDM1-RS and CGI 
rating scales and to minimize the potential bias, Baseline 
), Week (
) and Week 
 
) visits will be performed using both in-clinic and telehealth data collection 
approaches. The following analysis will be performed to evaluate the consistency of these 
two methods of data collection. The details of these and some other consistency analyses 
will be specified in the SAP. 
• Telehealth data will be plotted against corresponding in-clinic data for visual 
evaluation; the changes from baseline to various time points based on the 
corresponding telehealth and in-clinic data will also be plotted. 
• The various descriptive statistics for the difference between corresponding telehealth 
and in-clinic data will be evaluated; the changes from baseline for the corresponding 
telehealth and in-clinic data will be evaluated using various descriptive statistics and 
correlation analysis. 
According to the recommendations in the FDA Guidance “Statistical Considerations for 
Clinical Trials During the COVID-19 Public Health Emergency” the following sensitivity 
analyses will be performed in addition to the primary analysis performed (FDA, 2020). 
• If the data is missing due to a subject’s inability to attend clinic due to COVID-19 
related reasons, the corresponding telehealth data will be utilized, where applicable; 
the primary and key secondary analyses will then be performed. 
• If the dataset includes both in-clinic and telehealth data, the analysis stratified by the 
data acquisition method will be performed. Alternatively, the indicator variable with 
the values corresponding to the data acquisition approaches may be utilized in the 
model to determine the significance of the data acquisition impact on outcomes. 
• The missing data will be imputed using one of the imputation approaches described 
below and primary and key secondary analyses will be performed. 
The details of the sensitivity analyses will be described in the SAP. 

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As a supporting analysis, should the primary endpoint be met, the primary, key secondary 
and secondary endpoints may be evaluated using the permutation test (Berry-Kravis et al., 
2020 (accepted); Glaze et al., 2017; Jessup et al., 2011) based on the additional criteria for 
“success” specified in the SAP (for example, 3 secondary endpoints, including the key 
secondary, demonstrate numerical superiority of drug to placebo with the remaining 
secondary endpoints demonstrating non-inferiority of drug to placebo based on the pre- 
specified threshold). Full details of the resampling procedure will be included in the 
Statistical Analysis Plan. 
The exploratory endpoint analysis will be outlined in the SAP. The details of the analysis 
methods will be determined after exploratory endpoint data review. 
The following exploratory endpoints, the NIH toolbox assessments (i.e. Dimensional 
Change Card Sort Test and Picture Sequence Memory Test) and the Peabody Picture 
Vocabulary Test (PPVT) will not be completed by telehealth in the event that a subject 
cannot attend clinic due to a COVID-19 related reason, as telehealth administration is non- 
standard administration for these tests. As described above, sensitivity analyses will be 
performed on the primary, the key secondary and one secondary endpoint to support 
telehealth administration, but additional sensitivity analyses for these exploratory 
endpoints are not planned. 
A subject-level (scorecard) analysis will be performed based on the composite of primary 
and secondary endpoints (details will be provided in the SAP). 
11.6 
Missing data 
In the analysis of the primary, key secondary, and secondary endpoints, sensitivity analyses 
will be performed to examine the potential influence of missing data. Depending on the 
actual data patterns, various imputation methodologies may be employed. Multiple 
imputation methodology may be used with missing data imputed by randomized arm 
according to the within arm distribution of the observed, non-missing data. Alternatively, 
the mean value within treatment group at a given time point may be imputed. Full details 
of the approach to examine the influence of missing data will be included in the Statistical 
Analysis Plan. The missing data will not be imputed for mixed effects models. No 
imputations will be performed for per protocol analysis. 
If in-clinic data are missing due to a subject’s inability to attend clinic due to COVID-19 
related reasons, the corresponding telehealth data can be utilized instead. If both in-clinic 
and telehealth data are missing, the imputations described above may be utilized. 

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11.7 
Statistical Methods for Pharmacokinetics 
Individual pharmacokinetic data will be tabulated and concentration vs. time curves 
presented by treatment dose. Derived parameters will be summarized by dose group. 
Detailed information will be outlined in the pharmacokinetic analysis plan. 
 
 
12. END OF THE STUDY 
The end of the study is defined as the last subject’s last study assessment, which for this 
protocol is the final follow-up visit conducted 
post-treatment for those subjects 
not proceeding into the extension protocol AMO-02-MD-2-004, or the final study 
assessment for subjects who do proceed into the extension protocol. 
 
