A Single-Blind, Phase 2 Study To Evaluate The Safety And Efficacy Of Tideglusib 400mg Or 1000mg For The Treatment Of Adolescent And Adult Congenital And Juvenile-Onset Myotonic Dystrophy
Phase: PHASE2
Conditions: Myotonic Dystrophy 1
Sponsor: AMO Pharma Limited

Study Protocol 
Official Title: 
A Single-Blind, Phase 2 Study to Evaluate the Safety and Efficacy 
of Tideglusib 400mg or 1000mg for the Treatment of Adolescent 
and Adult Congenital and Juvenile-Onset Myotonic Dystrophy 
NCT Number:  
NCT02858908 
Document Date: 
09 January 2017 
 

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Protocol No.: AMO-02-MD-2-001 
 
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CLINICAL STUDY PROTOCOL 
A Single-Blind, Phase 2 Study To Evaluate The Safety And Efficacy Of Tideglusib 400mg Or 
1000mg For The Treatment Of Adolescent And Adult Congenital And Juvenile-Onset 
Myotonic Dystrophy 
EudraCT No: 2016-000067-16 
 
Protocol No.: AMO-02-MD-2-001 
 
Version No: Version 4.0 
 
Date of Protocol: 09 January 2017 
 
 
 
Sponsor:  
 
AMO Pharma Ltd. 
Throwsters, 
The Street, 
Wonersh, 
Surrey, 
GU5 0PF, 
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 Single-Blind, Phase 2 Study To Evaluate The Safety And 
Efficacy Of Tideglusib 400mg Or 1000mg For The 
Treatment Of Adolescent And Adult Congenital and 
Juvenile-Onset Myotonic Dystrophy 
PROTOCOL NO. 
AMO-02-MD-2-001 
CHIEF INVESTIGATOR 
 
SPONSOR 
AMO Pharma Ltd. 
INVESTIGATIONAL MEDICINAL 
PRODUCT  
Tideglusib 
PHASE OF DEVELOPMENT 
II 
INDICATION AND RATIONALE 
Adolescent And Adult Congenital and Juvenile Myotonic 
Dystrophy 
STUDY DESIGN 
This is a single-blind, 
 week study in adolescent and adult 
subjects with congenital or juvenile-onset type 1 myotonic 
dystrophy (DM-1). 
Approximately 16 subjects are planned to be enrolled in 
total. 
The study will have 4 distinct phases: 
 Screening (weeks 
  Subjects will be 
screened to ensure adherence to eligibility criteria. 
 
run in (weeks 
) 
 Single-blind treatment with tideglusib 1000mg (N = 
8) (Cohort 1) or 400mg (N = 8) (Cohort 2) for 12 
weeks (weeks 0 to 12) 

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 Follow-up visit 
 after end-of-treatment 
(EOT) (weeks 
) 
Data Safety Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) consisting 
of clinical and other experts will be established by the 
sponsor to review interim safety findings during the study 
and to help oversee subject safety. 
STUDY OBJECTIVES 
 
Primary objective: 
 To investigate the safety and tolerability, between 
baseline and end-of-treatment, of tideglusib in 
adolescent and adult subjects with congenital or 
juvenile-onset myotonic dystrophy. 
Secondary objectives: 
 To investigate the blood pharmacokinetics of 
tideglusib in adolescent and adult subjects with 
congenital or juvenile-onset myotonic dystrophy  
 To investigate differences in outcomes reflective of 
efficacy, between baseline and end-of-treatment, 
with tideglusib in adolescent and adult subjects 
with congenital or juvenile-onset myotonic 
dystrophy. 
STUDY ENDPOINTS 
 
Primary endpoint: 
 Incidence of adverse events (AE), including 
Serious adverse events (SAE). AEs will be 
evaluated between baseline and Follow-up Visit, 
while SAEs will be evaluated between screening 
and the last clinic visit or until resolution, 
whenever possible. The incidence of abnormal 
findings in objective assessments (e.g. laboratory 
values, ECGs, and vital signs) during the course of 
the study will also be assessed. 
Secondary endpoints: 

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 Blood pharmacokinetics (PK) of tideglusib 
 10 metre walk/run test (self-selected and fastest 
velocity) 
 Computerised handgrip myometer measure of grip 
strength and muscle relaxation time  
 Respiratory Forced Vital Capacity (FVC)  
 Dual-energy X-ray absorptiometry (DXA) whole 
body scan of lean muscle mass (g) legs, arms, and 
total 
 Clinical Global Impressions– Severity and –
Improvement (CGI-S and CGI-I) 
 Actigraphy (measure daily averages of: number of 
bouts of activity, number of steps taken and energy 
expenditure) 
 Nine Hole Peg Test (NHPT) 
 Top 3 Concerns Visual Analogue Scale (VAS) 
(caregiver-completed and where possible, also 
subject-completed)  
 OSU Autism Rating Scale (OARS) 
 OSU Autism CGI 
 Clinician-completed Domain Specific Causes for 
Concern VAS: Myotonic Dystrophy 
 Peabody Picture Vocabulary Test (PPVT) 
 
 levels and activity 
 
PLANNED SAMPLE SIZE AND 
STATISTICAL 
CONSIDERATIONS 
16 Subjects are planned to be enrolled. 
Adverse event and other safety data will be summarised as 
frequencies and percentages, and described in terms of 
severity and relationship to study treatment. Objective 
safety assessments, including laboratory and ECG values, 
will be summarised by treatment period (screening, run-in, 
 treatment) and treatment dose. Changes in safety 
parameters over time will be described, and shift tables at 
time points of interest will be generated as required. 
Analyses of changes in efficacy variables from baseline will 
be performed where applicable using repeated measures 

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analysis of covariance (ANCOVA) models with study site 
(if more than one is used) and treatment dose as fixed 
effects, and baseline value as a covariate. Least square mean 
estimates will be produced by dose group and study visit 
and will be presented with 95% confidence intervals and 
two-sided p-values. 
The safety and efficacy analyses will be specified in detail 
in the Statistical Analysis Plan (SAP). 
 
SUBJECT POPULATION 
 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
1. Subjects under study must be adolescents or adults 
with a diagnosis of congenital or juvenile-onset 
type 1 myotonic dystrophy (DM-1). For the 
purposes of this study, the following definitions 
apply: 
Congenital: in addition to the genetic 
confirmation of DM-1, one or more of 
the following signs or symptoms was 
evident within the first week after 
birth:  
a) Hypotonia 
b) Generalized weakness 
c) Respiratory insufficiency 
d) Feeding difficulties 
e) Clubfoot or another 
musculoskeletal deformity 
 
Childhood/juvenile-onset: 
in 
addition to the genetic confirmation of 
DM-1, at least 2 signs or symptoms 
(not caused by another, unrelated 
condition) were evident prior to 12 
years of age that can be clearly 
assigned to DM-1, for example: 
a) Muscle weakness 
b) Myotonia (delayed muscle 
relaxation) 

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c) Difficulty using hands, including 
fine motor problems  
d) Excessive daytime sleepiness 
e) Problems with upper or lower 
gastrointestinal functioning 
f) Problems with concentration or 
focusing (including symptoms of 
attention-deficit/hyperactivity 
disorder)  
g) Learning difficulties (including 
dyslexia) 
2. Diagnosis must be genetically confirmed 
3. Subjects must be male or female aged 12 years to 
45 years (the first 3 subjects in Cohort 1 must be 
≥18 years)  
4. Subjects must have a Clinical Global Impression – 
Severity (CGI-S) score of 4 or greater at 
 
 
5. Subjects must be ambulatory and able to complete 
the 10 metre walk/run test (splints allowed) 
6. Subject’s legally authorised representative (LAR) 
must provide written informed consent and there 
must be written consent or assent (as age 
applicable and developmentally appropriate) by the 
subject before any study-related procedures are 
conducted 
7. Subject’s caregiver must be willing and able to 
support subject’s participation for duration of study 
and if different from the LAR, must consent to this 
in writing 
 
Exclusion Criteria: 
1. Non-ambulatory (full time) wheel chair user 
2. Receiving stimulant medication 
3. Receiving other medications/therapies not stable 
(changed) within 4 weeks prior to Run-in 
 
4. Medical illness or other concern which would 
cause investigator to conclude subjects will not be 
able to perform the study procedures or 

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assessments or would confound interpretation of 
data obtained during assessment. 
5. Current enrolment in a clinical trial of an 
investigational drug or enrolment in a clinical trial 
of an investigational drug in the last 6 months 
6. Women of child bearing potential who are 
pregnant, lactating or not willing to use a protocol-
defined acceptable contraception method if 
sexually active and not surgically sterile. 
7. Men, if engaged in sexual relations with a female 
of child-bearing potential, not using an acceptable 
contraceptive method if not surgically sterile. 
8. Gastrointestinal disease which 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) cardiovascular, renal, hepatic, 
endocrine or respiratory disease 
10. Clinically significant heart disease (in the opinion 
of the investigator) or second or third degree heart 
block, atrial flutter, atrial fibrillation, ventricular 
arrhythmias, or is receiving medication for 
treatment of a cardiac arrhythmia 
11. Average QTcF value of >450msec at 
 
12. Kidney disease requiring ongoing treatment 
13. A history of chronic liver disease with current out 
of range values for ALT, clinically relevant hepatic 
steatosis or other clinical manifestations of ongoing 
liver disease 
14. Current ALT value > 2X the upper limit of the 
normal reference range at 
 
 (may repeat to confirm) 
15. Current total bilirubin value greater than the upper 
limit of the normal reference range at 
 
 
(unless due to Gilbert’s syndrome) 
(may repeat to confirm) 
16. HbA1c values greater than 6% or 42.0mmol/mol at 
 (may repeat to confirm) 

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17. TSH values outside of the normal reference range 
 