 
13. ETHICS COMMITTEE REVIEW/INFORMED CONSENT 
13.1 
Independent Ethics Committee/Institutional Review Board and 
Relevant Authorities 
The final study protocol, the parent/LAR information and consent form and the patient 
information and assent forms will be approved by an appropriately constituted independent 
ethics committee (IEC). Approval will be received in writing before initiation of the study. 
Clinical Study Authorisation will be obtained prior to initiation of the study from the 
relevant Regulatory Authority. 
 
 
13.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the local regulations, the principals of 
Good Clinical Practice (GCP) as described by the International Council on Harmonisation 
(ICH), and the ethical principles that have their origins in the Declaration of Helsinki. 
 
 
13.3 
Informed Consent and/or Assent 
For each study subject, written informed consent will be obtained from the subject’s 
parent/LAR prior to any protocol-related activities and assent obtained from the subject 
according to the local institutional policies and guidelines. As part of the informed consent 
procedure, the principal investigator or one of his/her associates will explain orally and in 
writing the nature, duration, purpose of the study, and the action of the study drug in such 
a manner that the parent/LAR is aware of the potential risks, inconveniences, or adverse 
effects that may occur. They will be informed that the subject’s medical records may be 

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reviewed by appropriately qualified monitors of the Sponsor or Sponsor Representative, 
and by auditors or regulatory authorities to ensure the accuracy of the details recorded as 
part of the study. They will be informed that they or the subject may withdraw from the 
study at any time without prejudice to further treatment. They will receive all information 
that is required by local regulations and ICH guidelines. 
 
Local institutional policies and guidelines regarding assent should be followed. 
 
 
14. STUDY AND DATA MANAGEMENT 
14.1 
Protocol Amendments 
Once approved by the Regulatory Authority and Independent Review Board (IRB)/ Ethics 
Committee (EC)/Research Ethics Board (REB), the protocol cannot be amended without 
approval by AMO Pharma Ltd. Unless a substantial amendment needs to be implemented 
urgently in the interests of safety, substantial amendments to the protocol must be 
authorized by the Regulatory Authority and IRB/EC prior to implementation. 
 
 
14.2 
Monitoring 
The investigator and institution will permit study-related monitoring, providing direct 
access to source data/documents. 
 
 
14.3 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the 
investigator and institution will permit study-related audits, IRB/IEC review, and 
regulatory inspections, providing direct access to source data/documents. 
 
 
14.4 
Data Recording 
14.4.1 Data to be Considered as Source Data 
Source data is defined as the first place that data is documented. Source data must meet the 
following “ALCOAC” principles: 
• Attributable 
• Legible 
• Contemporaneous 
• Original 

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• Accurate 
• Complete 
For this study, source data can include, but is not limited to, medical records, study specific 
source sheets (as applicable), laboratory reports, laboratory sample collection forms, ECG 
traces, clinician correspondence, subject, caregiver and clinician completed tests, scales 
and questionnaires. Source data can be recorded electronically or on paper. Electronic 
records must be in a validated system that allows ALCOAC principles to apply. 
 
 
14.5 
CRF 
An electronic Case Report Form (eCRF) will be used to capture subject data. Access to 
enter data in the eCRF will be limited to delegated and trained investigator site staff only. 
Data in the eCRF will be verified by monitors according to a risk-appropriate monitoring 
strategy. 
 
 
14.6 
Confidentiality 
The Investigator must assure that the subject’s anonymity will be maintained. On all study 
documentation, with the exception of the consent form and subject ID logs, subjects will 
only be identified by their unique identification code and will not be referred to by name. 
The Sponsor may transfer some data collected during the study to a different company or 
regulatory authority within/outside Europe for the purpose of processing, review, analysis 
or storage. Whenever the subject’s personal data is transferred, it will be kept confidential 
and secure, and will be used only for the purpose for which it was collected. 
 
 
14.7 
Retention of Study Data 
Following closure of the study, the Investigator must maintain all site study records, except 
for those required by local regulations to be maintained by someone else, in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when 
needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review 
of data in conjunction with assessment of the facility, supporting systems, and staff. Where 
permitted by local laws/ regulations or institutional policy, some or all of these records can 
be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution needs to be exercised before such action is taken. The Investigator must 
assure that all reproductions are legible and are a true and accurate copy of the originals, 
and meet accessibility and retrieval standards, including re-generating a hard copy, if 

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required. Furthermore, the Investigator must ensure there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions. 
AMO Pharma Ltd. will inform the Investigator of the time period for retaining these 
records to comply with all applicable regulatory requirements. The minimum retention 
time will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, or AMO Pharma Ltd. or delegated 
CRO’s SOPs; otherwise, the retention period will default to 25 years. 
The Investigator must notify AMO Pharma Ltd. of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the Investigator leaves the site. The Investigator may 
not dispose of any records without prior approval from AMO Pharma Ltd. 
 
 
14.8 
Communication and Publication of Results 
This study will be registered in Clinicaltrials.gov and the EudraCT database. Study results 
will be submitted to EudraCT in accordance with timelines for pediatric studies according 
to The European Clinical Trials Directive 2001/20/EC. 
In accordance with FDAAA 801 requirements this study will be registered and have results 
submitted to ClinicalTrials.gov according to the published guidelines. 
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. 
Both authors and publishers have ethical obligations. In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results. Negative as 
well as positive results should be published or otherwise publicly available. Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 
in the publication. Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
 
 
14.9 
Indemnification 
In the event of study-related damage or injuries, the public liability insurance of the 
Sponsor provides compensation for claims that arise in accordance with the regulatory 
requirements of the countries involved, except for claims that arise from wilful misconduct 
or gross negligence. A copy of the insurance certificates will be held in the Trial Master 
File and in the Investigator Site File. 

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15. REFERENCES 
 
Amer Psychiatric Pub Inc; 1st edition (July 15, 2000) 
Handbook 
of 
Psychiatric 
Measures, 
Pages 
125 
& 
126. 
ebook: 
https://www.amazon.com/Handbook-Psychiatric-Measures-CD-ROM- 
Windows/dp/0890424152/ref=pd cp 14 1?pf rd m=ATVPDKIKX0DER&pf rd p=56 
82957075090298297&pf_rd_r=01SH9XT4Z6VQ2RH7W8ND&pd_rd_wg=TRtKG&pf_ 
rd_s=desktop-dp-sims&pf_rd_t=40701&pd_rd_w=tRxcZ&pf_rd_i=desktop-dp- 
sims&pd_rd_r=73e8721c-89d6-11e8-aafc- 
3933c5359799&pd rd i=0890424152&psc=1&refRID=01SH9XT4Z6VQ2RH7W8ND 
 
Berry-Kravis E, Horrigan JP, Tartaglia N, Hagerman R, Kolevzon A, Erickson CA, Hatti 
S, Snape M, Alex, Yaroshinsky A, Stoms G, FXS-001 Investigators, Glass L, Jones NE. 
(2020). 
A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the 
Treatment of Fragile X Syndrome. 
Pediatric Neurology: accepted. 
 
Beurel E, Mines MA, Song L, Jope RS. (2012) 
Glycogen synthase kinase-3 levels and phosphorylation undergo large fluctuations in 
mouse brain during development. 
Bipolar Disord. 14:822-830 
 
Campbell G, Pennello G, Yue L. (2011) 
Missing Data in the Regulation of Medical Devices. 
J Biopharm Stat. 21 (2):180-195. 
 
Charizanis K, Lee KY, Batra R, Goodwin M, Zhang C, Yuan Y, Shiue L, Cline M, Scotti 
MM, Xia G, Kumar A, Ashizawa T, Clark HB, Kimura T, Takahashi MP, Fujimura H, 
Jinnai K, Yoshikawa H, Gomes-Pereira M, Gourdon G, Sakai N, Nishino S, Foster TC, 
Ares M Jr, Darnell RB, Swanson MS. (2012) 
Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation 
in myotonic dystrophy. 
Neuron. 75:437-450 
 
de Die-Smulders CEM, Howeler CJ, Thijs C, Mirandolle JF, Anten HB, Smeets JHM, 
Chandler KE, Geraedts JPM (1998) 
Age and causes of death in adult-onset myotonic dystrophy 
Brain. 121:1557–1563 
 
Dogan C, De Antonio M, Hamroun D, Varet H, Fabbro M, Rougier F, Amaro K, Arne Bes 
M, Bedat-Millet A, Behin A, Bellance R, Bouhour F, Boutte C, Boyer F, Campana-Salort 
E, Chapon F, Cintas P, Desnuelle C, Deschamps R, Drouin-Garraud V, Ferrer X, Gervais- 
Bernard H, Ghorab K, Laforet P, Magot A, Magy L, Menard D, Minot M, Nadaj-Pakleza 