 (may repeat to 
confirm) 
18. Serum creatinine >150 µmol/L and creatinine 
clearance ≤ 60 mL/m (according to Cockcroft-
Gault formula) 
 (may repeat to 
confirm) 
19. Clinical history of hepatitis, previous or current 
positive serological evidence for hepatitis B or C 
20. Serological evidence of Hepatitis A at 
 
in the 
 preceding 
  
21. A history of significant drug allergy (such as 
Steven-Johnson syndrome, anaphylaxis)  
22. A history of alcohol or substance use disorders 
23. Current malignancy or any history of malignancy 
except for surgically-cured skin cancer or 
pilomatricoma (benign tumour of the hair follicle 
that is associated with DM-1). 
24. Severe arthritis or other medical condition (besides 
DM-1) that would significantly impact ambulation 
25. Use within 4 weeks prior to 
 of strong 
CYP3A4 inhibitors e.g. clarithyromycin, 
telithromycin, ketoconazole, itarconazole, 
posaconazole, nefazadone, indinavir, ritonavir 
26. Concurrent use of drugs metabolised by CYP3A4 
with a narrow therapeutic window e.g. warfarin 
and digitoxin 
27. 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. 
28. Hypersensitivity to tideglusib or any components 
of its formulation including allergy to strawberry 
29. BMI of less than 14.0 kg/m2 or greater than 40.0 
kg/m2 at 
 
 
TIDEGLUSIB 
FORMULATION/DOSE 
Unidose sachets of 
 and 
 dry powder to be 
 

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ROUTE OF ADMINISTRATION 
Oral suspension. 
DURATION/FREQUENCY OF 
TREATMENT 
Once Daily, 
 
. 
A 
 
 treatment phase, 
followed by 12 weeks of 1000mg tideglusib in Cohort 1 
and 400mg tideglusib in Cohort 2. 
SAFETY ASSESSMENTS 
The incidence of adverse events (AE), including Serious 
adverse events (SAE), between Screening (for SAEs) or 
Baseline (for AEs) and end-of-treatment with tideglusib 
400mg or 1000mg for 12 weeks. 
Clinical laboratory values, urinalysis, physical exam 
findings, vital signs, weight and ECG will be assessed at 
Screening, during treatment and at follow-up visit.  
EFFICACY ASSESSMENTS 
The study will evaluate the main domains of the 
phenotype of congenital and juvenile-onset myotonic 
dystrophy type 1.  These domains relate to muscle 
symptoms, CNS symptoms, disorder specific rating scales 
and biological markers pertinent to the molecular 
pathology of the disorder.  The domains will be assessed 
using the measures described below. 
 Assessments of muscle functioning and muscle 
mass: 
o 10 metre/walk run test (self-selected and 
fastest velocity) 
o Computerised handgrip myometer measure 
of grip strength and muscle relaxation time  
o Respiratory Forced Vital Capacity (FVC)  
o Actigraphy (measure daily averages of: 
number of bouts of activity, number of 
steps taken and energy expenditure)  
o Nine hole peg test (NHPT) 
o Dual-energy X-ray absorptiometry (DXA) 
whole body scan of lean muscle mass 

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 Clinician and caregiver rating scales of syndrome-
specific symptoms: 
o Clinician-completed Domain Specific 
Causes for Concern VAS: Myotonic 
Dystrophy 
o Clinical Global Impression Scales (Severity 
and Improvement) 
o Top 3 Concerns VAS (caregiver and where 
possible, subject; related to the subject’s 
myotonic dystrophy)  
 Assessments of cognitive functioning and 
associated neurodevelopmental symptoms: 
o Peabody Picture Vocabulary Test (PPVT) 
o OSU Autism Rating Scale (OARS) 
o OSU Autism CGI 
 
  
o 
 levels and activity 
 
PHARMACOKINETIC 
ASSESMENTS 
Pharmacokinetic samples will be collected for tideglusib 
and metabolite NP04113. Pharmacokinetic  samples will 
be collected at two clinic visits (Week 
 and Week 
 on each occasion two Pharmacokinetic samples 
will be taken separated by at least two hours, with the 
initial sample taken prior to the subject ingesting his/her 
daily dose of the study medication. Population 
pharmacokinetic methods of analysis will be used to 
analyze the data. If the data does not support a model on 
its own, the data may be combined with a previously 
developed model in order to strengthen the predictions. 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 will be correlated with Pharmacokinetic 
parameters estimated for each dose, if appropriate.  These 
associations may be statistically tested using correlation 
coefficients and general linear models, if appropriate. 
 
 

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STATISTICAL METHODS 
The present study is an initial Phase IIa study in a 
condition in which there are no published data that inform 
formal power analyses. Accordingly, no power analysis is 
reported here. 
Cohort 1 subject data will be analysed and evaluated once 
all subjects have completed their planned 
 
 
treatment period (or discontinued prior to 
). 
 
 
NUMBER OF STUDY CENTRES 
1-2 sites in the United Kingdom 
ESTIMATED FIRST SUBJECT 
SCREENED 
June 2016 
ESTIMATED LAST SUBJECT 
LAST VISIT 
June 2017 
 
 
 

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2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ........................................................................................................ 2 
2. 
TABLE OF CONTENTS ...................................................................................................... 14 
3. 
LIST OF ABBREVIATIONS ............................................................................................... 17 
4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE .......................................... 19 
5. 
BACKGROUND INFORMATION ..................................................................................... 21 
5.1 
Myotonic dystrophy .............................................................................................................. 21 
5.2 
Tideglusib .............................................................................................................................. 22 
5.3 
Pre-clinical Research ............................................................................................................. 23 
5.4 
Clinical Experience ............................................................................................................... 27 
5.5 
Rationale for this Study ......................................................................................................... 34 
6. 
STUDY OBJECTIVES AND PURPOSE ............................................................................. 36 
6.1 
Primary objectives ................................................................................................................. 36 
6.2 
Secondary objectives ............................................................................................................. 36 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................................ 37 
7.1 
Subject numbers .................................................................................................................... 37 
7.2 
Inclusion criteria .................................................................................................................... 37 
7.3 
Exclusion criteria .................................................................................................................. 38 
7.4 
Withdrawal criteria ................................................................................................................ 40 
8. 
STUDY DESIGN .................................................................................................................. 41 
8.1 
Primary endpoints ................................................................................................................. 41 
8.2 
Secondary endpoints ............................................................................................................. 41 
8.3 
Study design .......................................................................................................................... 42 
9. 
STUDY MEDICATION AND ADMISTRATION .............................................................. 45 
9.1 
Study medication ................................................................................................................... 45 
9.1.1 
Subjects in Cohort 1 will receive the following cartons of medication: .............................. 45 
9.1.2 
Subjects in Cohort 2 will receive the following cartons of medication: .............................. 46 
9.2 
Selection of doses in the study .............................................................................................. 46 
9.3 
Allocation to Treatment ........................................................................................................ 47 
9.4 
Study Treatment and Administration .................................................................................... 47 
9.5 
Duration of Subject Participation .......................................................................................... 48 
9.6 
Discontinuation criteria ......................................................................................................... 48 
9.7 
Treatment Accountability and Compliance Checks .............................................................. 50 
9.8 
Treatment Blinding Code ...................................................................................................... 51 
9.9 
Permitted concomitant medications/non-pharmacological therapies .................................... 51 
9.10 
Prohibited concomitant medication ....................................................................................... 51 
10. 
STUDY SCHEDULE ........................................................................................................... 52 
10.1 
Safety assessments ................................................................................................................ 52 
10.1.1 
Medical/Surgical and Medication History ........................................................................... 52 

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10.1.2 
Physical Examination ........................................................................................................... 52 
10.1.3 
Height ................................................................................................................................... 53 
10.1.4 
Weight .................................................................................................................................. 53 
10.1.5 
Adverse Event Collection..................................................................................................... 53 
10.1.6 
Vital Signs ............................................................................................................................ 54 
10.1.7 
Clinical Laboratory Evaluations........................................................................................... 54 
10.1.8 
ECG ...................................................................................................................................... 55 
10.2 
Efficacy assessments ............................................................................................................. 56 
10.2.1 
10 metre walk/run test .......................................................................................................... 56 
10.2.2 
Computerised handgrip myometer measure of grip strength and relaxation time ............... 56 
10.2.3 
Respiratory - FVC ................................................................................................................ 57 
10.2.4 
Actigraphy ............................................................................................................................ 57 
10.2.5 
Nine Hole Peg Test (NHPT) ................................................................................................ 58 
10.2.6 
Dual-energy X-ray absorptiometry (DXA) scan .................................................................. 58 
10.2.7 
Clinical Global Impressions Severity and Improvement ..................................................... 58 
10.2.8 
Top 3 Concerns VAS ........................................................................................................... 59 
10.2.9 
Clinician completed Domain Specific Causes for Concern VAS: Myotonic Dystrophy .... 60 
10.2.10 
The OSU Autism Rating Scale—DSM-IV (OARS-4) ......................................................... 61 
10.2.11 
OSU Autism CGI scale ........................................................................................................ 61 
10.2.12 
Peabody Picture Vocabulary Test ........................................................................................ 62 
10.2.13 
 ............................................................................................................................. 62 
10.2.14 
Pharmacokinetics ................................................................................................................. 63 
10.3 
Other Assessments ................................................................................................................ 63 
10.3.1 
Diary ..................................................................................................................................... 63 
10.3.2 
 .................................................................................................................. 64 
10.3.3 
Sample ........................................................................................................................ 64 
10.4 
Adverse events ...................................................................................................................... 64 
10.4.1 
Definitions ............................................................................................................................ 65 
10.4.2 
Severity Categorisation ........................................................................................................ 66 
10.4.3 
Assessment of Causality....................................................................................................... 67 
10.4.4 
Outcome Categorisation ....................................................................................................... 67 
10.4.5 
Symptoms of Disease Under Study ...................................................................................... 67 
10.4.6 
Clinical Laboratory Evaluations........................................................................................... 68 
10.4.7 
Abuse, Misuse, Overdose or Medication Error .................................................................... 68 
10.4.8 
Serious Adverse Event Reporting ........................................................................................ 68 
10.4.9 
Time Period, Frequency, and Method of Detecting AEs and SAEs .................................... 70 
11. 
STATISTICAL CONSIDERATIONS .................................................................................. 71 
11.1 
Estimated Sample Size .......................................................................................................... 71 
11.2 
Study Populations.................................................................................................................. 71 
11.3 
Demographics and Baseline Characteristics ......................................................................... 72 