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Page 122 of 161 
 
 
 
A, Pellieux S, Pereon Y, Preudhomme M, Pouget J, Sacconi S, Sole G, Stojkovich T, 
Tiffreau V, Urtizberea A, Vial C, Zagnoli F, Caranhac G, Bourlier C, Riviere G, Geille A, 
Gherardi RK, Eymard B, Puymirat J, Katsahian S, Bassez G (2016) 
Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity 
and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study 
PLoS ONE 11(2): e0148264. 
 
Ekström AB, Hakenäs-Plate L, Samuelsson L, Tulinius M, Wentz E. (2008) 
Autism spectrum conditions in myotonic dystrophy type 1: a study on 57 individuals with 
congenital and childhood forms. Am J Med Genet B Neuropsychiatr Genet. 147B:918-926 
 
Ekström AB, Hakenäs-Plate L, Tulinius M, Wentz E. (2009) 
Cognition and adaptive skills in myotonic dystrophy type 1: a study of 55 individuals with 
congenital and childhood forms. 
Dev Med Child Neurol. 51:982-990 
 
FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials, 2005. 
 
FDA Guidance for Industry: Nonclinical Safety Evaluation of Pediatric Drug Products. 
February, 2006. 
 
FDA Guidance for Industry: Statistical Considerations for Clinical Trials During the 
COVID-19 Public Health Emergency. June, 2020. 
 
Glaze DG, Neul JL, Percy A, Feyma T, Beisang A, Yaroshinsky A, Stoms G, Zuchero D, 
Horrigan JP, Glass L, Jones NE. (2017) 
A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the 
Treatment of Rett Syndrome. 
Pediatric Neurology. 76: 37-46. 
 
Genevieve H, Cardamone M, Farar M (2015) 
Congenital and childhood myotonic dystrophy: Current aspects of disease and future 
directions. 
World J Clin Pediatr. 4(4):66-80. 
 
Gerst JW, Brumback RA, Staton RD. (1984) 
Lithium-induced improvement of myotonia. 
J Neurol Neurosurg Psychiatry. 47:1044-1046 
 
Guy W (1976) 
Clinical global impressions. 
ECDEU assessment manual for psychopharmacology (Revised). Rockville, Maryland, 
National Institute of Mental Health: 217-221. 

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Hanger DP, Noble W. (2011) 
Functional implications of glycogen synthase kinase-3-mediated tau phosphorylation. 
Int J Alzheimers Dis. 2011:352805 
 
Heatwole CR, Bode R, Johnson N, Quinn C, Martens W, McDermott MP, Rothrock N, 
Thornton C, Vickrey B, Victorson D, Moxley R. (2012) 
Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1) 
Neurology. 2012 Jul 24; 79(4): 348–357. 
 
Heatwole CR, Eichinger KJ, Friedman DI, Hilbert JE, Jackson CE, Logigian EL, Martens 
WB, McDermott MP, Pandya SK, Quinn C, Smirnow AM, Thornton CA, Moxley RT 3rd. 
(2011) 
Open-label trial of recombinant human insulin-like growth factor 1/recombinant human 
insulin-like growth factor binding protein 3 in myotonic dystrophy type 1. 
Arch Neurol. 68:37-44 
 
Hernández-Hernández O, Bermúdez-de-León M, Gómez P, Velázquez-Bernardino P, 
García-Sierra F, Cisneros B. (2006) 
Myotonic dystrophy expanded CUG repeats disturb the expression and phosphorylation of 
tau in PC12 cells. 
J Neurosci Res. 84:841-851 
 
Höglinger GU, Huppertz HJ, Wagenpfeil S, Andrés MV, Belloch V, León T, Del Ser T; 
TAUROS MRI Investigators. (2014) 
Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a 
randomized trial. 
Mov Disord. 29:479-487 
 
 
Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo 
KM, Dittrich H, Hajjar RJ, on behalf of the Calcium Upregulation by Percutaneous 
Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators. (2011) 
Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac 
Disease (CUPID) A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic 
Reticulum Ca2+-ATPase in Patients With Advanced Heart Failure. 
Circulation. 124:304-313. 
 
Jiang Y, Bao H, Ge Y, Tang W, Cheng D, Luo K, Gong G, Gong R. (2015) 
Therapeutic targeting of GSK-3β enhances the Nrf2 antioxidant response and confers 
hepatic cytoprotection in hepatitis C. 
Gut. 64:168-179 

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Johnson NE, Butterfield R, Berggren K, Hung M, Chen W, DiBella D, Dixon M, Hayes H, 
Pucillo E, Bounsanga J, Heatwole C, Campbell C. (2016) 
Disease burden and functional outcomes in congenital myotonic dystrophy: A cross- 
sectional study. 
Neurology. 87:160-167 
 
Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, Woodgett J, Killian 
J, Timchenko NA, Timchenko LT. (2012) 
GSK-3β mediates muscle pathology in myotonic dystrophy. 
J Clin Invest. 122:4461-4472 
 
Klein PS, Melton DA. (1996) 
A molecular mechanism for the effect of lithium on development. 
Proc Natl Acad Sci U S A. 93:8455-8459 
 
Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett 
J, Song W. (2013) 
Inhibition of GSK-3β-mediated BACE1 expression reduces Alzheimer-associated 
phenotypes. 
J Clin Invest., 123(1):224-35 
 
Mathieu J, Allard P, Potvin L, Prévost C, Bégin P (1999) 
A 10-year study of mortality in a cohort of patients with myotonic dystrophy 
Neurology. 52:1658–1662 
 
Moxley RT, Logigian EL, Martens WB, Annis CL, Pandya S, Moxley RT 4th, Barbieri 
CA, Dilek N, Wiegner AW, Thornton CA. (2007) 
Computerized hand grip myometry reliably measures myotonia and muscle strength in 
myotonic dystrophy (DM1). 
Muscle Nerve. 36(3):320-8. 
 
Nakamori M, Hamanaka K, Thomas JD, Wang ET, Hayashi YK, Takahashi MP, Swanson 
MS, Nishino I, Mochizuki H (2017) 
Aberrant myokine signaling in congenital myotonic dystrophy. 
Cell Rep. 21(5): 1240–1252. 
 
Ratitch B, O’Kelly M, Tosiello R. (2013), 
Missing data in clinical trials: from clinical assumptions to statistical analysis using pattern 
mixture models. 
Pharmaceut. Statist., 12:337-347 
 
Reardon W, Newcombe R, Fenton I, Sibert J, Harper PS. (1993) 
The natural history of congenital myotonic dystrophy: mortality and long term clinical 
aspects. 
Arch Dis Child. 68:177-181 

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Rui Y, Myers KR, Yu K, Wise A, De Blas AL, Hartzell HC, Zheng JQ. (2013) 
Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase 
kinase 3β. 
Nat Commun. 4:2628. 
 
Thomas JD, Sznajder LJ, Bardhi O, Aslam FN, Anastasiadis ZP, Scotti MM, Nishino I, 
Nakamori M, Wang ET, Swanson MS (2017) 
Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy. 
Genes & Development. 31:1122-1133. 
 
Walthall K, Cappon GD, Hurtt ME, Zoetis T. (2005) 
Postnatal Development of the Gastrointestinal System: A Species Comparison. 
Birth Defects Research, (part B). 74:132-156. 
 
Wang M, Weng W, Stock L, Lindquist D, Martinez A, Gourdon G, Timchenko N, Snape 
M, Timchenko L (2019) 
Correction of Glycogen Synthase Kinase 3beta in Myotonic Dystrophy 1 Reduces the 
Mutant RNA and Improves Postnatal Survival of DMSXL 
Mice. Mol Cell Biol 39(21). 
 
Wei C, Jones K, Timchenko NA, Timchenko L. (2013) 
GSK-3β is a new therapeutic target for myotonic dystrophy type 1. 
Rare Dis. 1:e26555 
 
Weinbauer GF, Chellman GJ, Rasmussen AD, Vogelwedde E. Chapter 13: Use of Primate 
Pediatric Model, In: Pediatric Nonclinical Drug Testing: Principles, Requirements, and 
Practices. Hoberman AM and Lewis EM, eds. John Wiley & Sons, Inc., Hoboken, New 
Jersey, 2011. ebook: 
https://play.google.com/books/reader?id=5vfPOMEoGqIC&printsec=frontcover&output 
=reader&hl=en&pg=GBS.PP1. 
 