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11.4 
Statistical Methods for Safety ............................................................................................... 72 
11.5 
Statistical Methods for Efficacy ............................................................................................ 73 
11.6 
Statistical Methods for Pharmacokinetics ............................................................................. 73 
12. 
END OF THE STUDY ......................................................................................................... 74 
13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT .............................................. 75 
13.1 
Independent Ethics Committee (IEC) and Relevant Authorities .......................................... 75 
13.2 
Ethical Conduct of the Study ................................................................................................ 75 
13.3 
Informed Consent and/or Assent ........................................................................................... 75 
14. 
STUDY AND DATA MANAGEMENT .............................................................................. 77 
14.1 
Protocol Amendments ........................................................................................................... 77 
14.2 
Monitoring............................................................................................................................. 77 
14.3 
Quality Assurance ................................................................................................................. 77 
14.4 
Data Recording ...................................................................................................................... 77 
14.4.1 
Data to be Considered as Source Data ................................................................................. 77 
14.4.2 
CRF ...................................................................................................................................... 78 
14.5 
Confidentiality....................................................................................................................... 78 
14.6 
Retention of Study Data ........................................................................................................ 78 
14.7 
Communication and Publication of Results .......................................................................... 79 
14.8 
Indemnification ..................................................................................................................... 79 
15. 
REFERENCES ...................................................................................................................... 80 
16. 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ........................................ 84 
17. 
APPENDICES ...................................................................................................................... 87 
17.1 
Appendix A: 10 Metre Walk Test Instructions ..................................................................... 88 
17.2 
Appendix B: Pulmonary Function Test Instructions ............................................................. 91 
17.3 
Appendix C: Nine Hole Peg Test .......................................................................................... 93 
17.4 
Appendix D: Clinical Global Impressions Severity and Improvement ................................. 95 
17.5 
Appendix E: Subject and Caregiver Top 3 Concerns ......................................................... 101 
17.6 
Appendix F: Clinician-completed Domain Specific Causes for Concern: Myotonic Dystrophy 
(VAS) .................................................................................................................................. 106 
17.7 
Appendix G: OSU Autism Rating Scale—DSM-IV (OARS-4) ......................................... 112 
 
 

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3. 
LIST OF ABBREVIATIONS 
AD 
Alzheimer’s Disease 
ADME 
Absorption, Distribution, Metabolism and Excretion 
AE 
Adverse event 
AKT 
Protein kinase B 
ALT 
Alanine amino transferase 
ANCOVA 
Analysis of Covariance 
ASD 
Autism Spectrum Disorder 
AST 
Aspartate amino transferase 
AUC 
Area Under Curve 
CGI 
Clinical Global Impression 
CGI-S 
Clinical Global Impression - Severity scale 
CGI-I 
Clinical Global Impression - Improvement scale 
Cmin 
Minimum Serum/Plasma Concentration 
Cmax 
Maximum Serum/Plasma Concentration 
CNS 
Central Nervous System 
CPK 
Creatinine Phosphokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSF 
Cerebro-spinal Fluid 
Css 
Steady State Concentration 
CTG/CUG 
Cytosine, Thymine/Uracil, Guanine nucleotides 
CTIMP 
Clinical Trial of an Investigational Medicinal Product 
CYP 
Cytochrome P450 Enzymes 
DXA 
Dual-energy X-ray absorptiometry 
DM-1 
Type 1 Myotonic Dystrophy 
DM-2 
Type 2 Myotonic Dystrophy 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
EOT 
End-of-Treatment 
FAS 
Full Analysis Set 
FVC 
Forced Vital Capacity 
FEV 
Forced Expiratory Volume 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GSK3β 
Glycogen Synthase Kinase 3 beta 
HAV 
Hepatitis A Virus 
HCV 
Hepatitis C Virus 

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ICH 
International Council on Harmonisation 
IMP 
Investigational Medicinal Product 
INR 
International Normalised Ratio 
LAR 
Legally Authorised Representative 
LFT 
Liver Function Tests 
LDH 
Lactate dehydrogenase 
MREC 
Multi-centre Research Ethics Committee 
NCE 
New Chemical Entity 
NHPT 
Nine Hole Peg Test 
OARS 
OSU Autism Rating Scale 
OSU 
Ohio State University 
PK 
Pharmacokinetics 
PKAS 
Pharmacokinetics Analysis Set 
PPS 
Per-Protocol Set 
PPVT 
Peabody Picture Vocabulary Test 
PSP 
Progressive Supranuclear Palsy 
PV 
Pharmacovigilance 
PT 
Prothrombin Time 
QTcF 
Corrected QT – Fridericia’s Formula 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T½ 
Half-life 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time to Maximum Concentration 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
 
 
 

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4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE 
List of Investigators and Affiliations 
 
 
 
  
  
  
 
 
 
Medical Monitor (Sponsor) 
Contract Research Organisation / Monitors 
Statistical Consultants 

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Pharmacovigilance 
Central Laboratory 
 
 

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5. 
BACKGROUND INFORMATION 
5.1 
Myotonic dystrophy 
GSK-3 is a serine/threonine protein kinase that recently emerged as a key target in drug discovery.  
GSK-3 has two isoforms - GSK3α and GSK3β.  GSK3β is implicated in neurodevelopmental disorders.  
GSK3β is highly expressed in brain (Woodgett, 1990) and is important in central nervous system 
(CNS) ontology (Beurel et al., 2012) and is a key signalling element in activity dependent synaptic 
plasticity (Rui et al., 2013).   
Myotonic dystrophy is a monogenetic disorder caused by expansion repeats in the DMPK gene 
(myotonic dystrophy type 1 or DM-1 or Steinert disease), which is located on chromosome 19, or the 
ZNF9 gene (myotonic dystrophy type 2 or DM-2), which is located on chromosome 3.  DM-1 most 
commonly has an onset in early adulthood, where presentation is primarily characterised by a 
progressive muscle weakness that starts in the distal musculature (lower leg, hands, neck and face).  
Adult onset DM-1 is also associated with increased risk of cataracts, cardiac conduction block, 
excessive sleepiness, attentional problems and premature baldness and infertility in males. 
DM-1 may also be present at birth (congenital myotonic dystrophy) or during childhood (juvenile 
myotonic dystrophy).  Congenital myotonic dystrophy 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 
wheel chairs.  Less than a quarter of congenital myotonic dystrophy patients were able to attend 
mainstream schooling due to intellectual disability, 15 percent were still faecally 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 reported learning disability in 95 and 89 percent of 
congenital and juvenile myotonic dystrophy patients, respectively.  Ekström et al., (2008) also reported 
that 68 percent and 50 percent, respectively, of individuals with congenital and juvenile DM-1 had an 
autism spectrum disorder. 
Whilst clinical practice commonly refers to “congenital onset” and “classical adult onset” forms of 
DM-1 myotonic dystrophy, these categorisations do not readily separate as biologically distinct 
medical entities.  Rather, there is a continuum with a greater number of expansion repeats in the DMPK 
gene being associated with earlier onset and more severe symptoms (Turner and Hilton-Jones, 2012).  
However, there is large phenotypic variation and a number of known genetic modifiers within this 
general picture.  For example, Ekström et al., (2009) define severe congenital DM-1, mild congenital 
DM-1 and childhood onset DM-1 on the basis of phenotype and age of diagnosis.  These groups have 
substantially overlapping expansion repeat numbers (median and range 1600 (730 - 2400), 1000 (130 
- 2100) and 930 (260 - 1300) for severe congenital, mild congenital and childhood groups 
respectively).  Furthermore, congenital and childhood onset DM-1 defined as having an age of onset 
between one and ten years of age share many features (Ho et al., 2015).  Therefore, it is not apparent 

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that other than age of diagnosis there are clear distinctions between congenital onset and childhood 
onset DM-1.  Conversely, the course and progression of congenital and childhood onset in later life 
parallels that of classical adult onset DM-1, albeit with emerging signs and symptoms superimposed 
on a different baseline.  Accordingly, it is not readily apparent that the different ages of onset of DM-
1 represent categorical differences, rather than a broad age and severity continuum of a condition in 
which there is substantial phenotypic variability, influenced in part by genetic mosaicism.  As 
discussed above congenital and juvenile onset DM-1 is a life threatening disorder on which less than 
half of subjects survive to adulthood, and surviving subjects reaching adulthood will develop signs and 
symptoms of the classical adult onset form, which may in turn be life limiting. Within this broad 
analysis, Reardon et al., (1993) show that after the post-natal period, the increased probability of 
mortality in congenital DM-1 increases only relatively slowly until patients reach 40 years and above. 
Given the above, the research intended by the Sponsor seeks to investigate the potential therapeutic 
utility of tideglusib in all age ranges of subjects affected by congenital, juvenile and classical adult 
onset DM-1.  The present protocol is a safety study also assessing signals of efficacy in adolescents 
and adults with DM-1 documented to have a congenital or juvenile onset.  Subject to the data obtained, 
future study will investigate the effects of this agent in children with congenital and juvenile onset 
DM-1.  We have elected to define adolescence and adulthood as meaning 12 to 45 years (post puberty).  
The justification of safety and tolerability in this age range is discussed in section 5.5. 
 
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. It is formulated as a powder for oral 
suspension filled into unit dose sachets. 
 
 The 
 obtained is orally administered to patients/subjects. 
One of the potential indications of this product is for the treatment of patients with some 
neurodegenerative disorders, such as Alzheimer’s disease (AD). However, additional indications 
where GSK-3 is implicated, such as autistic spectrum disorder (ASD), Progressive Supranuclear Palsy 
(PSP) and DM-1 may also be a target for tideglusib. Tideglusib has been subject to clinical 
investigation in AD and PSP. 
Jones et al. reported in 2012 that GSK3β mediates muscle pathology in myotonic dystrophy based on 
increased GSK3Kβ activity in DM-1 expressing cell lines, muscle biopsy samples from DM-1 
expressing transgenic mice and DM-1 patient tissue samples. Further, tideglusib and related 

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Figure 1: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  

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5.4 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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More detailed summaries of the clinical trials can be found in the Investigator Brochure. 
 
Safety Summary 
Phase I studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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In conclusion, tideglusib has been administered to 499 human subjects and has generally been well 
tolerated.  With respect to the population intended to be investigated in the present protocol, there are 
no clear safety signals that could be considered specifically relevant.  
 
  
 
 
 
 
  
 
 
 
 
 
 
Table 4: 
 
 
 
 
 
 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n 
% 
n 
% 
n 
% 
 
 
 
 
 
 
 
 
Table 6: 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
 
 
 
 
 
 
 
 
 
 

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Efficacy Summary 
 
 
 
 
 
 
 
 
 

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  These doses are also estimated to produce plasma levels of tideglusib that are in the range shown 
to be safe according to toxicology studies with the oral formulation of tideglusib intended to be used 
here.  The safety and toxicology data gathered with the proposed oral formulation to be used is 
extensive, covering mice, rat, mini-pigs and primates, for oral treatment periods of up to 
 
months.  The dose formulation is a dry powder for suspension with flavouring that is suitable for use 
in subjects that have potentially have swallowing difficulties as a consequence of DM-1 and may 
therefore not be able to manage solid dose forms. 
Pharmacokinetics: 
 
  In these studies the 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety:  Tideglusib has been administered to 499 human subjects and has generally been well tolerated.  
With respect to the population intended to be investigated in the present protocol, there are no clear 
safety signals that could be considered specifically relevant.  A
 
 
 
 
 
 
 
 
 
 
 
 
Duration: 
The duration of treatment (twelve weeks) is appropriate in light of the rapidity of onset 
of tideglusib and analogues in CNS and muscle tissue in relevant transgenic models of DM-1 and 
 (Jones et al., 2012; Franklin et al., 2013).  This duration is also less than that used 
in previous clinical studies in which the doses proposed in the present protocol were generally safe 
and well tolerated during double blind, placebo controlled administration for periods of either 
 or 
 months.  This period is longer than the period of assessment used in previous studies to show 
benefit of intervention in the DM-1 myotonic dystrophy population (Logigian et al., 2010). 

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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1 
Primary objectives 
The primary objective of this study is to investigate the safety and tolerability between, baseline and 
end-of-treatment, of tideglusib in adolescent and adult subjects with congenital or juvenile-onset 
myotonic dystrophy. 
 
6.2 
Secondary objectives 
Secondary objectives of this study are: 
To investigate the blood pharmacokinetics of tideglusib in adolescent and adult subjects with 
congenital or juvenile-onset myotonic dystrophy  
To investigate differences in outcomes reflective of efficacy, between baseline and end-of-treatment, 
with tideglusib in adolescent and adult subjects with congenital or juvenile-onset myotonic dystrophy. 
 

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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Subject numbers 
A total of 16 subjects are planned to be enrolled in the study to receive active IMP. Subjects that 
withdraw during the 
 run-in phase, will be replaced. Subjects that withdraw from the study 
after receiving active IMP, will not be replaced. 
Subject eligibility will not be re-assessed 
 run-in period; the run-in period is for the 
purposes of analysis. 
 
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 adolescents or adults with a diagnosis of congenital or juvenile-
onset type 1 myotonic dystrophy (DM-1). For the purposes of this study, the following 
definitions apply: 
Congenital: in addition to the genetic confirmation of DM-1, one or more of the 
following signs or symptoms was evident within the first week after birth:  
a) Hypotonia 
b) Generalized weakness 
c) Respiratory insufficiency 
d) Feeding difficulties 
e) Clubfoot or another musculoskeletal deformity 
 
Childhood/juvenile-onset: in addition to the genetic confirmation of DM-1, at 
least 2 signs or symptoms (not caused by another, unrelated condition) were 
evident prior to 12 years of age that can be clearly assigned to DM-1, for example: 
a) Muscle weakness 
b) Myotonia (delayed muscle relaxation) 
c) Difficulty using hands, including fine motor problems  
d) Excessive daytime sleepiness 
e) Problems with upper or lower gastrointestinal functioning 
f) Problems with concentration or focusing (including symptoms of 
attention-deficit/hyperactivity disorder)  
g) Learning difficulties (including dyslexia) 
2. Diagnosis must be genetically confirmed 
3. Subjects must be male or female aged 12 years to 45 years (the first 3 subjects in Cohort 1 
must be ≥18 years) 

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4. Subjects must have a Clinical Global Impression – Severity (CGI-S) score of 4 or greater at 
 
5. Subjects must be ambulatory and able to complete the 10 metre walk/run test (splints allowed) 
6. Subject’s legally authorised representative (LAR) must provide written informed consent and 
there must be written consent or assent (as age applicable and developmentally appropriate) by 
the subject before any study-related procedures are conducted 
7. Subject’s caregiver must be willing and able to support subject’s participation for duration of 
study and if different from the LAR, must consent to this in writing 
 
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 user 
2. Receiving stimulant medication 
3. Receiving other medications/therapies not stable (changed) within 4 weeks prior to Run-in 
(
) 
4. Medical illness or other concern which would cause investigator to conclude subjects will not 
be able to perform the study procedures or assessments or would confound interpretation of 
data obtained during assessment 
5. Current enrolment in a clinical trial of an investigational drug or enrolment in a clinical trial of 
an investigational drug in the last 6 months 
6. Women of child bearing potential who are pregnant, lactating or not willing to use a protocol-
defined acceptable* contraception method if sexually active and not surgically sterile 
7. Men, if engaged in sexual relations with a female of child-bearing potential, not using an 
acceptable* contraceptive method if not surgically sterile 
8. Gastrointestinal disease which 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) cardiovascular, renal, hepatic, 
endocrine or respiratory disease 
10. Clinically significant heart disease (in the opinion of the investigator) or second or third degree 
heart block, atrial flutter, atrial fibrillation, ventricular arrhythmias, or is receiving medication 
for treatment of a cardiac arrhythmia 
11. Average QTcF value of >450msec at 
 
12. Kidney disease requiring ongoing treatment 
13. A history of chronic liver disease with current out of range value for ALT, clinically relevant 
hepatic steatosis or other clinical manifestations of ongoing liver disease  
14. Current ALT value > 2X the upper limit of the normal reference range at 
 
(
) (may repeat to confirm) 

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15. Current total bilirubin value greater than the upper limit of the normal reference range at 
 (unless due to Gilbert’s syndrome) (may repeat to confirm) 
16. HbA1c values greater than 6% or 42.0mmol/mol at 
 (may repeat to confirm) 
17. TSH values outside of the normal reference range at 
 (may repeat to 
confirm) 
18. Serum creatinine >150 µmol/L and creatinine clearance ≤ 60 mL/m (according to Cockcroft-
Gault formula) at 
 (may repeat to confirm) 
19. Clinical history of hepatitis, previous or current positive serological evidence for hepatitis B 
or C 
20. Serological evidence of Hepatitis A at 
 or in the 
 preceding 
 
21. A history of significant drug allergy (such as Steven-Johnson syndrome, anaphylaxis)  
22. A history of alcohol or substance use disorders 
23. Current malignancy or any history of malignancy except for surgically-cured skin cancer or 
pilomatricoma (benign tumour of the hair follicle that is associated with DM-1). 
24. Severe arthritis or other medical condition (besides DM-1) that would significantly impact 
ambulation 
25. Use within 4 weeks prior to 
 of strong CYP3A4 inhibitors e.g. clarithyromycin, 
telithromycin, ketoconazole, itarconazole, posaconazole, nefazadone, indinavir, ritonavir 
26. Concurrent use of drugs metabolised by CYP3A4 with a narrow therapeutic window e.g. 
warfarin and digitoxin 
27. 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. 
28. Hypersensitivity to tideglusib or any components of its formulation including allergy to 
strawberry 
29. BMI of less than 14.0 kg/m2 or greater than 40.0 kg/m2 at 
 
 
 
* 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: 
• 
Surgical sterilisation of either the female subject in study (e.g., bilateral tubal ligation) or 
of her male partner (vasectomy with documented azoospermia) if he is the sole partner of 
that subject 
• 
Established hormonal contraception (implantable, patch, oral or intramuscular [IM]) 
administered for at least one month prior to study medication administration 
• 
An intrauterine device (IUD) or intrauterine system (IUS) with failure rate of less than 1% 
per year inserted by qualified physician at least one month prior to study medication 
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7.4 
Withdrawal criteria 
A subject should be withdrawn from treatment if they meet the discontinuation criteria in section 9.6. 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 
) 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. 
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 enrolment 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 
(section 9.10). 
 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. 
 
 
 

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8. 
STUDY DESIGN 
8.1 
Primary endpoints 
Incidence of adverse events (AE), including Serious adverse events (SAE). AEs will be evaluated 
between baseline and Follow-up Visit, while SAEs will be evaluated between screening and the last 
clinic visit or until resolution, whenever possible. 
The incidence of abnormal findings in objective assessments (e.g. laboratory values, ECGs, and vital 
signs) during the course of the study will also be assessed. 
 
8.2 
Secondary endpoints 
Secondary endpoints will include the following: 
 Blood pharmacokinetics (PK) of tideglusib 
 10 metre walk/run test (self-selected and fastest velocity) 
 Computerised handgrip myometer measure of grip strength and muscle relaxation time  
 Respiratory Forced vital capacity (FVC)  
 Clinical Global Impressions– Severity and –Improvement (CGI-S and CGI-I) 
 Actigraphy (measure daily averages of: number of bouts of activity, number of steps taken and 
energy expenditure)  
 
Nine Hole Peg Test (NHPT) 
 
Dual-energy X-ray absorptiometry (DXA) whole body scan of lean muscle mass (g) legs, arms, 
and total 
 Top 3 Concerns VAS (caregiver-completed and where possible, subject-completed also) 
 OSU Autism Rating Scale (OARS) 
 OSU Autism CGI 
 Clinician-completed Domain Specific Cause for Concern VAS: Myotonic Dystrophy 
 Peabody Picture Vocabulary Test 
 
 levels and activity 

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8.3 
Study design 
This is a single-blind, 
 week study in adolescent and adult subjects with congenital or juvenile onset 
type 1 myotonic dystrophy (DM-1).  
Approximately 16 subjects in total are planned to be enrolled and receive active IMP. 
Participation for individual subjects will consist of an initial Screening of up to weeks (minimum of 
 week) followed by a  
 treatment phase.  After this, subjects in Cohort 
1 will be treated 
 once daily orally for 12 weeks and Cohort 2 
will be treated 
 once daily orally for 12 weeks.   
Once 
out of the  subjects from Cohort 1, who have received active treatment with 1000mg of 
tideglusib, have completed or discontinued from the study (
), the DSMC will meet to review the 
available data and a recommendation will be made to the Sponsor whether Cohort 2 should be initiated.  
 
.  No screening will take place for 
Cohort 2 until after the recommendation has been made from the DSMC, to the Sponsor, on if Cohort 
2 should be initiated.  
The study will have 4 distinct phases: 
 Screening (weeks 
 
Informed consent and assent (as applicable – see section 13.3) must be performed before any 
protocol procedures are carried out. Subjects will be screened to ensure adherence to eligibility 
criteria. This must be performed at least 1 week prior to Run-in (
). Laboratory tests may be 
repeated once during the screening window if laboratory exclusion criteria are met. 
 
 run in (weeks 
) 
Subjects and their caregiver will be dispensed 
 provided with 
instructions on when and how to administer the medication. Subject diaries will be dispensed 
to record the date and time of dose, any issue with taking the dose, information on the subject’s 
 status, time of first meal after dosing and the type of food eaten.  These will be reviewed 
by the investigator site at each visit. 
 Single-blind treatment with tideglusib 1000mg (N = 8) (Cohort 1) or 400mg (N = 8) (Cohort 
2) for 12 weeks (weeks 0 to 12) 

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The initial DSMC review will take place after the 3rd subject has completed Week 
 to review all 
available safety and tolerability data available up to that point. Then the DSMC will meet at least 
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 to suggest changes to the protocol e.g. replacement of subjects if appropriate.  Based 
on the results of their data reviews, the DSMC will submit its recommendations in written form to the 
sponsor who is charged with responding to the recommendations of the DSMC and to take appropriate 
action. 
The DSMC will have an additional meeting to review data from Cohort 1 prior to any screening of 
subjects for Cohort 2. This additional meeting will be triggered once 
, 
 
 
), but will include all Cohort 1 data available. 
 

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doses are also estimated to produce plasma levels of tideglusib that are in the range shown to be safe 
according to toxicology studies with the oral formulation of tideglusib intended to be used here.  The 
safety and toxicology data gathered with the proposed oral formulation to be used is extensive, 
covering mice, rat, mini-pigs and primates, for oral treatment periods of up to 
months.  The 
dose formulation is a dry powder for suspension with flavouring that is suitable for use in subjects that 
potentially have swallowing difficulties as a consequence of DM-1 and may therefore not be able to 
manage solid dose forms. 
As described above, the first cohort of subjects in this study will be dosed with 1000mg of tideglusib 
given orally once daily.  This dose has previously been shown to be generally safe and well tolerated 
over periods of administration longer than presently proposed. As additional safeguards, sentinel 
dosing of the first 3 subjects in Cohort 1 has been included in the study design with these first 3 subjects 
needing to be ≥18 years old and a DSMC will be in place. 
 
 
 
 
 
 
  
 
9.3 
Allocation to Treatment 
This study is single-blind, where the Sponsor/delegate and the Investigator site will know what 
treatment the subjects is receiving at each point during the study, but the subject and caregiver will be 
blinded to know if they are receiving active or placebo. Subjects will be allocated into Cohort 1 
(1000mg) or 2 (400mg) in sequence. 
 
9.4 
Study Treatment and Administration 
IMP and placebo will be administered orally once daily by dispersing one or two sachets (depending 
on dose) in 
 
. 
The IMP must be administered in an 
; 
 
 

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The whole content of the sachet(s) should be a
 
 
. 
The date and time 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). 
 
9.5 
Duration of Subject Participation 
The overall expected duration of subject participation is 
 weeks.  Subjects undergo up to 
 week 
screening period, followed by a
 
.  Subjects will then receive 
 treatment for up to 12 weeks. There will be a follow-up visit at week 
 
(approximately 
 after the last dose). 
 
9.6 
Discontinuation criteria 
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 within 
, and at 
that time, repeat blood work will be obtained (e.g. 
 
 
, 
 
 a physical examination will be conducted, 
and the protocol-defined study assessments for end-of-treatment will be completed. 
 

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At each visit, the subject diary will be reviewed and compared to the accountability evidence to further 
ascertain compliance and ensure dose times are recorded for PK sample visits (Week 
 and Week 
 
 of IMP from 1000mg to 400mg, the number of sachets for both 
 
or placebo and 
 or placebo should be counted and documented in medical notes before returning 
the 
 sachets to the subject and caregiver. 
 
9.8 
Treatment Blinding Code 
The study is single-blind, with the subject/caregiver/LAR being blind to whether the subject is 
receiving placebo or active medication. Therefore a blinding code will not be required. 
 
9.9 
Permitted concomitant medications/non-pharmacological therapies 
All concomitant medications and non-pharmacological therapies (e.g. physiotherapy, yoga) taken or 
implemented during the study will be recorded in the CRF with indication, dose information, frequency 
and dates of administration as applicable. 
Any permitted medication or therapy that the subject was taking on entry to the study should be 
continued at the same dose (as applicable) and frequency throughout the study. 
If the subject is taking 
 
. 
 
9.10 
Prohibited concomitant medication 
Strong CYP3A4 inhibitors e.g. clarithyromycin, telithromycin, ketoconazole, itarconazole, 
posaconazole, nefazadone, indinavir, ritonavir are not permitted during this study.  
Stimulant medication is not permitted during the study. 
Drugs metabolised 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. 
 
 

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10. 
STUDY SCHEDULE 
Refer to Table 1 for a schedule of assessments for each timepoint. 
 
10.1 
Safety assessments 
All assessments will be performed by the investigator or appropriately delegated and trained personnel. 
 
10.1.1 
Medical/Surgical and Medication History 
The investigator must record all medically and clinical relevant information regardless of the time 
since the date of diagnosis 
History should include (but is not limited to): 
- 
All current and past medications taken during 1 year before the Screening Visit 
  
- 
All current and past non-pharmacologic therapies taken 3 months before the Screening Visit 
 
- 
History of respiratory, cardiovascular, renal, gastro-intestinal, hepatic, endocrine, 
haematological, neurological, psychiatric and any other diseases 
 
10.1.2 
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 (including new and worsening 
findings) between the Screening Visit 
 and Run-in Visit 
will be recorded either on the 

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medical/surgical history CRF page if a non-serious medical occurrence, or as a baseline sign or 
symptom if a non-serious sign or symptom. Any changes between the Run-in Visit 
and end of 
study should 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. 
 
10.1.3 
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. 
 
10.1.4 
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 0.1kg.  Bulky items should be 
removed whenever possible to ensure the most accurate weight is recorded. 
 
10.1.5 
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?” SAEs will be collected from the time of 
informed consent. Non-serious AEs will be collected from the time of single-blind dosing.  Any non-
serious medical occurrences occurring between Screening 
and Run in 
will be recorded as 
Medical/Surgical History. Any non-serious signs and symptoms occurring between Screening 
 
and Run in 
) will be recorded and classified as baseline signs and symptoms. Refer to section 10.4 
for additional details of AE collection and reporting. 
 

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10.1.6 
Vital Signs 
Vital signs will include the following measures: oral 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. 
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. 
 
10.1.7 
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.  
Biochemistry 
A biochemistry sample will be collected at every visit. Biochemistry blood samples can be drawn with 
the subject in either a fasting or non-fasting state (this state should be kept consistent for blood 
sampling throughout the study).  If a sample needs to be repeated, the subsequent sample should be 
drawn from the subject in the same fasting/non-fasting state. 
The biochemistry analysis will include 
 
  
At screening 
 biochemistry sample will also be 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 is obtained 
indicating an active Hepatitis C infection, the result will need to be confirmed and a further 4mL blood 
sample will be collected from the subject.  

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Additionally, at screening 
, run-in 
, baseline 
Week  
 and EOT, it should also be 
requested to get a 
 analysed. 
Haematology 
A full blood count with differential should be collected at each visit. This should include 
 
 
Additionally, at screening 
 baseline 
, Week 
and EOT, 
 should also be analysed. 
 
 
 
Urinalysis 
Urinalysis will be performed by dipstick and documented in source documents. Abnormal results 
should be investigated further by sending to the study 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. 
 
10.1.8 
ECG 
The HR, PR interval, QRS interval, and QT interval will be measured and QTcB and QTcF will be 
calculated for all ECGs. 
Subjects will be assessed in a quiet state (after 5 minutes of rest) in the supine position. A standard 
ECG recording device will be used with the standard paper rate of 25 mm/second and the standard 
scale setting of 10mm/volt. 
Three ECGs will be obtained at the Screening Visit 
to determine subject eligibility.  For all other 
visits, where ECG is requested according to schedule of assessment, these will also be performed in 
triplicate (ideally separated by at least five minutes) with the average values calculated and 
documented prior to recording in the eCRF. 
 

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10.2 
Efficacy assessments 
All assessments will be performed by the investigator or appropriately delegated and trained personnel. 
The study will evaluate the main domains of the phenotype of congenital and juvenile-onset DM-1.  
These domains relate to muscle symptoms, CNS symptoms, disorder specific rating scales and 
biological markers pertinent to the molecular pathology of the disorder.  Each domain will be assessed 
using the measures described below. 
Assessment of Muscle Functioning 
10.2.1 
10 metre walk/run test 
The 10 metre walk/run test is a performance measure used to assess walking speed in metres per second 
over a short distance. It can be used as an assessment of functional mobility. The test will be conducted 
according to the schedule of assessments (Table 1) and will be performed at the subject’s preferred 
walking speed and then at the fastest speed possible.  For each speed, 3 assessments will be completed 
with a rest period until the subject has recovered. 
The subject walks without assistance for 12 metres while the time taken to walk from metre 1 to meter 
11 is recorded. The timing starts and stops when the toes of the leading foot cross the 1 and 11 metre 
marks respectively. If assistive devices are needed, these can be used but 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 
assessments, this will also be recorded. 
Appendix A provides further information on the test including verbal instructions to give to the subject. 
 
10.2.2 
Computerised handgrip myometer measure of grip strength and relaxation time 
Handgrip myometry is used as a measure of myotonia and muscle strength and has been validated as 
a reliable measure in patients with myotonic dystrophy type 1 (Moxley et al., 2007). 
The force of concentration exerted on the handle of a handgrip dynamometer is measured in addition 
to the time of contraction and relaxation. A computer stores the force curves for analysis to calculate 
the force of contraction/grip strength (Kg) and the time taken for the hand to relax from 90% contracted 
to 5% contracted (seconds).  

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Each assessment session consists of two trials per hand, each with three squeezes (maximum voluntary 
isometric contraction) on the handgrip dynamometer. Sessions are performed in accordance with the 
schedule of assessments. Both hands will be assessed. 
The tester will allow an adequate amount of time after the first squeeze for the force curve to return to 
and remain at the level at the beginning of the trial (approx. 20 seconds) prior to proceeding with the 
remaining two grip contractions within the trial. The subsequent two squeezes will be approximately 
3 seconds of contraction followed by 10 seconds of relaxation.  After the first trial (3 squeezes), the 
subject will rest that hand for approximately one minute. While one hand is recovering, the other hand 
can be tested. 
 
10.2.3 
Respiratory - FVC  
Forced Vital Capacity (FVC) is a measure of lung function which is obtained via spirometry.  FVC is 
the total amount of air exhaled during a Forced Expiratory Volume (FEV) test using a spirometer. 
Measurements will be taken according to the schedule of assessments. 
The subject should be sitting in a chair for the test.  The evaluator will either explain or demonstrate 
the procedure to the subject and explain that they will be performing the test at least 3 times.  The 
specific wording of instructions is detailed in Appendix B. 
The test should be repeated at least 3 times, making sure that the subject has recovered between 
attempts.  If at each attempt there is an improvement in the results, further tests can be conducted until 
the subject has achieved his/her best result. 
 
10.2.4 
Actigraphy 
Actigraphy is a non-invasive method of monitoring physical activity via an actigraph device. The 
Actigraph device will be worn on the waist during waking hours, according to the device’s instruction 
manual. 
In this study, actigraphic assessments will occur on a regular basis throughout the study as detailed in 
the schedule of assessments. Each assessment will consist of approximately 7 full days of activity 
information from subjects, and this information will be used to calculate the average number of steps 
per day, bouts of activity and total energy expenditure. 
 

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10.2.5 
Nine Hole Peg Test (NHPT) 
The NHPT is a measure of fine manual dexterity.  
The NHPT is composed of a square board with 9 pegs. At one end of the board are holes for the pegs 
to fit into, and at the other end a shallow round dish to store the pegs. The NHPT is administered by 
asking the subject to take the pegs from a container, one by one, and placing them into the holes on 
the board as quickly as possible.  Subjects must then remove the pegs from the board, one by one, and 
replace them back in the container.   
Subjects are scored on the time taken to complete the activity in seconds. Timing begins when the 
subject touches the first peg and finishes when the last peg hits the container. 
Both the dominant and non-dominant arm should be tested; the dominant hand should be tested first. 
One practice trial should be completed with each hand prior to performing the actual test, which will 
include 1 attempt with each hand. The evaluator should demonstrate the test to the subject prior to the 
practice test and should be sitting next to the subject. 
The NHPT will be administered in accordance with the schedule of assessments.  Detailed instructions 
on the NHPT are contained in Appendix C.  
 
10.2.6 
Dual-energy X-ray absorptiometry (DXA) scan 
DXA (previously DEXA) utilises two low energy X-ray beams, with different energy levels, which 
are aimed at the subject’s bones.  The DXA scan is more typically used to measure bone mineral 
density, however it can also be used to measure total body composition, lean muscle mass and fat 
content. The amount of radiation used in a DXA scan is very low. 
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. The DXA scans will be administered in accordance 
with the schedule of assessments. 
 
Clinician and caregiver rating scales of syndrome-specific symptoms  
10.2.7 
Clinical Global Impressions Severity and Improvement 
The clinician administered Clinical Global Impressions of Severity (CGI-S) and Improvement (CGI-
I) scale (Guy, 1976) will be performed in accordance with schedule of assessment (Table 1).  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 assessments. 

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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 requires the clinician to rate how much the subject’s illness has improved or worsened 
relative to a baseline state.  A seven point Likert type scale is used from 1 = very much improved, 2 = 
much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = 
very much worse. 
The CGI-I at Baseline 
should be rated against the CGI-S at Run-in 
 For subsequent CGI-I 
ratings completed from Week  
 onwards, the assessment should be compared against the CGI-S, 
done at Baseline 
  
In this study, a standard set of probes/prompts will be provided to the sites to assist the evaluator in 
eliciting commentary from the subject or their caregiver across each of the core domains and also on 
associated symptoms.  Every effort will be made so that the same evaluator will also observe the 
subject at each visit to the clinic. 
As part of the physician evaluation of the subject for the CGI-S and CGI-I ratings, if additional 
information is volunteered by the subject and/or caregiver which the physician feels supports the 
ratings, but is not captured elsewhere in the CRF, this information will be recorded in the source and 
captured within a comments field within the eCRF. 
A copy of the CGI-S and CGI-I to be used in the study, along with instructions is included in Appendix 
D. 
 
10.2.8 
Top 3 Concerns VAS 
The Top 3 concerns VAS allows subjects and caregivers to identify their main three causes of concern, 
related to the subject’s myotonic dystrophy, rather than these being pre-specified within a scale and 
then rating how these concerns have changed at specific time-points during the study. 
Subjects, where possible, and caregivers will be asked to rate three causes for concern by drawing a 
vertical mark on a 10cm long visual analogue scale with anchors of “not at all severe” at the left end 
and “very severe” at the right end. 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 at Week 
 and EOT 
using the same scales. 
A copy of the Top 3 concerns VAS is included in Appendix E. 

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10.2.9 
Clinician completed Domain Specific Causes for Concern VAS: Myotonic Dystrophy  
The Clinician-completed Domain Specific Concerns is a Visual Analogue Scale (VAS) completed by 
the clinician that scores the severity of concerns in the following domains that are clinically relevant 
in myotonic dystrophy: 
o Limitations with mobility or walking 
o Problems with hands or arms 
o Inability to do activities 
o Fatigue 
o Pain 
o Gastrointestinal issues 
o Problems with vision 
o Communication difficulties 
o Impaired sleep or daytime sleepiness 
o Emotional issues 
o Difficulty thinking 
o Decreased satisfaction in social situations 
o Decreased performance in social situations 
o Myotonia 
o Breathing difficulties 
o Choking or swallowing issues 
o Hearing difficulties 
This list of domains is derived from the 17 subscales of the Myotonic Dystrophy Health Index (MDHI) 
(Heatwole et al., 2014). The severity of the clinician’s concern in each domain is scored by using a 
10-cm visual analogue scale (VAS), with anchors of “not at all severe” at the left end and “very severe” 
at the right end. The clinician is asked to make a vertical line indicating his/her level of concern in 
each domain, using a time frame of the past week for reference. A score for each domain is determined 
by measuring the number of centimetres on the 10-cm VAS line from the anchor point on the left side 
of the line. A total VAS score for each subject is calculated as the sum of the scores for the 17 domains 
and is reported as both an absolute number and a percentage of the total possible line length (e.g. 170 
cm). 
The Clinician-completed Domain Specific Causes for Concern-VAS: Myotonic Dystrophy will be 
administered according the schedule of assessments. 
A copy of the Clinician Domain Specific Causes for Concern VAS: Myotonic Dystrophy is included 
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Assessments of cognitive functioning and associated neurodevelopmental symptoms 
10.2.10 
The OSU Autism Rating Scale—DSM-IV (OARS-4)  
The OARS-4 contains the autism signs and symptoms in the Diagnostic and Statistical Manual of 
Mental Disorders, 4th Edition (DSM—IV). These should be rated with the degree of impairment the 
subject experiences for the given symptom. The symptoms should be elicited in a semi-structured 
interview with the subject’s primary caregiver. While scoring, the assessor should try to take both 
frequency/duration and degree of impairment into account as well as how much the item interferes 
with relationships, learning, and/or activities of daily living. Thus, rituals or preoccupations that 
severely interfere with most attempts to transition or that are present most of the time should be scored 
2 or 3. Conversely, a ritual or preoccupation that is very mild, occupies little time, and interferes only 
mildly with daily events may be scored as 1. 
The OARS-4 provides two summary scores (a) A weighted score based on severity of autism or autism 
spectrum symptoms derived from the clinical interview and (b) A symptom count, based on the same 
clinical interview 
The OARS-4 should be completed according to the schedule of assessments, a copy of the scale is 
included in Appendix G. 
 
10.2.11 
OSU Autism CGI scale 
The OSU Autism CGI scale contains separate subscales for symptom severity and for global 
improvement. These are rated in a similar way to the NIMH CGI Severity scale (see Clinical Global 
Impressions Severity and Improvement section in 10.2.6), but it is focused on autism spectrum 
symptoms. Symptoms frequently associated with autism spectrum—such as compulsions, 
hyperactivity, and self-injury should also be considered. 
The CGI-I at Baseline (
) should be rated against the CGI-S at Run-in (
). The subsequent CGI-I 
ratings should be compared against the second CGI-S, done at Baseline (
). 
The OSU Autism CGI scale provides 2 summary score (a) A global severity scale for autism, which 
takes autism spectrum and related symptoms (e.g., compulsions, problems transitioning, SIB) into 
account; and (b) A global improvement scale for autism. 
The OSU Autism CGI scale (CGI-S and CGI-I) should be completed according to the schedule of 
assessments, a copy of the scale is included in Appendix G. 
 

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10.2.12 
Peabody Picture Vocabulary Test 
The PPVT–4 scale is a norm-referenced instrument for measuring the receptive (hearing) vocabulary 
of children and adults. It contains training items and 228 test items, each consisting of four full-colour 
pictures as response options on a page. For each item, the examiner says a word, and the examinee 
responds by selecting the picture that best illustrates that word’s meaning. 
Each administration of the test produces a raw score 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 test will be performed at Run-in 
 Baseline 
and End-of-Treatment 
to compare 
scores prior and after single-blind placebo and single-blind tideglusib respectively. 
 
10.2.13 
 
 
  
A 4ml blood sample will be taken for 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Details on collection, handling, storage, processing and shipment of the 
sample will be 
provided in a separate laboratory manual. 
 

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10.2.14 
Pharmacokinetics 
 PK samples will be collected for tideglusib and the major metabolite NP04113 at both 
 
 
 
 
  
 
. 
 
 
 
 
Individual concentration data will be determined and Tmax, T½, AUC(0-12hr), Cmax, Cmin and Css will be 
calculated. Population pharmacokinetic methods of analysis will be used to analyze the data. If the 
data does not support a model on its own, the data may be combined with a previously developed 
model in order to strengthen the predictions. 
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 PK parameters estimated for each dose.  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. 
 
10.3 
Other Assessments 
10.3.1 
Diary 
A diary will be provided to the subject/caregiver at each visit from Run-in 
 to Week
 which 
should be completed every day. The diary should be returned at each subsequent visit and the diary 
should be reviewed by a delegated member of the study team. 
The diary should be completed in full so that the following can be ascertained: 
- 
Time and date of each dose 
- 
If there was any issue with taking the dose  
- 
Whether the subject 
 
- 
Time of 
 
- 
Type of food 
 

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If any information is missing, this should be discussed with the caregiver so that missing information 
can be completed from the caregiver’s recollection. It must be documented in the medical notes which 
information has been completed retrospectively. 
The diary review should be performed in parallel with checking returned used and unused sachets of 
IMP. 
 
10.3.2 
 
For purposes of inclusion in the study, subjects need to have a confirmed genetic diagnosis of myotonic 
dystrophy type 1
 
 
 
 
Where possible and with additional consent,
 
 
Instructions for the collection, handling, storage, processing and shipment of the 
 
will 
be provided in a separate laboratory manual. 
 
10.3.3 
 
A 5ml blood sample will be taken for 
 analysis at the timepoints described in the 
schedule of assessments.  
Instructions for the collection, handling, storage, processing and shipment 
 
 will be 
provided in a separate laboratory manual. 
 
10.4 
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. 
 

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10.4.1 
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 unfavourable 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 and 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 
 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 hospitalisation or prolongation of existing hospitalisation (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 hospitalisation, but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above may be considered a 
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Hospitalisations are defined as initial or prolonged admissions that include an overnight stay. 
Hospitalisation or prolonged hospitalisation 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 10.4.8. 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. 
Due to the disease under study and the potential intellectual disability of the study subjects, along with 
the age of some of the potential study subjects, information on how and to whom, a positive pregnancy 
result will be communicated will be addressed in the study information sheet. 
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 Investigational Medicinal Product). 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
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. 
 
10.4.2 
Severity Categorisation 
The severity (intensity) of each AE will be classified as: 
 Mild  
Awareness of sign or symptom, but easily tolerated 

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 Moderate 
Sign or symptom causes discomfort, but does not interfere with normal 
activities 
 Severe  
Sign or symptom of sufficient intensity to interfere with normal activities 
A change in severity should be captured as a new AE. 
 
10.4.3 
Assessment of Causality 
A delegate physician/investigator 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 
 
 
10.4.4 
Outcome Categorisation 
All AEs should have an outcome recorded, which should be updated if it changes during the reporting 
and follow-up period (defined in section 10.4.9). The possible outcomes should be: 
 Fatal 
 Recovered/Resolved 
 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 DSMC. 
 
10.4.5 
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) should not be classed as AEs as long as they are within 
the normal day to day fluctuation or expected progression of the disease; however, significant 
worsening of the symptoms should be recorded as an AE. 
 

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10.4.6 
Clinical Laboratory Evaluations 
Abnormal laboratory findings (e.g. haematology, liver function, biochemistry, urinalysis) or other 
abnormal assessments (e.g. ECGs, vital signs) that are judged by the Investigator as clinically 
significant will be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 
10.4.1  
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 (especially LFT abnormalities) will be followed up 
until recovery or stabilisation of the condition. 
 
10.4.7 
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 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. 
 
10.4.8 
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  

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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 authorised 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 10.4.3 of this protocol. 
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 
 follow-up visit 
 will be followed until resolution or 
stabilisation of subject condition, whichever occurs first. In such cases, follow-up SAE forms will be 
completed at the 
 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). 
SAE email contact: 
SAE Fax number: 
SAE Telephone contact: 
 
Medical monitor contact: 

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All SAE and AE data will be reviewed by the 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, including the European Commission Clinical Studies 
Directive (2001/20/EC). 
All investigators will receive a safety letter notifying them of relevant SUSAR reports.  In accordance 
with the European Commission Directive 2001/20/EC, AMO Pharma Ltd or delegate will notify the 
relevant Ethics Committees in concerned Member States 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. 
 
10.4.9 
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 obtained) that do not result in the exclusion of the subject from 
participating in the study, should be recorded as Medical/Surgical History.  In addition, any non-
serious medical occurrence which is reported after informed consent is obtained, but prior to the subject 
receiving single-blinded study medication, should be documented as Medical/Surgical History. 
Medical occurrences that meet the definition for an SAE should be recorded and reported as an SAE.  
Any non-serious signs and symptoms present at the time before the first dose of single-blinded study 
medication is administered should be documented as baseline signs and symptoms.  If a baseline sign 
or symptom worsens following dosing, then this should be recorded as an AE or SAE.  
All AEs occurring after administration of the dose of single-blinded study medication 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. 
 
 
 

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11. 
STATISTICAL CONSIDERATIONS 
Details of all planned analyses will be specified in a separate statistical analysis plan (SAP) which will 
be finalised 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. An analysis and evaluation of study data will be performed once all 
subjects in Cohort 1 have either completed or discontinued from active treatment. The analysis and 
evaluation will be performed on a subset of the study data as described in the SAP.  
The study data will be reported using summary tables, figures and data listings. Continuous variables 
will be summarised using mean, standard deviation (SD), coefficient of variation (CV%, as 
appropriate), median, minimum, maximum and, as appropriate, geometric mean. Categorical variables 
will be summarised by presenting the number (frequency) and percentage in each category.  Separate 
summaries will be provided for subjects in each dose group, as well as overall. 
Statistical analyses will be performed using methods and modelling techniques which are appropriate 
for the types variables (continuous, categorical, ordinal, binary, censored etc.) being analysed and 
which account for the data structure (e.g. study visits and assessments, methods for handling missing 
data) and known potential confounding data (e.g. baseline characteristics, treatment dose).  Estimates 
will be presented with appropriate two-sided 95% confidence intervals. The results of statistical tests 
will be presented with two-sided p-values.  
Subjects who 
 
 will be classified as screening failures. Subjects who 
 will be classified 
as run-in failures. 
 
11.1 
Estimated Sample Size 
Sufficient subjects will be entered into the study to ensure at least 16 are dosed with tideglusib. 
Enrolment will occur at one, or maybe two, study sites.  Eight subjects will be dosed in each of the 
two dose groups. 
No formal sample size calculation was performed. 
 
11.2 
Study Populations 
Assignment of subjects to analysis populations will be agreed prior to database lock. 

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The Safety Set (SAF) will include all subjects who took at least one dose of tideglusib.  The SAF will 
be used for all summaries of safety data. 
The Full Analysis Set (FAS) will include all subjects in the SAF for whom any efficacy data were 
collected after first dose of tideglusib.  The FAS is the primary population for analyses of efficacy 
data. 
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.  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  Pharmacokinetic 
samples were taken for the derivation of  Pharmacokinetic parameters and for whom the corresponding 
time since last dose prior to sampling is available. 
Listings of study data will be based on all subjects who were enrolled in the study.  
 
11.3 
Demographics and Baseline Characteristics 
Summaries of demographic and baseline characteristics (including medical history, DM-1 history, 
prior treatments) will be provided by treatment dose 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 summarised by treatment using 
frequencies and percentages as appropriate.  
Other safety data, including laboratory, vital signs and ECG values including change from baseline 
will be summarised. 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 
 of 
 treatment. 
 

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11.5 
Statistical Methods for Efficacy 
Analyses of efficacy will be based primarily on the FAS. 
Changes in efficacy variables from the start of the 
 run-in 
to baseline 
 
for each subject will be summarised and will be considered as indicative of the effect of 
 of 
 treatment. Changes from baseline 
to post-treatment visits will be summarised by 
treatment dose at each study visit. 
Analyses of changes from baseline will be performed where applicable using repeated measures 
analysis of covariance (ANCOVA) models with study site (if more than one is used) and treatment 
dose as fixed effects, and baseline value as a covariate. Least square mean estimates will be produced 
by dose group by study visit and will be presented with 95% confidence intervals and two-sided p-
values. 
 
11.6 
Statistical Methods for Pharmacokinetics 
Individual concentration data will be tabulated and concentration vs. time curves presented by 
treatment dose if warranted.  Derived parameters will be summarised by dose group. Detailed 
information will be outlined in the pharmacokinetic analysis plan. 
 
 
 

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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. 
 
 

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13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT 
13.1 
Independent Ethics Committee (IEC) and Relevant Authorities 
The final study protocol, the patient assent and consent forms and the caregiver/guardian information 
and consent form 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 legally authorised 
representative (LAR) prior to any protocol-related activities.  Where the subject lacks the mental 
capacity to give informed consent, the LAR will be acting as the subject’s consultee. The consultee 
must be informed that, when being asked to act as a consultee for a person who lacks mental capacity, 
they are being asked to consider what they believe the potential subject would have decided 
themselves, had they the mental capacity to give informed consent. The personal consultee must 
themselves have capacity and be prepared to be consulted by the researcher about the possible 
involvement of the subject who lacks capacity. 
As part of this procedure, the principal investigator or one of his 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 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 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. 

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The subject will provide assent or informed consent depending on the subject’s age and on the 
investigator’s assessment of what is developmentally appropriate. This must be documented prior to 
any protocol-related activities being conducted. 
For subjects under 16 years old, a children’s assent form and information sheet should be used in 
conjunction with parent/guardian Informed Consent Form. 
For adults (16 years or older), the investigator or delegated sub-investigator must assess the subject’s 
capacity to consent. Then, the appropriate Participant Information Sheet and Informed Consent Form 
or Assent Form should be used. 
The assessment of capability to consent should be done following guidelines in the Clinical Trials 
Regulation for CTIMPs. Consent from the LAR remains valid but the participant should be informed 
and his/her wishes respected for inclusion and withdrawal to this study. 
If the person providing day to day care for the subject and, will be fulfilling the role of caregiver in 
this study, is not the appropriate person to give consent on behalf of the subject or act as their consultee, 
consent will also be obtained from the caregiver for their own participation in the study.  In this case, 
the LAR will consent for the patient to take part in the study while the caregiver will consent to their 
own involvement. 
 
 

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14. 
STUDY AND DATA MANAGEMENT 
14.1 
Protocol Amendments 
Once approved by the Regulatory Authority and Ethics Committee, 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 authorised by the 
Regulatory Authority and Ethics Committee 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 
“ALCOA” principles: 
- 
Attributable 
- 
Legible 
- 
Contemporaneous 
- 
Original 
- 
Accurate 
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 ALCOA principles to apply. 

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14.4.2 
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.  
 
14.5 
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 initials 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. 
 
14.6 
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 
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 15 years. 

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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. 
 
14.7 
Communication and Publication of Results 
This study will be registered in the EudraCT database. A clinical study report will be submitted to 
EudraCT in accordance with timelines for paediatric studies according to The European Clinical Trials 
Directive 2001/20/EC. 
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. 
 
14.8 
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 
 
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Glycogen synthase kinase-3 levels and phosphorylation undergo large fluctuations in mouse brain 
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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. 
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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 
 
Franklin AV, King MK, Palomo V, Martinez A, McMahon LL, Jope RS.  (2014) 
Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in 
fragile X mice. 
Biol Psychiatry. 75:198-206 
 
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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Heatwole C, Bode R, Johnson N, Dekdebrun J, Dilek N, Heatwole M, Hilbert JE, Luebbe E, Martens 
W, Mcdermott MP, Rothrock N, Thornton C, Vickrey BG, Victorson D, Moxley RT (2014) 
Myotonic Dystrophy Health Index: initial evaluation of a disease-specific outcome measure. 
Muscle Nerve. 49(6):906-14. 
 
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 
 
Hagerman, R.J.  (1997) 
Fragile X syndrome:  Molecular and Clinical Insights and Treatment Issues 
West J Med 166:129 – 137 
 
Hanger DP, Noble W.  (2011) 
Functional implications of glycogen synthase kinase-3-mediated tau phosphorylation. 
Int J Alzheimers Dis. 2011:352805 
 
Ho G1, Cardamone M1, Farrar M1.  (2015) 
Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions. 
World J Clin Pediatr. 4:66-80 
 
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 
 
Jiang Y, Bao H, Ge Y, Tang W, Cheng D, Luo K, Gong G, Gong R. (2015) 
Therapeutic targeting of GSK3β enhances the Nrf2 antioxidant response and confers hepatic 
cytoprotection in hepatitis C. 
Gut. 64:168-179 
 
Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, Woodgett J, Killian J, 
Timchenko NA, Timchenko LT.  (2012) 
GSK3β mediates muscle pathology in myotonic dystrophy. 
J Clin Invest. 122:4461-4472  
 
Klein PS, Melton DA.  (1996) 

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A molecular mechanism for the effect of lithium on development. 
Proc Natl Acad Sci U S A. 93:8455-8459 
 
Logigian EL, Martens WB, Moxley RT 4th, McDermott MP, Dilek N, Wiegner AW, Pearson AT, 
Barbieri CA, Annis CL, Thornton CA, Moxley RT 3rd.  (2010) 
Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. 
Neurology. 74:1441-1448 
 
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 GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. 
J Clin Invest., 123(1):224-35 
 
Min WW, Yuskaitis CJ, Yan Q, Sikorski C, Chen S, Jope RS, Bauchwitz RP.  (2009) 
Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence 
for treatment potential. 
Neuropharmacology. 56:463-472 
 
Mines MA, Yuskaitis CJ, King MK, Beurel E, Jope RS.  (2010) 
GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse 
model of fragile X syndrome and autism. 
PLoS One. 5:e9706 
 
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. 
 
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 
 
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. 
 
Turner C, Hilton-Jones D.  (2010) 
The myotonic dystrophies: diagnosis and management. 
J Neurol Neurosurg Psychiatry. 81:358-637 

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Wei C, Jones K, Timchenko NA, Timchenko L.  (2013) 
GSK3β is a new therapeutic target for myotonic dystrophy type 1. 
Rare Dis. 1:e26555 
 
Woodgett JR.  (1990) 
Molecular cloning and expression of glycogen synthase kinase-3/factor A. 
EMBO J. 9:2431-2438 
 
 

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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. 
 
 
 
 
Signature: 
____________________ 
 
Date: 
 
 
____________________ 
Name of Principal Investigator: 
 
 
____________________ 
Title 
 
 

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17. 
APPENDICES 
Appendix A: 
10 Metre Walk Test Instructions 
Appendix B: 
Pulmonary Function Test Instructions 
Appendix C: 
Nine Hole Peg Test 
Appendix D: 
Clinical Global Impressions Severity and Improvement 
Appendix E: 
Subject and Caregiver Top 3 Concerns 
Appendix F: 
Clinician-completed Domain Specific Causes for Concern: Myotonic 
Dystrophy (VAS) 
Appendix G:  
OSU Autism Rating Scale—DSM-IV (OARS-4) and OSU Autism CGI 
 
 
 

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17.1 
Appendix A: 
10 Metre Walk Test Instructions 
 
 
 
 
 

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Timed 10-Meter Walk/Run Test (adapted from Standard Procedure from OMMYD-
3/IDMC-10 - June 8th, Paris, France) 
Description 
This test measures the short duration walking speed.  
Equipment 
- 
Stopwatch 
- 
Walkway with at least 12 meters of walking course 
Draw lines on the wall with tape at 0, 1, 11 and 12 meters. 
 
Instructions 
Patient preparation:  
- 
Patient should wear comfortable clothing, appropriate shoes for walking and any 
orthosis if patient wears it daily;  
- 
Patients should use their usual walking aids during the test (cane, walker, etc.) and it 
should be recorded. 
Administration: 
- 
Give the participant the following instructions: “You are going to walk a distance of 
about 12 meters at your normal comfortable speed. We will repeat the distance 3 
times. Do you have any questions?” 
- 
Position the participant at the 0m-line. Before the first trial, tell to the participant: 
“You are going to walk at a comfortable speed until I say stop (do not refer to the tape 
on the wall). Continue walking until I say “STOP” and start when I say “Ready, GO”.” 
- 
When the participant is ready, say “Ready, GO”.  
- 
Start the stopwatch when the toes of the leading foot crosses the 1-meter mark and 
stop the stopwatch when the toes of the leading foot crosses the 11-meter mark. Have 
the participant continue walking until he or she reaches the chair after the 12-m line.  
- 
To ensure accuracy of the recorded time, the evaluator must follow the participant by 
standing behind him/her all the time to avoid influencing the walking speed.  
- 
Record the time (in seconds to the hundredths) to walk the 10-m distance. 
- 
The participant can rest until recovered. The participant can rest on a chair if needed. 
Repeat the same procedure as described above at a comfortable speed 2 more times 
(total of 3 trials). 

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- 
Repeat for 3 other trials but this time at the maximum speed the participant can 
manage. Instruct the participant that he/she must walk or run as fast as possible for 
the same distance as above. 
- 
Document whether the participant walks, walks fast or runs (both feet off the ground). 
 
 
 

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17.2 
Appendix B: 
Pulmonary Function Test Instructions 
 
 
 
 
 
 

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Pulmonary Function test (FVC - SITTING) 
 
Forced Vital Capacity (FVC) will be performed in the sitting position. 
The patient should be sitting comfortably in a chair.  The evaluator explains /demonstrates the 
procedure to the subject and explains that they will be performing the test at least 3 times.  The 
specific wording of instructions should be followed closely. 
 
 Ask the patient to ‘take as big a breath in as possible and then blow out through the mouth 
as hard and as long as you can’.  The evaluator should verbally encourage the subject to 
keep going for as long as possible.  ATS criteria state a 6 second plateau is required.  
 The test should be repeated three times making sure that the patient has recovered between 
attempts.  If at each attempt there is an improvement in the results further tests can be 
conducted until the subject has achieved his best result.  
 The subject can place the mouthpiece in his own mouth unless he is unable to reach his 
mouth with his hands or flexes his head and shoulders to reach the tube.  In this case the 
evaluator should place the tube into the subject’s mouth.  
 The tube can be placed in the mouth either before the beginning of inspiration (closed circuit 
technique) or at the end of inspiration just prior to expiration (open circuit technique) 
whichever the subject finds most comfortable.   
 Whichever technique is used the same method should be used at each evaluation and 
documented on the worksheets. 
 A nose clip should be applied just prior to expiration. If a tight seal cannot be made around 
the tube then a mask may be used.  
 The subject should not be allowed to flex forward during expiration. 
 Calibrate the spirometry system on the day of testing 
 
 
 

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17.3 
Appendix C: 
Nine Hole Peg Test 
 
 
 
 
 

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17.4 
Appendix D: 
Clinical Global Impressions Severity and Improvement 
 
 
 
 
 
 
 
 
 
 
 
 

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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, 
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 definite and unequivocal.  A score of 4 is appropriate for 
slight variation in either direction of a magnitude that is likely due to chance, natural history, 
external events, or rating error. 
 

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17.5 
Appendix E: 
Subject and Caregiver Top 3 Concerns 
 
 
 
 
 
 
 

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17.6 
Appendix F: 
Clinician-completed Domain Specific Causes for Concern: 
Myotonic Dystrophy (VAS) 
 
 

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17.7 
Appendix G: OSU Autism Rating Scale—DSM-IV (OARS-4) 
 
 
 

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OSU Autism Rating Scale—DSM-IV (OARS-4) 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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References: 
The OSU Research Unit on Pediatric Psychopharmacology (2005, November):  OSU Autism 
Rating Scale—DSM-IV (OARS-4). Columbus, OH: Author. 
© by OSU Research Unit on Pediatric Psychopharmacology, 2005 ; investigators and clinicians 
may make free copies.