Westfall PH, Young SS. (1993) 
Resampling-based multiple testing: Examples and methods for p-value adjustment. 
Eds John Wiley & Sons. 
 
Woodgett JR. (1990) 
Molecular cloning and expression of glycogen synthase kinase-3/factor A. 
EMBO J. 9:2431-2438 
 
Yan X. (2009) 
Missing data handling methods in medical device clinical trials. 
J Biopharm Stats. 19(6):1085-98 
 
Zoetis T, Hurtt M. (2003) 

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Species Comparison of Anatomical and Functional Renal Development. 
Birth Defects Research (part B) 68:111-120 

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16. SIGNATURES AND AGREEMENT WITH THE PROTOCOL 
 
 
Sponsor Approval 
 
 
I have reviewed and approved the protocol and confirm that the protocol follows GCP. 
 

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Coordinating Investigator Approval 
 
 
I agree to conduct the study according to the terms and conditions of this protocol, current 
Good Clinical Practice and with applicable regulatory requirements. All information 
pertaining to the study shall be treated in a confidential manner. 
 
 

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Date: 
Title: 
Name of Principal Investigator: 
 
Principal Investigator Approval 
 
 
I agree to conduct the study according to the terms and conditions of this protocol, current 
Good Clinical Practice and with applicable regulatory requirements. All information 
pertaining to the study shall be treated in a confidential manner. 
 
 
 
 

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17. APPENDICES 
APPENDIX A: Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS) 

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APPENDIX B: Clinical Global Impressions (Severity and Improvement) 
 
CGI-S and CGI-I 
The Clinical Global Impression – Severity of Illness (CGI-S) and Clinical Global 
Impression – Improvement of Illness (CGI-I) are brief, easy to administer, clinician-rated 
measures (Guy, 1976). The CGI-S asks the clinician to rate the patient’s current severity 
of illness based on the clinician’s total clinical experience with the relevant population. 
The CGI-S is rated on a 7-point scale, with a range of responses from 1 (normal, not at all 
ill) through 7 (amongst the most extremely ill patients). The CGI-I asks the clinician to rate 
the patients’ total improvement since baseline, whether or not the improvement is judged 
to be due entirely to the experimental treatment. The CGI-I is rated on a 7-point scale, with 
a range of responses from 1 (very much improved) to 7 (very much worse). For both the 
CGI-S and the CGI-I, the clinician is allowed to use all available information at the time 
of the rating. 
The CGI-I has emerged as a convention for bifurcating clinical trial subjects into 
“responders” and “non-responders”. In this application, the CGI-I can be a useful tool for 
gaining a general overview of the therapeutic potential of an experimental treatment. One 
of the relative detriments of both the CGI-S and –I is the lack of the measures’ assessment 
of specific sign or symptoms associated with the disorder under study (Busner et al., 2009). 
An approach that has been developed to enhance the precision and clinical meaningfulness 
of CGI ratings is to utilize anchor points that are specific to the signs and symptoms of the 
disorder under study. 
 
 
References: 
Busner J, Targum SD, and Miller DS (2009), The Clinical Global Impressions scale: errors 
in understanding and use. Comprehensive Psychiatry 50:257-262 
Guy W (1976). Clinical global impressions. In: Guy W, editor. ECDEU assessment manual 
for psychopharmacology (Revised). Rockville, Maryland, National Institute of Mental 
Health: 217-221. 

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Clinical Global Impression – Severity of Illness Scale (CGI-S): 
“Considering your total clinical experience with myotonic dystrophy patients, how 
severely ill is this patient at this time?” 
 
1- Normal, not at all ill: The patient is indistinguishable from other individuals that do not 
have myotonic dystrophy (DM). The patient has no overt DM symptoms and no persistent 
dysfunction in the wake of having been diagnosed with DM. 
2- Borderline ill: The patient has very occasional DM symptoms that seem modestly 
excessive in intensity, frequency or duration compared to individuals that have not been 
diagnosed with DM. These symptoms have only a transient impact on functioning, with no 
need for any special intervention. 
3- Mildly ill: The patient has occasional DM symptoms that seem modestly excessive in 
intensity or duration, or the patient experiences very occasional DM symptoms that are 
modestly excessive both in intensity and duration as compared to individuals without a DM 
diagnosis. These symptoms have a limited impact on the patient’s functioning, generally 
only in one setting, and require that others make some adjustments or accommodations in 
interacting with this patient. 
4- Moderately ill: This DM patient is clearly distinguishable from other individuals because 
of his/her DM symptoms and the impairment that they cause. The patient’s DM symptoms 
are clearly excessive in frequency, intensity or duration compared to others that have not 
received a DM diagnosis, and have limited impact on the patient’s functioning in multiple 
settings or moderate impact in one setting. Caregivers, family members, teachers and co- 
workers make adjustments when interacting with this patient to avoid exacerbation of 
his/her symptoms and to deal with them when they occur. 
5- Markedly ill: This patient’s DM symptoms occur frequently and are noticeable in intensity 
or duration to even casual observers or occur infrequently but are quite intense or long- 
lasting. There is moderate impact on the patient’s functioning in multiple settings or 
extreme impact in one setting. Caregivers, family members, teachers and co-workers utilize 
interventions that are necessary in order to deal with this patient’s symptoms. Special 
accommodations related specifically to the patient’s DM symptoms are likely necessary at 
home, at school or in the workplace. 
6- Severely ill: The patient’s DM symptoms occur very frequently and are noticeable in 
intensity or duration to even casual observers or occur infrequently but are severely intense 
or extremely long-lasting. Often there is marked impairment of normal day–to–day 
capabilities or skills necessary to function at school or in the workplace. Multiple 
interventions are required to address the patient’s DM symptoms to minimize 
consequences. 
7- Among the most extremely ill patients: The patient’s DM symptoms occur the majority of 
the time and are very disruptive to functioning in multiple areas. There are very few times, 

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if any, of normal functioning. There are often serious concerns about the patient’s ability 
to provide adequate care for him/herself as a consequence of the DM symptoms. The 
patient requires almost constant monitoring by caregivers or others. 
 
 
 

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CGI—Improvement – A User’s Guide 
1. Very Much Improved designates marked improvement, across settings and/or across 
multiple problem areas. Although a CGI-I of 1 does not strictly require that the patient 
qualify for a CGI-S rating better than baseline, usually the CGI-S does also improve. Such 
improvement must be very substantial and is usually accompanied by considerable patient 
and/or caregiver enthusiasm. Such patients are usually noticeably improved in the clinic as 
well. 
2. Much Improved may denote moderate improvement in a single symptom area, especially 
if seen across settings. Likewise, moderate improvements in several areas, even if confined 
to one setting, may warrant a rating of “Much improved.” Durability of the change should 
be taken into account. For example, a change reported for the last few hours probably 
would not warrant such a rating. On the other hand, a change that was clearly in evidence 
for the last several days or longer probably would warrant a rating of 2. It is not necessary 
that the patient qualify for a CGI-S rating better than baseline to receive a CGI—I rating 
of 2, but often (not always) the CGI-S also improves. 
3. Minimal Improvement indicates modest improvements, especially if confined to one 
setting. Trivial changes or changes that are possibly present or require guesswork usually 
would be scored as 4 (the level below this one). 
4. No Change indicates, by definition, the absence of change in behavior or clinical 
presentation from baseline to subsequent assessments. Chance fluctuations and equivocal 
improvements or declines should be included here. 
5. Minimally Worse indicates some worsening in symptoms that are mild to moderate or 
may be confined to one setting. 
6. Much Worse designates moderate to moderately serve worsening. This may include 
moderate levels of worsening in a single symptom area when observed across settings. 
Moderately severe changes that are confined to one setting may warrant a rating of “Much 
Worse.” 
7. Very Much Worse designates significant worsening, across settings and/or across 
multiple symptoms. 
N.B. The CGI-I is a rating of change; normalization is not necessary for a rating of 1, 
although if the clinical presentation is unequivocally improved and is evident across 
settings, it suggests an Improvement score of 1. A CGI-I of 2 is appropriate for definite, 
unequivocal improvement of a magnitude that makes the clinician confident that the 
treatment is helping. An improvement score of 3 (or 5) is appropriate if variations in ratings 
and other criteria appear to represent more than random chance or rating error, but are not 

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APPENDIX C: Autism Behavior Inventory- Clinician (ABI-C) 
 
 

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APPENDIX D: Congenital and Childhood Myotonic Dystrophy Health Index (CC-MDHI) 
Parent Proxy Instrument 
 

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APPENDIX G: