A Double-blind, Placebo-controlled, Phase IIb, Multi-center, Ten-week Prospective Study to Evaluate the Efficacy and Safety of NOE-105 in Adult Male Patients With Childhood Onset Fluency Disorder (Orpheus)
Phase: PHASE2
Conditions: Childhood-Onset Fluency Disorder
Sponsor: Noema Pharma AG

Clinical Study Protocol 
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NOE-CFD-201  
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Clinical Study Protocol 
Compound 
NOE-105 
Protocol Number 
NOE-CFD-201 
Version 
2.0 Amendment 3 US 
Date 
25 May 2023  
A Double-blind, Placebo-controlled, Phase IIb, Multi-center, 
Ten-week Prospective Study to Evaluate the Efficacy and Safety of 
NOE-105 in Adult Male Patients with Childhood Onset Fluency 
Disorder 
CONFIDENTIAL 
The information contained in this document, especially unpublished data, is the property of 
Noema Pharma AG, and therefore provided to you in confidence as an investigator, 
potential investigator or consultant, for review by you, your staff and an applicable 
Independent Ethics Committee/Institutional Review Board. It is understood that this 
information will not be disclosed to others without written authorization from Noema 
Pharma AG except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered. 
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Sponsor Name: Noema Pharma AG 
Legal Registered Address: Noema Pharma AG, 4051 Basel, Switzerland 
Regulatory Agency Identifier Number(s): 
 
Protocol Number: NOE-CFD-201 
Version Number: 2.0 Amendment 3 US 
Study Intervention: NOE-105 
Study Phase: IIb 
Short Title: A 10-week efficacy study of NOE-105 in childhood onset fluency disorder 
(COFD). 
Study Physician Name and Contact Information will be provided separately 
Principal investigator 
 
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PROTOCOL APPROVAL PAGE 
 
Sponsor Signatory: 
 
 
Date 
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5/25/2023

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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document  
Date  
Version 2.0 Amendment 3 US (US only) 
25 May 2023 
Version 2.0 Amendment 2 US (US only) 
01 September 2022 
Version 2.0 Amendment 1 US (US only) 
13 May 2022 
Version 1.0 Amendment 1 Australia (Australia only) 
05 May 2022 
Version 2.0 and Version 2.0 Addendum 1 (US only) 
03 March 2022 and 29 March 2022 
Original Protocol (Version 1.0) 
30 November 2021  
 
 
Version 2.0 Amendment 3 US (25 May 2023)  
This is a substantial amendment as it contains changes to planned analyses.  
 
Overall Rationale for the Amendment:  
The primary rationale for this amendment is to implement health authority requests with 
regards to the timing of the primary endpoint assessment and the updating of study objectives, 
and subsequent analysis, to use the estimand framework. 
 
Section # and 
Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Synopsis 
Changes made for consistency with 
the body of the protocol. 
To ensure consistency throughout  Substantial 
Number of evaluable patients 
removed from table.  
Redundant information 
Non-substantial 
Section 3 
Objectives, 
Endpoints, and 
Estimands 
Title of section changes to include 
estimands 
For consistency with section content Non-substantial 
Change of timepoint for assessment 
of the primary endpoint from end 
point (first visit after administration 
of the final dose of study 
medication) to end of 6 weeks. 
Health authority request to measure 
change from randomization over the 
same duration among patients  
Substantial 
Addition of a Supportive Primary 
Endpoint 
To have an additional comparison 
of interest, as supportive to primary 
estimand, that considers the full 
double-blind treatment period of up 
to 10 weeks 
Substantial 
Sub-division of secondary endpoints 
into ‘KEY Secondary’ and ‘Other 
Secondary Endpoints’. 
To highlight the importance of the 
secondary end point effect on 
functional impairment 
Substantial 
Change of objective ‘To evaluate the 
patient’s satisfaction in treatment 
with NOE105’ from secondary to 
exploratory. 
To highlight that the evaluation of 
patient’s satisfaction using the MSQ 
is exploratory/hypothesis generating 
Substantial 
Addition of estimand details for 
primary and secondary objectives. 
Health authority request to apply 
estimand framework to the study 
objectives 
Substantial 
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Section # and 
Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Addition of ‘suicidality’ to safety 
endpoints. 
Previously omitted in error 
Substantial 
Section 3 
Objectives, 
Endpoints, and 
Estimands 
Section 4.2 
Scientific Rationale 
for Study Design 
Section 8.2.1 
Speech Fluency 
Section 9.1 
Statistical 
Hypotheses 
Section 9.4.4.1 
Primary Estimand 
(previously Primary 
Endpoint) 
Change of name of assessment of 
MLGSSS from assessment of 
severity subset to assessment of total 
score. 
To ensure consistency in 
terminology 
Non-substantial 
Section 3 
Objectives, 
Endpoints, and 
Estimands 
Section 9.1 
Statistical 
Hypotheses 
Section 9.4.4.1 
Primary Estimand 
(previously Primary 
Endpoint) 
Change of timepoint for assessment 
of the primary endpoint from end 
point (first visit after administration 
of the final dose of study 
medication) to end of 6 weeks.  
Health authority request to measure 
change from randomization over the 
same duration among patients 
Substantial 
Section 4.1 
Overall Design 
Description of duration of dosing 
updated. 
To provide additional clarity. 
Non-substantial 
Section 5.2 
Exclusion Criteria 
Criteria 3 and 4 renumbered to form 
sub points of criterion 2.  
Correction 
Non-substantial 
Section 9.2 
Sample Size 
Determination 
Changed term from 60 patients 
should be randomized to 60 patients 
are planned to be randomized. 
To provide flexibility 
Non-substantial 
Number of evaluable patients 
removed.  
All randomized patients, including 
subsequent drop-outs, will be 
included in the analyses  
Non-substantial 
Section 9.3 
Populations for 
Analysis 
In Table 4: 
• 
Description of Full Analysis Set 
updated 
• 
Description of Secondary Full 
Analysis Set added 
• 
Description of Per Protocol 
analysis set updated 
Analysis set definitions have been 
updated to align with the estimand 
descriptions 
Substantial 
Section 9.4 
Statistical Analyses 
Removed reference to the SAP 
describing the handling of missing 
data 
Some information on the handling 
of missing values has now been 
included in the protocol 
Non-Substantial 
Section 9.4.2 
New text added providing 
information on overall control of 
family-wise false-positive rate of 5% 
Clarification on how inferential 
statistics will be performed given 
Substantial 
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Section # and 
Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Inferential Statistics 
and Significance 
Testing 
that there are multiple secondary 
endpoints. 
Section 9.4.4.1 
Primary Estimand 
(previously Primary 
Endpoint) 
Details of primary estimand and 
analysis added.  
Health authority request to apply 
estimand framework to the study 
objectives 
Substantial 
Section 9.4.4.2 
Supportive Primary 
Estimand  
New section added with description 
of the analysis of the supportive 
primary estimand.  
Include analysis description of the 
additional comparison of interest, as 
supportive to primary estimand, that 
considers the full double-blind 
treatment period of up to 10 Weeks 
Substantial 
Section 9.4.4.3 
Secondary 
Estimand(s) 
(formerly Secondary 
Endpoints) 
Description of secondary estimands 
and associated analysis added.  
Health authority request to apply 
estimand framework to the study 
objectives 
Substantial 
Section 9.4.5 
Safety 
Addition of QIDS-16 (previously 
listed in secondary efficacy endpoint 
section) 
Correction 
Substantial 
CGI-C, Clinical Global Impression of Change; MLGSSS, Maguire-Leal-Garibaldi Self-rated Stuttering Scale; 
QIDS-16, Quick inventory of depressive symptomology; SAP, statistical analysis plan. 
 
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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
PROTOCOL APPROVAL PAGE .............................................................................................. 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .................................................... 4 
TABLE OF CONTENTS ........................................................................................................... 7 
1 
PROTOCOL SUMMARY .................................................................................... 12 
1.1 
Synopsis ................................................................................................................ 12 
1.2 
Schedule of Activities ........................................................................................... 15 
2 
INTRODUCTION ................................................................................................ 19 
2.1 
Study Rationale ..................................................................................................... 19 
2.2 
Background ........................................................................................................... 19 
2.2.1 
NOE-105 ............................................................................................................... 20 
2.2.1.1 
NOE-105 Non-clinical Studies ............................................................................. 21 
2.2.1.2 
NOE-105 Clinical Studies .................................................................................... 23 
2.3 
Benefit/Risk Assessment ...................................................................................... 26 
2.3.1 
Risk Assessment ................................................................................................... 26 
2.3.2 
Benefit Assessment ............................................................................................... 27 
2.3.3 
Overall Benefit: Risk Conclusion ......................................................................... 27 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ............................................ 29 
3.1 
Primary Estimand ................................................................................................. 30 
3.2 
Supportive Primary Estimand ............................................................................... 31 
3.3 
Secondary Estimands ............................................................................................ 31 
3.3.1 
Secondary Estimand 1: Functional Impairment ................................................... 32 
3.3.2 
Secondary Estimand 2: Change of Illness Severity as Rated by the Clinician ..... 32 
3.3.3 
Secondary Estimand 3: Change of Illness Severity as Rated by the Patient ........ 32 
3.3.4 
Secondary Estimand 4: Illness Severity as Rated by the Patient .......................... 33 
3.3.5 
Secondary Estimand 5: Change in Stuttering Severity ......................................... 33 
4 
STUDY DESIGN ................................................................................................. 34 
4.1 
Overall Design ...................................................................................................... 34 
4.2 
Scientific Rationale for Study Design .................................................................. 34 
4.2.1 
Participant Input into Design ................................................................................ 36 
4.3 
Justification for Dose ............................................................................................ 36 
4.4 
End of Study Definition ........................................................................................ 36 
4.5 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 37 
5 
STUDY POPULATION ....................................................................................... 37 
5.1 
Inclusion Criteria .................................................................................................. 38 
5.2 
Exclusion Criteria ................................................................................................. 38 
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5.3 
Lifestyle Considerations ....................................................................................... 40 
5.3.1 
Meals and Dietary Restrictions ............................................................................. 40 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................................................ 40 
5.3.3 
Activity ................................................................................................................. 40 
5.4 
Screen Failures...................................................................................................... 40 
6 
STUDY INTERVENTION ................................................................................... 40 
6.1 
Study Intervention(s) Administered ...................................................................... 41 
6.1.1 
Investigational Products........................................................................................ 41 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 41 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 42 
6.4 
Study Intervention Compliance ............................................................................ 42 
6.5 
Concomitant Therapy ........................................................................................... 43 
6.6 
Dose Modification ................................................................................................ 43 
6.7 
Stopping Criteria ................................................................................................... 44 
6.7.1 
Participant Level Stopping Criteria ...................................................................... 44 
6.7.2 
Study Level Stopping Criteria .............................................................................. 44 
6.8 
Intervention After the End of the Study ................................................................ 45 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.............................................................. 45 
7.1 
Discontinuation of Study Intervention.................................................................. 45 
7.2 
Participant Withdrawal from the Study ................................................................ 45 
7.3 
Lost to Follow up .................................................................................................. 46 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 46 
8.1 
Medical History, Physical Examination, Electrocardiogram, Weight, and Vital 
Signs ..................................................................................................................... 47 
8.1.1 
Medical History and Physical Examinations ........................................................ 47 
8.1.2 
Vital Signs ............................................................................................................. 48 
8.1.3 
Electrocardiograms ............................................................................................... 48 
8.2 
Efficacy Assessments ............................................................................................ 48 
8.2.1 
Speech Fluency ..................................................................................................... 48 
8.2.2 
Overall Functioning .............................................................................................. 48 
8.2.3 
Severity of Patient’s Illness .................................................................................. 48 
8.2.4 
Acceptability Assessment ..................................................................................... 48 
8.3 
Safety Assessments ............................................................................................... 49 
8.3.1 
Clinical Safety Laboratory Assessments .............................................................. 49 
8.3.2 
Other Safety Assessments ..................................................................................... 50 
8.4 
Adverse Events and Serious Adverse Events ....................................................... 51 
8.4.1 
Adverse Events of Special Interest ....................................................................... 51 
8.4.2 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information ................................................................................................. 51 
8.4.3 
Follow-up of Adverse Events and Serious Adverse Events.................................. 52 
8.4.4 
Causality Collection.............................................................................................. 53 
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8.4.5 
Adverse Events Based on Signs and Symptoms................................................... 53 
8.4.6 
Adverse Events Based on Examinations and Tests .............................................. 53 
8.4.7 
Reporting of Serious Adverse Events ................................................................... 54 
8.4.8 
Pregnancy ............................................................................................................. 54 
8.4.9 
Medication Error ................................................................................................... 54 
8.5 
Overdose ............................................................................................................... 55 
8.6 
Human Biological Samples .................................................................................. 55 
8.6.1 
Pharmacokinetics .................................................................................................. 55 
8.6.2 
Immunogenicity Assessments ............................................................................... 55 
8.6.3 
Pharmacodynamics ............................................................................................... 55 
8.7 
Human Biological Sample Biomarkers ................................................................ 56 
8.7.1 
Collection of Optional Biomarker Samples .......................................................... 56 
8.7.2 
Other Study Related Biomarker Research ............................................................ 56 
8.8 
Optional Genomics Initiative Sample ................................................................... 56 
8.9 
Health Economics or Medical Resource Utilization and Health Economics ....... 56 
9 
STATISTICAL CONSIDERATIONS ................................................................... 56 
9.1 
Statistical Hypotheses ........................................................................................... 56 
9.2 
Sample Size Determination .................................................................................. 56 
9.3 
Populations for Analyses ...................................................................................... 57 
9.4 
Statistical Analyses ............................................................................................... 57 
9.4.1 
Descriptive Statistics ............................................................................................ 58 
9.4.2 
Inferential Statistics and Significance Testing ...................................................... 58 
9.4.3 
General Considerations ......................................................................................... 59 
9.4.3.1 
Participant Accountability .................................................................................... 59 
9.4.3.2 
Protocol Deviations .............................................................................................. 59 
9.4.3.3 
Demographic and Baseline Characteristics .......................................................... 59 
9.4.3.4 
Compliance to Study Treatment ........................................................................... 59 
9.4.4 
Efficacy ................................................................................................................. 59 
9.4.4.1 
Primary Estimand ................................................................................................. 59 
9.4.4.2 
Supportive Primary Estimand ............................................................................... 60 
9.4.4.3 
Secondary Estimand(s) ......................................................................................... 60 
9.4.5 
Safety .................................................................................................................... 60 
9.5 
Interim Analyses ................................................................................................... 61 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ............................................................................................ 61 
ABBREVIATIONS ................................................................................................................. 97 
11 
REFERENCES ................................................................................................... 100 
 
LIST OF TABLES 
Table 1 
Schedule of Activities ................................................................................. 15 
Table 2 
Risk Assessment .......................................................................................... 26 
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Table 3 
Laboratory Safety Assessments .................................................................. 49 
Table 4 
Populations for Analysis ............................................................................. 57 
Table 5 
Highly Effective Contraception Methods ................................................... 73 
 
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LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations .......................... 62 
Appendix B 
AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................... 67 
Appendix C 
Contraceptive and Barrier Guidance ........................................................... 73 
Appendix D 
Handling of Human Biological Samples ..................................................... 75 
Appendix E 
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ................................ 77 
Appendix F 
Amendment History .................................................................................... 79 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A double-blind, placebo-controlled, Phase IIb, multi-center, 10-week 
prospective study to evaluate the efficacy and safety of NOE-105 in adult male patients with 
childhood onset fluency disorder. 
Short Title: A 10-week efficacy study of NOE-105 in COFD. 
Rationale: The need to develop strategies for the clinical management of COFD and 
associated disorders is high. The accompanying symptoms and discomforts due to stuttering 
have a profound impact on the overall functioning and quality of life of the children and adults 
who stutter and constitute a significant burden to society. The impact of stuttering on social, 
other aspects of functioning, and quality of life is substantial. It is estimated that deficit in 
earnings associated with stuttering exceeds US$ 7000 per year in the United States. Persons 
who stutter also have a higher probability of being unemployed compared with non-stutterers. 
There are currently no approved pharmacotherapies for COFD. Antipsychotics are often used 
off-label and they show efficacy with significant intolerance including motor and metabolic 
disorders.  Therefore, the need for safe and well tolerated therapies for the management of the 
motor, cognitive, and affective symptoms of the disorder remains high. 
NOE-105 is an investigational selective PDE10A inhibitor with a potential therapeutic effect 
for the treatment of COFD. Inhibition of PDE10A, an enzyme predominantly present in 
cortico-striatal circuit, triggers inhibition of D2 receptors. The control of dopamine neuronal 
signaling in the cortico-striatal area, known as “indirect pathway” is expected to enhance 
speech fluency in patients with DS. 
This study in adults with COFD is designed to evaluate the effectiveness of NOE-105 on 
speech fluency without the severe motor, extrapyramidal, and metabolic side effects. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of NOE105 on speech 
fluency in adult patients with COFD 
• 
Primary: Change from baseline to end of 6 weeks in 
the total MLGSSS score 
• 
Supportive Primary: Change from baseline to end 
point in the total MLGSSS score 
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Key Secondary 
• 
To evaluate the effect of NOE105 on 
functional impairment 
• 
Change from baseline to end point in SDS 
Other Secondary 
• 
To evaluate the effect of NOE105 on the 
change of illness severity as rated by the 
patient 
• 
PGI-C rating at end point 
• 
To evaluate the effect of NOE105 on the 
change of illness severity as rated by the 
clinician 
• 
CGI-C rating at end point 
• 
To evaluate the effect of NOE105 on the 
severity of illness as rated by patients 
• 
PGI-S rating at end point 
• 
To evaluate the effect of NOE105 on the 
change in stuttering severity (number of 
syllables stuttered and duration of hesitance) 
• 
Change from baseline to end point in clinician-rated 
SSI-4 
Safety 
• 
To evaluate the safety and tolerability of 
NOE105 
• 
Incidence and severity of AEs, plus assessment of 
hematology, clinical chemistry, urinalysis, ECG, vital 
signs, and suicidality. 
• 
To evaluate the effect of NOE-105 on change 
in mood as rated by the patient 
• 
Change from baseline to end point in QIDS-16 
NOTE: End point refers to the first visit following the last dose of study medication. 
AE, adverse event; CGI-C, clinical global impression of change; COFD, childhood onset fluency disorder; ECG, 
electrocardiogram; MLGSSS, Maguire-Leal-Garibaldi Self-rated Stuttering Scale; MSQ, medication satisfaction 
questionnaire; PGI-C, patient global impression of change; PGI-S, patient global impression of severity; QIDS-
16, quick inventory of depressive symptomology; SDS, Sheehan disability scale; SSI-4, stuttering severity 
instrument -4. 
 
Exploratory endpoints are presented in Section 3.  
Overall Design 
This is a multicenter, double-blind, parallel arm, placebo-controlled study in male patients 
with COFD. Following screening to confirm eligibility, patients will commence a blinded 
placebo run-in period for 7 days. Any participating patient may be randomized 1:1 to 
NOE-105 or placebo on study days 1, 15, or 29. Patients will complete up to 10 weeks of 
double-blind treatment (to Study Day 71). Patients will then visit the study site for a follow-up 
visit within 28 ( 7) days of the date of the last dose of study treatment.  
 
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Disclosure Statement: This is a parallel-group efficacy and safety study with 2 arms that are 
blinded.  
Number of Patients: 
Enrolled 
Estimated 67 patients 
Randomly assigned 
Estimated 60 patients 
 
Note: “Enrolled” means a patient’s agreement to participate in the clinical study following 
completion of the informed consent process and who are eligible to enter the placebo run-in. 
Patients who have signed the ICF and are screened for the purpose of determining eligibility 
for the study, but do not join the placebo run-in phase, are considered “screen failures”.  
Intervention Groups and Duration: 
Following screening to confirm eligibility, on day -7, patients will enter a blinded placebo run-
in period for 7 days. Patients may be randomized to NOE-105 or placebo on study days 1, 15, 
or 29. During the first 3 weeks of treatment following randomization, patients will receive 
escalating doses of NOE-105 or escalation of placebo until they reach a daily dose of 15 mg or 
their individual MTD is achieved. Thereafter, patients will be maintained at this dose until 
they have completed up to 10 weeks of treatment. 
Statistical Methods 
Continuous variables will be summarized using the following statistics: number of available 
data, number of missing values, mean, standard deviation, median, Q1, Q3, minimum and 
maximum values. When relevant, CIs will be computed for the mean. 
Categorical variables will be summarized by frequency counts, and percentages for each 
category. Generally, percentages will be calculated using the number of available data as the 
denominator (ie, not including missing values). 
Between group comparisons will be performed using appropriate two-sided hypothesis tests at 
the 5% two-sided significance level, except if specified otherwise.
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1.2 
Schedule of Activities 
 
Table 1 
Schedule of Activities 
Procedure 
SCREENING 
PLACEBO 
RUN-IN 
TREATMENT 
Day 
 
FOLLOW 
UP  
Notes 
 
Screening 
(W-4 to -1) 
Clinic visit 
Run-In  
(W-1 to 0) 
Day 1 
(BL) 
Day 
8 
Day 
15  
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50  
Day 
57 
Day 
64 
Day 
71 
or 
EoT 
28 days 
after last 
dose 
 
For patients who are 
receiving prior 
medications used to treat 
stuttering, the screening 
period will be from W-4 
to -2). 
Clinic (C) or 
Remote (R) 
Visit 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
R 
R 
C 
C 
Patients who do not 
complete the full 
treatment period will 
complete an EoT 
assessment as soon as 
possible after last dose of 
study medication. 
Time Window 
(Days) 
NA 
NA 
+ 3  
+ 3  
+ 3  
+ 3  
+ 3  
+ 3  
+ 3  
+ 3  
+ 3  
+ 3  
+ 3  
 7  
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix A 1.2 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
This may include a video 
interview to confirm a 
minimum severity of 
moderate stuttering. 
Section 5.1 and 
Section 5.2 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Procedure 
SCREENING 
PLACEBO 
RUN-IN 
TREATMENT 
Day 
 
FOLLOW 
UP  
Notes 
 
Screening 
(W-4 to -1) 
Clinic visit 
Run-In  
(W-1 to 0) 
Day 1 
(BL) 
Day 
8 
Day 
15  
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50  
Day 
57 
Day 
64 
Day 
71 
or 
EoT 
28 days 
after last 
dose 
 
For patients who are 
receiving prior 
medications used to treat 
stuttering, the screening 
period will be from W-4 
to -2). 
Medical 
History, 
including 
stuttering and 
psychiatric 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.1 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Section 8.1.1 
Randomization 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Patients will be 
randomized to NOE-105 
or placebo on Day 1, 15, 
or 29 
MLGSSS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 8.2.1 
QIDS-16 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Section 8.2.3 
SSI-4 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Section 8.2.1 
PGI-C 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
The baseline assessment 
will be through a voice 
recording see 
Section 8.2.3 
PGI-S 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 8.2.3 
CGI-C 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
The baseline assessment 
will be made by using 
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Procedure 
SCREENING 
PLACEBO 
RUN-IN 
TREATMENT 
Day 
 
FOLLOW 
UP  
Notes 
 
Screening 
(W-4 to -1) 
Clinic visit 
Run-In  
(W-1 to 0) 
Day 1 
(BL) 
Day 
8 
Day 
15  
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50  
Day 
57 
Day 
64 
Day 
71 
or 
EoT 
28 days 
after last 
dose 
 
For patients who are 
receiving prior 
medications used to treat 
stuttering, the screening 
period will be from W-4 
to -2). 
investigator’s notes see 
Section 8.2.3 
SDS 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Section 8.2.2 
MSQ 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Section 8.2.4 
Vital signs 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Section 8.1.2 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Section 8.1.3 
Clinical 
chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Section 8.3.1 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Section 8.3.1 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Section 8.3.1 
Serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.3.1 
Urine drug test 
X 
 
As required 
X 
 
Section 8.3.1 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
The baseline assessment 
will be made at Week -1 
Section 8.3.2 
Administration 
of IP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Section 6.2 
Accountability 
of IP 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Section 6.2 
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Procedure 
SCREENING 
PLACEBO 
RUN-IN 
TREATMENT 
Day 
 
FOLLOW 
UP  
Notes 
 
Screening 
(W-4 to -1) 
Clinic visit 
Run-In  
(W-1 to 0) 
Day 1 
(BL) 
Day 
8 
Day 
15  
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50  
Day 
57 
Day 
64 
Day 
71 
or 
EoT 
28 days 
after last 
dose 
 
For patients who are 
receiving prior 
medications used to treat 
stuttering, the screening 
period will be from W-4 
to -2). 
Adverse 
Events 
X 
X 
Section 8.4 
Concomitant 
medications 
X 
X 
Section 6.5 
BL, baseline; C, clinic (visit); CGI-C, clinical global impression of change; C-SSRS, Columbia-Suicide Severity Rating Scale; ECG, electrocardiogram; EoT, 
end of treatment; IP, investigational product; MLGSSS, Maguire-Leal-Garibaldi self-rated stuttering scale; MSQ, medication satisfaction questionnaire; PGI-C, 
patient global impression of change; PGI-S, patient global impression of severity; QIDS-16, quick inventory of depressive symptomology; R, remote (visit); 
SDS, Sheehan disability scale; SSI-4, stuttering severity index-4; W, week.  
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2 
INTRODUCTION 
NOE-105 (formerly known as RO5545954) is a selective, orally active inhibitor of PDE10A, 
which dose-dependently increases cyclic nucleotides in rat striatum, and triggers inhibition of 
D2 receptors (Kehler and Nielsen 2011). NOE-105 also produced pro-cognitive effects in 
several nonclinical assays. In addition, NOE-105 did not increase motor disorders in 
cynomolgus monkeys and had no impact on glucose tolerance or fasting insulin levels in rats. 
NOE-105 has the potential to have a more favorable tolerability profile than existing therapies 
without the induction of metabolic syndrome in patients with COFD.  
2.1 
Study Rationale 
Several data indicate that COFD may be related to a dysfunction in dopaminergic 
neurotransmission; moreover, it can be relieved by dopaminergic receptor blockers (Murray 
and Newman 1997, Shaygannejad et al 2013), and PET studies have shown substantial 
increase in dopamine uptake activity in cortical and subcortical areas (Wu et al 1996). The 
control of dopamine neuronal signaling in the cortico-striatal area, known as “indirect 
pathway”, is expected to enhance speech fluency in patients with COFD. 
NOE-105 is an investigational selective PDE10A inhibitor with a potential therapeutic effect 
for the treatment of COFD. Inhibition of PDE10A, an enzyme predominantly present in 
cortico-striatal circuit, triggers inhibition of D2 receptors.  
This study in adults with COFD is designed to evaluate the effectiveness of NOE-105 on 
speech fluency without the known severe motor, extrapyramidal, and metabolic side effects. 
2.2 
Background 
COFD, otherwise known as stuttering or stammering, is a developmental speech disorder that 
occurs in 5% of children with spontaneous remission in approximately 70% of cases around 
the age of 18. Males are affected more than females (ratio 4:1) (Andrews and Dozsa 1977 , 
Baptista et al 2004 , Chang et al 2008 , Shaygannejad et al 2013). The treatment of stuttering 
has been described as a controversial and puzzling issue for speech language pathologists 
(Ingham and Riley 1998), and recent concerns have been expressed about the absence of strict 
documentation regarding the efficacy of some interventions. 
It is generally agreed that stuttering is a speech disorder that has an adverse effect on 
communication. Communication difficulties are a central component of stuttering (Wu et al 
1996). The accompanying symptoms and discomforts due to stuttering have a profound 
impact on the overall functioning and quality of life of the children and adults who stutter and 
constitute a significant burden to society. It is estimated that deficit in earnings associated with 
stuttering exceeds US$ 7000 per year in the US (Gerlach et al 2018). Persons who stutter also 
have a higher probability of being unemployed compared with non-stutterers.  
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Haloperidol has been used to treat COFD with some success. However, in many patients, any 
beneficial effects are accompanied by extrapyramidal side effects (Shireen and Haleem 2011) 
and drowsiness can also cause discontinuation of treatment (Andrews and Dozsa 1977). A few 
reports have shown the possible effects of olanzapine to treat stuttering (Lavid et al 1999, 
Shaygannejad et al 2013, Maguire et al 2004). However, olanzapine also induces obesity and 
insulin resistant states, which haloperidol does not (Baptista et al 2004, Mathews and Muzina 
2007).  
There are currently no approved pharmacotherapies for COFD. Antipsychotics are often used 
off-label and they show efficacy with high rates of AEs. Therefore, the need for safe and well 
tolerated therapies for the management of the motor, cognitive, and affective symptoms of the 
disorder remains high. 
2.2.1 
NOE-105 
NOE-105 is a selective, orally active inhibitor of PDE10A, which dose-dependently increases 
cyclic nucleotides in rat striatum. NOE-105 also produced pro-cognitive effects in several 
nonclinical assays. In addition, NOE-105 did not increase motor disorders in cynomolgus 
monkeys and had no impact on glucose tolerance or fasting insulin levels in rats. NOE-105 
has the potential to have a more favorable tolerability profile than existing standard of care 
without the induction of metabolic syndrome in patients with COFD.  
PDE10A is part of a superfamily of phosphodiesterases with 11 family members (Lugnier 
2006). The role of the phosphodiesterase is to hydrolyze both 3’,5’-cyclic adenosine 
monophosphate (cAMP) and 3’,5’- cGMP in neurons. PDE10A mRNA is strongly expressed 
in the CNS of mammals and is expressed at much lower levels in peripheral tissues, with the 
exception of the testis. Within the brain, PDE10A is highly expressed in the striatal complex, 
including the caudate putamen, nucleus accumbens, and olfactory tubercle. The overall pattern 
of PDE10A protein localization reported in rat brain has been confirmed and extended to 
include multiple species, including mice, dogs, cynomolgus monkeys, and humans (Andrews 
and Dozsa 1977; Baptista et al 2004; Chang et al 2008; Andrews and Dozsa 1977 
Andrews G, Dozsa M. Haloperidol and the treatment of stuttering. J Fluency Disorders 
1977;2:217-24. 
Baptista et al 2004 
Baptista T, Zárate J, Joober R, Colasante C, Beaulieu S, Páez X, et al. Drug induced weight 
gain, an impediment to successful pharmacotherapy: Focus on antipsychotics. Curr Drug 
Targets 2004;5:279–99. 
Chang et al 2008 
Chang SE, Erickson KI, Ambrose NG, Hasegawa-Johnson MA, Ludlow CL. Brain anatomy 
differences in childhood stuttering. Neuroimage 2008;39:1333–44. 
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Coskran et al 2006). At the cellular level, PDE10A is localized in the GABA-containing 
MSNs, which comprise more than 95% of striatal neurons. 
The striatal MSNs function as the principal molecular integrators of cortical glutamatergic and 
midbrain dopaminergic inputs to basal ganglia to facilitate planning and executing of relevant 
motor and cognitive patterns, while suppressing unwanted or irrelevant patterns (Graybiel 
2000). The MSNs are organized in two neurochemically distinct striatal output pathways, both 
converging to the thalamus. The direct or striato-nigral pathway is generally considered to 
promote behavioral activity and is stimulated by dopamine due to MSN expression of 
dopaminergic D1 receptors, positively coupled to adenylyl cyclase. In contrast, the indirect or 
striato-pallidal pathway tonically suppresses behavioral output and is inhibited by dopamine 
due to MSN expression of dopaminergic D2 receptors, negatively coupled to adenylyl cyclase.  
The high level of expression of PDE10A in the MSNs suggests that inhibition of this enzyme 
will result in functional changes affecting the circuitry. This hypothesis is confirmed by results 
of studies in which selective pharmacological inhibition of PDE10A causes a reduction in 
locomotor activity induced by NMDA-R antagonists (Kehler and Nielsen 2011), an effect 
which is similar to that of dopamine antagonists that are currently used therapies for the 
treatment of COFD. These effects on locomotion are believed to be due to the reduction of the 
D2 signaling or indirect pathway, whereas the effect on the direct pathway, through activation 
of D1 signaling, is thought to contribute to the modulatory effects on reward-based learning, 
motivation and cognition of PDE10A inhibitors. Therefore, PDE10A inhibition represents a 
new approach for the treatment of diseases characterized by a dysregulation of MSNs, such as 
COFD. 
2.2.1.2 
NOE-105 Non-clinical Studies 
Non-clinical Pharmacology 
In vitro, NOE-105 is a potent and selective non-competitive inhibitor of PDE10A with similar 
efficacy in human, rat, and cynomolgus monkey. 
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Pharmacokinetics and Metabolism  
Multiple-dose pharmacokinetic properties were studied during repeat-dose toxicity studies in 
rats and cynomolgus monkeys. 
 
  
 
. 
Relevant drug-drug interactions as a result of inhibition of metabolism or transporters by 
NOE-105 are not expected. However, increases in NOE-105 exposure as a result of co-
administration with CYP3A and CYP2C8 inhibitors or inducers cannot be excluded. 
Toxicology and Safety Pharmacology  
Oral administration of NOE-105 was well tolerated in rats and cynomolgus monkeys in 
studies for up to 13 weeks. 
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. 
 
 
 
. 
2.2.1.3 
NOE-105 Clinical Studies 
As of 20 October 2020, NOE-105 has been investigated in five completed Phase I clinical 
studies. Studies BP28373 and BP28845 recruited healthy subjects to assess the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of NOE-105.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• 
 
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• 
 
 
  
Clinical Pharmacology 
Safety 
Healthy subjects 
In healthy subjects treated with NOE-105, no deaths or SAEs have been reported as of 
20 October 2020. 
 
 
 
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Patients 
In patients with schizophrenia treated with NOE-105, no deaths have been reported as of 20 
October 2020. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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NOE-105 was well-tolerated in patients with schizophrenia at doses up to 7.5 mg for 12 days 
and up to 15 mg when administered using an up-titration regimen. 
A detailed description of the clinical data for NOE-105 is provided in the IB. 
2.3 
Benefit/Risk Assessment 
To assess the benefit/risk for participation in this study, preclinical and clinical data for the 
investigational product have been taken into consideration as well as the risks associated with 
the study procedures.  
More detailed information about the known and expected benefits and potential risks of 
NOE-105 may be found in the IB. 
2.3.1 
Risk Assessment 
Table 2 
Risk Assessment 
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2.3.2 Benefit Assessment 
Patients are expected to have therapeutic benefit from the study medication. Participation in 
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this study will help to design future therapeutic studies assessing the efficacy, safety, and 
tolerability of the study medication in the intended final population. 
2.3.3 Overall Benefit: Risk Conclusion 
Potential risks include the occurrence of acute motor reactions including dystonia, sedation, as 
well as somnolence or dizziness. These side-effects are reversible and can be treated. Thus, the 
overall potential long-term benefits to patients outweigh the potential risks to patients 
participating in this study. 
Considering the measures to minimize risk to patients participating in this study, the potential 
risks identified in association with NOE-105 are justified by the anticipated benefits that may 
be afforded with NOE-105. 
More detailed information about the known and expected benefits, risks and expected AEs 
with NOE-105 can be found in the IB. 
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of NOE105 on speech fluency 
in adult patients with COFD 
• 
Primary: Change from baseline to end 
of 6 weeks in the total MLGSSS score 
• 
Supportive Primary: Change from 
baseline to end point in the total 
MLGSSS score 
Secondary 
• 
To evaluate the effect of NOE105 on functional 
impairment 
• 
Change from baseline to end point in 
SDS 
Other Secondary 
• 
To evaluate the effect of NOE105 on the change of 
illness severity as rated by the patient 
• 
PGI-C rating at end point. 
• 
To evaluate the effect of NOE105 on the change of 
illness severity as rated by the clinician 
• 
CGI-C rating at end point 
• 
To evaluate the effect of NOE105 on the severity of 
illness as rated by the patient 
• 
PGI-S rating at end point 
• 
To evaluate the effect of NOE105 on the change in 
stuttering severity (number of syllables stuttered and 
duration of hesitance) 
• 
Change from baseline to end point in 
clinician-rated SSI-4 
Exploratory 
 
• 
To evaluate the patient’s satisfaction in treatment with 
NOE-105  
• 
Rating of the MSQ at end point 
Safety 
• 
To evaluate the safety and tolerability of NOE105 
• 
Incidence and severity of AEs, plus 
assessment of hematology, clinical 
chemistry, urinalysis, ECG, vital signs, 
and suicidality 
• 
To evaluate the effect of NOE-105 on change in mood 
as rated by the patient 
• 
Change from baseline to end point in 
QIDS-16 
NOTE: End point refers to the first visit following the last dose of study medication. 
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AE, adverse event; CGI-C, clinical global impression of change; COFD, childhood onset fluency disorder; ECG, 
electrocardiogram; MLGSSS, Maguire-Leal-Garibaldi Self-rated Stuttering Scale; MSQ, medication satisfaction 
questionnaire; PGI-C, patient-reported global assessment of change; PGI-S, patient global impression of severity; 
QIDS-16, quick inventory of depressive symptomology, SDS, Sheehan disability scale; SSI-4, stuttering severity 
instrument-4. 
 
3.1 
Primary Estimand 
This study will compare daily dosing of NOE-105 with 3 weeks escalating dose to 15 mg or 
individual maximum tolerated dose (MTD) versus placebo in adult patients with childhood 
onset fluency disorder (COFD) for ≥ 2 years (with onset consistent with being developmental 
in nature before age 8 years).  
The primary comparison of interest is the difference between means in the change from 
baseline to end of Week 6 in speech fluency assessed using the total MLGSSS score. The 
primary comparison will be made regardless of whether a dose modification or treatment 
discontinuation occurred due to intolerance or lack of efficacy and regardless of changes in 
background medication. 
The primary estimand is described by the following attributes: 
• The treatment of interest is 6 weeks of NOE-105, dosed daily and escalating from 2.5 
mg to 15 mg or individual MTD, regardless of any dose modifications or treatment 
discontinuations due to intolerance or lack of efficacy, which will be compared to daily 
dosing of placebo.  
• The target population is adult male patients with COFD for a minimum of 2 years, 
with onset consistent with being developmental in nature before 8 years of age.  
• The variable of interest is the change from baseline in the total MLGSSS score. The 
baseline is the last assessment prior to randomization, and the change will be observed 
at the end of 6 weeks of treatment. 
 
.  
• The population-level summary will be the difference in mean change from baseline in 
the total MLGSSS score for NOE-105 versus placebo.  
• There are potential intercurrent events which could affect the experimental 
measurements required to answer the clinical question. The events and the 
accompanying strategies for handling these are: 
o Use of concomitant medication will be handled by the treatment policy 
strategy, where data are collected and analyzed regardless of the occurrence of 
an intercurrent event, and so will form part of the treatment effect of interest.  
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o Reduction, interruption, lack of compliance or withdrawal of study treatment 
due to intolerance or lack of efficacy are included in the treatment intervention 
of interest and are handled by the treatment policy strategy. 
o Withdrawal of study treatment for reasons unrelated to treatment (e.g., personal 
circumstance such as relocation) will be handled using the hypothetical 
strategy, that is, assuming treatment had not stopped. Data that are collected 
after such study treatment discontinuations are disregarded and not included 
within the analysis. 
o Deaths are not expected in this study. 
o Post-randomization treatment administration errors will be handled using the 
hypothetical strategy, that is as if the procedural issue did not occur. Data that 
are collected after the error are disregarded and not included within the 
analysis. 
3.2 
Supportive Primary Estimand 
An additional comparison of interest is the difference between means in the change from 
baseline to end of the treatment period of up to 10 Weeks, regardless of whether a dose 
modification occurs, and regardless of changes in background medication. 
The attributes for this estimand are the same as for the primary estimand except for the below: 
• The treatment of interest is up to 10 weeks of NOE-105, dosed daily and escalating 
from 2.5 mg to 15 mg or individual MTD, regardless of any dose modifications, which 
will be compared to daily dosing of placebo.  
• The variable of interest is the change from baseline in the total MLGSSS score. The 
baseline is the last assessment prior to randomization, and the change will be observed 
at the end of treatment whether discontinued early or not.  
• Intercurrent events: 
o Withdrawal of study treatment for any reason will be handled using the while 
on treatment strategy using data that are collected up to and including the first 
visit after such study treatment discontinuations. 
3.3 
Secondary Estimands 
There are several secondary objectives for which secondary estimands are described. The 
objectives not referenced below are considered non-confirmatory. 
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3.3.1 
Secondary Estimand 1: Functional Impairment 
The comparison of interest is the difference between means in the change from baseline to end 
of treatment in functional impairment assessed using the SDS. The comparison will be made 
regardless of whether a dose modification occurs, and regardless of changes in background 
medication. 
The attributes for this estimand are the same as the supportive primary estimand except for the 
below: 
• The variable of interest is the change from baseline in the SDS score. The baseline is 
the last assessment prior to randomization, and the change will be observed at the end 
of treatment whether discontinued early or not.  
3.3.2 
Secondary Estimand 2: Change of Illness Severity as Rated by the 
Clinician 
The comparison of interest is the win odds in the rating of illness severity given by the 
clinician at end of treatment assessed using the CGI-C. The comparison will be made 
regardless of whether a dose modification occurs, and regardless of changes in background 
medication. 
The attributes for this estimand are the same as the supportive primary estimand except for the 
below: 
• The variable of interest is the CGI-C rating. The rating will be observed at the end of 
treatment whether discontinued early or not.  
• The population-level summary will be the win odds for NOE-105 versus placebo. That 
is, the odds of a randomly selected patient in the NOE-105 group having a better 
outcome than a randomly selected patient in the placebo group. 
3.3.3 
Secondary Estimand 3: Change of Illness Severity as Rated by the 
Patient 
The comparison of interest is the win odds in the rating of illness severity given by the patient 
at end of treatment assessed using the PGI-C. The comparison will be made regardless of 
whether a dose modification occurs, and regardless of changes in background medication. 
The attributes for this estimand are the same as the supportive primary estimand except for the 
below: 
• The variable of interest is the PGI-C rating. The rating will be observed at the end of 
treatment whether discontinued early or not.  
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• The population-level summary will be the win odds for NOE-105 versus placebo. 
3.3.4 
Secondary Estimand 4: Illness Severity as Rated by the Patient 
The comparison of interest is the win odds in the rating of illness severity given by the patient 
at end of treatment assessed using the PGI-S. The comparison will be made regardless of 
whether a dose modification occurs, and regardless of changes in background medication. 
The attributes for this estimand are the same as the supportive primary estimand except for the 
below: 
• The variable of interest is the PGI-S rating. The rating will be observed at the end of 
treatment whether discontinued early or not.  
• The population-level summary will be the win odds for NOE-105 versus placebo. 
3.3.5 
Secondary Estimand 5: Change in Stuttering Severity 
The comparison of interest is the difference between means in the change from baseline to end 
of treatment in stuttering severity assessed using the SSI-4. The comparison will be made 
regardless of whether a dose modification occurs, and regardless of changes in background 
medication. 
The attributes for this estimand are the same as the supportive primary estimand except for the 
below: 
• The variable of interest is the change from baseline in the SSI-4 score. The baseline is 
the last assessment prior to randomization, and the change will be observed at the end 
of treatment whether discontinued early or not. 
 
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4 
STUDY DESIGN 
4.1 
Overall Design 
This is a multicenter, double-blind, parallel arm, placebo-controlled study in male patients 
with COFD.  
Following screening to confirm eligibility which may include a video interview to confirm a 
minimal severity of moderate stuttering, on day -7, patients will commence the blinded 
placebo run-in period for 7 days. Patients will be randomized 1:1 to NOE-105 or placebo on 
study days 1, 15, or 29. During the first 3 weeks of treatment following randomization, 
patients will receive escalating doses of NOE-105 or double-blind escalation of placebo until 
their maximum tolerated dose or 15 mg NOE-105 is reached. Thereafter, patients will be 
maintained at this dose until they have completed up to 10 weeks of treatment (to study day 
71). 
Following the double-blind treatment, patients will visit the study site for a follow-up visit 
28 ( 7) days after the date of the last dose of study treatment.  
As the study has a staggered randomization, which may occur on either Study Day 1, 15 or 29, 
Study Day 1 may occur up to 4 weeks prior to randomization. All assessments taken post-
randomization will be described as 'relative’ to randomization day. For example, Relative Day 
43 will be the assessment at the end of 6 weeks of treatment, relative to the day of 
randomization. This could be Study Day 43, but could also be Study Day 58 or 71 depending 
on the day the patient was randomized. 
4.2 
Scientific Rationale for Study Design 
This study is designed to evaluate the effectiveness of NOE-105 on speech fluency without 
the known serious motor, extrapyramidal, and metabolic antipsychotic-induced side effects of 
commonly used treatments for COFD. The use of a parallel group, placebo-controlled design 
was included to reduce the potential for placebo effect in this population. The primary 
outcome variable of change from baseline in  the patients rated total MLGSSS score was 
included since this scale is expected to be devoid of the large placebo effect noted using other 
scales for stuttering, eg, the SSI-3 (Maguire et al 2004).  
MLGSSS is a revised version of the SSS scale. SSS was a fully validated scale, used in 
clinical trials (Maguire et al 2004). Over the years it has become obvious that the SSS can be 
improved in generalizability and in reduction of overlapping items. In generalizability, SSS 
had items about phone conversation and impact of authority figure. Feedback from patients 
and experts indicated that patients tend to avoid phone conversation and select jobs where 
interaction with an authority figure are not needed. Several items in SSS were found to be 
overlapping without additive value in assessing stuttering. Therefore, MLGSSS was structured 
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to address these two problems (Maguire et al 2004). The MLGSSS scale will be validated in 
this study and applied in future studies with NOE-105 in COFD.  
QIDS, including the clinician rated QIDS-C16 and self-report QIDS-SR16 formats, are scales 
that assess nine criterion symptom domains to diagnose a major depressive episode. There are 
16 items in the adult versions of the QIDS-16 measuring the nine criterion symptom domains 
(sleep, sad mood, appetite/weight, concentration/decision making, self-view, thoughts of death 
or suicide, general interest, energy level, and restlessness/agitation) that define a major 
depressive episode. All domains are scored from 0 to 3, with higher scores reflecting greater 
psychopathology. Total QIDS scores range from 0 to 27 with scores of 5 or lower indicative of 
no depression, scores from 6 to 10 indicating mild depression, 11 to 15 indicating moderate 
depression, 16 to 20 reflecting severe depression, and scores greater than 21 indicating very 
severe depression. QIDS-SR16 has good internal scale consistency and is a sensitive measure 
of change in depression severity associated with effective treatments. 
The primary estimand will be supported by endpoints intended to assess the impact of 
treatment on functioning, these include the SDS, CGI scale, PGI scale, and the SSI-4 scale. 
The SDS was originally designed to assess functional impairment associated with anxiety 
disorder. The SDS is a three-item self-completion scale measuring the impact of 
symptomatology on work, social, and family functioning. Because of its simplicity, brevity, 
and high face validity, the SDS has become a widely used outcome measure in clinical trials 
of a variety of mental health disorders. The CGI scale is a well-established research tool that 
provides clinician determined summary measure acceptable to all psychiatric disorders and is 
used in virtually all FDA regulated CNS trials. The PGI is a well-established global index that 
is used to rate severity and change of different CNS conditions. PGI-S is a single scale 
question asking the patient to rate their condition on scale 1-7, change of 1 point is considered 
clinically significant. Finally, the SSI-4 is a reliable stuttering assessment used for both 
clinical and research purposes. It is an objective assessment of severity and other 
examinations of stuttering speech. 
Patients will be eligible for this study if they have a history of stuttering for  2 years with 
onset consistent to developmental in nature before age 8 years. This duration works to support 
the persistence of the condition. In addition, patients will be required to discontinue any 
current therapies for COFD for at least 14 days prior to entering the study since variability in 
background medication could have confounding effects on the outcomes being measured. 
Further, a 7-day placebo run-in period, plus randomization at one of 3 timepoints will further 
allow potential placebo-effect to be accounted for. NOE-105 has been shown to have 
teratogenic effects in rabbits and, therefore, participation in this study will be limited to males.  
 
 
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.   
4.2.1 Participant Input into Design 
The protocol and associated procedures were reviewed by patients and a COFD specialist.  
4.3 
Justification for Dose  
For this study, the daily doses of NOE-105 will be between 2.5 mg to 15 mg given 
continuously and orally (for 6-10 weeks) with food, based on the safety, tolerability, and PK 
to date. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  
 
 
 Information on enzyme occupancy is provided in the IB. 
4.4 
End of Study Definition 
A patient is considered to have completed the study if he has completed all phases of the study 
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including the last visit. 
The end of the study is defined as the date of the last visit of the last patient in the study. 
4.5 
Study Conduct Mitigation During Study Disruptions Due to Cases 
of Civil Crisis, Natural Disaster, or Public Health Crisis 
The guidance given below supersedes instructions provided elsewhere in this clinical study 
protocol and should be implemented only during cases of civil crisis, natural disaster, or 
public health crisis (eg, during quarantines and resulting site closures, regional travel 
restrictions, and considerations if site personnel or study patients become infected with SARS-
CoV-2 or similar pandemic infection) which would prevent the conduct of study related 
activities at study sites, thereby compromising the study site staff or the patient’s ability to 
conduct the study. The investigator or designee should contact the study Sponsor 
representative to discuss whether the mitigation plans below should be implemented. The 
study patients will be required to complete the screening and randomization visits on site prior 
to having the option to participate in the mitigation plans.   
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with GCP, and minimize risks to study integrity.  
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options:  
• 
Obtaining consent/assent for the mitigation procedures (note, in the case of verbal 
consent/assent, the ICF should be signed at the patient’s next contact with the study site).  
• 
Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened patients. The 
investigator should confirm this with the designated study physician. 
• 
Home or Remote visit: Performed by a site qualified HCP or HCP provided by a TPV. 
• 
Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.  
• 
At-home IP administration: Performed by a site qualified HCP or HCP provided by a 
TPV, or by the patient or the patient’s caregiver, if possible. Additional information 
related to the visit can be obtained via telemedicine. 
  
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix E. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
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as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Age 
1 
Patient must be 18 to 55 years of age inclusive, at the time of signing the informed 
consent. 
Type of Patient and Disease Characteristics 
2 
Patients who satisfy DSM-5 criteria for childhood onset fluency disorder and are suitable 
for pharmacotherapy. 
3 
Have a history of stuttering for  2 years with onset consistent to developmental in 
nature before age 8 years.   
4 
Patient reported global stuttering experience rated as “moderate” at screening and 
baseline. 
5 
Patients must discontinue all medications used to treat stuttering for at least 14 days prior 
to receiving study treatment. With the exception of antipsychotic therapies (see exclusion 
criterion #13), other psychotropic drugs will be allowed provided they have been stable 
for at least 14 days prior to receiving study treatment and are expected to remain stable 
for the duration of the study. 
Weight 
6 
BMI within the range 19 to 35 kg/m2 (inclusive). 
Sex 
7 
 Male  
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
Male patients must use a condom during the treatment period and until the end of relevant 
systemic exposure in the male patient, plus a further 90-day period. In addition, for a non-
pregnant WOCBP partner, contraception should be used as described in Appendix C. 
Informed Consent 
8 
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
9 
Able to read and write in English.  
 
5.2 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
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Medical Conditions 
1. Stuttering is related to a known neurological cause eg, stroke, etc. 
2. Low IQ in the opinion of the investigator. 
a. Note: a previously conducted IQ level assessment can be used by the investigator and 
does not have to be repeated at screening for study purposes.  
b. Additionally, in the absence of a formal IQ test result, the assessment that the targeted 
IQ level is reached can be based on the investigator’s judgment. The investigator can 
use proxies to IQ score such as the participant’s education level (ie, completion of 
secondary school education) and/or their employment status. 
3. Patients with uncontrolled seizure disorders. 
4. A history of severe traumatic brain injury or stroke.  
5. Patients who are, in the investigator’s opinion, at imminent risk of suicide.   
6. Known to have tested positive for human immunodeficiency virus. 
7. Known DSM-5 diagnosis of substance abuse or dependence. 
8. Unstable medical illness or clinically significant abnormalities on screening tests/exams. 
9. Any unstable medical conditions or are currently ill (eg, congenital heart disease, 
arrhythmia or cancer), which, in the investigator's judgment, will put them at a risk of 
major AE during this trial, are expected to progress during the study, or will interfere with 
safety and efficacy assessments. 
 
Prior/Concomitant Therapy 
12 Initiation of new behavioral therapies for stuttering within 10 weeks prior to baseline.  
13 Use of antipsychotic drug therapy within 14 days prior to receiving treatment until the 
EoT visit. 
 
Prior/Concurrent Clinical Study Experience 
14 Participation in another clinical study with an IP administered in the last 30 days. 
15 Patients with a known hypersensitivity to NOE-105 or any of the excipients of the 
product. 
 
Diagnostic Assessments 
16 Positive urine drug screen for cannabinoids, cocaine, or nonprescribed opiates.  
 
Other Exclusions 
17 Involvement in the planning and/or conduct of the study (applies to both Noema staff 
and/or staff at the study site). 
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18 Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions, and requirements. 
19 Previous randomization in the present study.  
 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Use of any other nutrients known to modulate CYP3A4 activity (eg, grapefruit containing 
products) within 1 week before the first IP administration until the end of treatment is not 
permitted. 
It is important to remind patients that any use of cannabis or cannabis products may have a 
direct impact on the study outcome including NOE-105 safety and efficacy. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
Consumption of alcohol from screening until the end of treatment should not exceed an 
average of 2 units per day (1 unit equates to approximately 330 mL beer, 125 mL wine, or 
25 mL of spirits). There are no restrictions on consumption of caffeine or tobacco. 
5.3.3 
Activity 
Patients will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Patients may participate in light recreational activities during studies.  
5.4 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently included in the placebo run-in phase. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
CONSORT publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Only 2 times rescreening is allowed in the study. Rescreened patients should be 
assigned the same participant number as for the initial screening. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to or medical device(s) utilized by a study patient 
according to the study protocol. 
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6.1 
Study Intervention(s) Administered 
6.1.1 
Investigational Products 
Arm name 
Active 
Placebo 
Intervention 
name 
NOE-105  
Placebo 
Type  
Drug 
Drug 
 
 
 
 
 
 
 
 
 
 
 
 
Route of 
administration 
Oral 
Oral 
Use 
Experimental 
Placebo-comparator 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the 
sponsor 
Packaging and 
labelling 
Study Intervention will be provided 
in blister wallets. Each blister wallet 
will be labelled as required per 
country requirement 
Study Intervention will be 
provided in blister wallets. 
Each blister wallet will be 
labelled as required per 
country requirement 
IMP, Investigational medicinal product; NIMP, Non-investigational medicinal product. 
 
The dose of NOE-105 will be individually up titrated in a blinded fashion. 
 
 
Each patient will be maintained at their individual MTD or 15 mg until 10 
weeks treatment duration is achieved. 
 
  
6.2 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
Only patients enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labelled storage conditions with access limited to the investigator and authorized site 
staff. 
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Study Pharmacy Manual. 
All doses of NOE-105 will be taken once daily, orally. All doses will be taken in the morning 
with food. 
 
 
All other dosing can take place at home. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
At the end of the blinded, placebo run-in period, patients who continue to meet all entry 
criteria will enter the treatment phase and will be randomized via an IVRS/IWRS to receive 
one of two treatments (NOE-105 or placebo) on Day 1, Day 15, or Day 29.  
Routines for this will be described in the Pharmacy Manual that will be provided to each 
center. 
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomization. 
The investigator documents and reports the action to Noema, without revealing the treatment 
given to the patient to the Noema staff. 
The pharmacovigilance function assigned by the Sponsor retains the right to break the code 
for SAEs that are unexpected and are suspected to be causally related to an IP and that 
potentially require expedited reporting to regulatory authorities. Randomization codes will not 
be broken for the planned analyses of data until all decisions on the evaluability of the data 
from each individual patient have been made and documented. 
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study intervention will affect the 
immediate management of the patient’s condition (eg, antidote available), the investigator has 
the sole responsibility for determining if unblinding of a patients’ intervention assignment is 
warranted. Patient safety must always be the first consideration in making such a 
determination. If a patient’s intervention assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The investigator documents and reports the action to 
Noema, without revealing the treatment given to the patient to the Noema staff. 
6.4 
Study Intervention Compliance 
When patients self-administer study intervention(s) at home, compliance with study 
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intervention will be assessed at each visit. Compliance will be assessed by direct questioning, 
counting returned capsules, etc during the site visits and documented in the source documents 
and eCRF. Drug accountability should be recorded in the eCRF. 
A record of the number of capsules dispensed to and taken by each patient must be maintained 
and reconciled with study intervention and compliance records. Intervention start and stop 
dates, including dates for intervention delays and/or dose reductions will also be recorded in 
the eCRF. 
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the patient is receiving 
from the start of screening or receives during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
 
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Patients must abstain from taking prescription or non-prescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention until 
completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, the 
medication will not interfere with the study. 
Paracetamol/acetaminophen, at doses of  2 grams/day, is permitted for use any time during 
the study. Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the Study Physician if required. 
6.6 
Dose Modification 
The investigator will assess the patients and determine the patients’ experienced tolerability of 
the current dose. 
 
 
 
 
 
 
 
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In making this decision, the investigator will be guided by prior experience with the patient. 
 
 
  
 
 
 
   
 
 
 
6.7 
Stopping Criteria 
The IDMB will recommend termination of the study if the risk of treatment with NOE-105 
exceeds the potential benefit. In general, given that the actual stopping of a study is a complex 
decision involving several factors, the IDMB will take all the data together and analyze the 
data collectively, both quantitatively and qualitatively, including performing possible 
additional analyses and data gathering (eg, epidemiological data for background rates), before 
recommending that the study be stopped. As such, stopping rules based on inferential statistics 
will not be applied. The IDMB will be informed of all SAEs and AEs of special interest 
including dystonia.  
6.7.1 
Participant Level Stopping Criteria 
Patients experiencing any of the following high-risk events should have their treatment with 
the IP stopped and be discontinued from the study:  
• 
 
 
 
 
 
 
  
 
6.7.2 
Study Level Stopping Criteria 
The study will be placed on temporary hold (defined as treatment stop for enrolled subjects; 
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and stop of enrollment of subjects into the study) pending further safety data analysis if the 
following criteria are met: 
• 
 
 
 
 
 
 
 
  
 
The risk to all patients will be evaluated thoroughly before a decision is taken as to whether to 
terminate the study prematurely or limit dosing in agreement with the regulatory authorities. 
6.8 
Intervention After the End of the Study 
There will be no further study treatment available following the end of the study. If a patient is 
withdrawn from study treatment or completes the study, the patient will be treated as 
determined by the attending physician.  
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
It may be necessary for a patient to permanently discontinue (definitive discontinuation) study 
intervention. If study intervention is permanently discontinued, the patient will remain in the 
study to be evaluated as per the SoA. See the SoA for data to be collected at the time of 
discontinuation of study intervention (EoT/D71) and patient should also attend follow-up visit 
for any further evaluations that need to be completed. 
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study. 
Discontinued patients may be replaced to ensure 54 evaluable patients (Section 9.2). 
7.2 
Participant Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
A patient who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records). 
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At the time of withdrawal from the study, if possible, an EoT visit should be conducted, as 
shown in the SoA. See SoA for data to be collected at the time of study withdrawal and 
follow-up and for any further evaluations that need to be completed. 
The patient will discontinue the study intervention and be withdrawn from the study at that 
time. 
If the patient withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, it should be confirmed if he still agrees for existing 
samples to be used in line with the original consent. If he requests withdrawal of consent for 
use of samples, destruction of any samples taken and not tested should be carried out in line 
with what was stated in the informed consent and local regulation. The investigator must 
document the decision on use of existing samples in the site study records and inform the 
Global Study Team. 
7.3 
Lost to Follow up 
A patient will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study. 
• 
Before a patient is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
• 
Should the patient continue to be unreachable, he will be considered to have withdrawn 
from the study.  
 
Discontinuation of specific sites or of the study are handled as part of Appendix A. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
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Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Procedures conducted as part of the patient’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 100 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
8.1 
Medical History, Physical Examination, Electrocardiogram, 
Weight, and Vital Signs 
8.1.1 
Medical History and Physical Examinations 
A physical examination will be performed and include assessments of the following: general 
appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, 
nose, and throat), lymph nodes, thyroid, muscular-skeletal (including spine and extremities) 
and neurological systems.  
Any abnormality identified at screening (prior to signing the ICF) should be recorded on the 
Medical History eCRF. At subsequent visits (or as clinically indicated), limited, symptom-
directed physical examinations should be performed. Changes from baseline abnormalities 
should be recorded in patient’s notes. New or worsened clinically significant abnormalities 
should be recorded as AEs on the AE eCRF. 
Investigators should pay special attention to clinical signs related to any previous serious 
illnesses. 
Physical examinations will be performed at timepoints as specified in the SoA.  
Relevant medical history should be obtained from the patient at screening, including stuttering 
and psychiatric conditions.  
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8.1.2 
Vital Signs 
Vital signs will be performed at timelines as specified in the SoA.  
Weight, height (at screening only), temperature, pulse rate, and blood pressure will be 
assessed. 
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the patient in a quiet setting without distractions (eg, television, cell phones). 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, and pulse. 
8.1.3 
Electrocardiograms 
An electrocardiogram will be performed at timepoints as specified in the SoA. 
Single 12-lead ECG will be obtained as outlined in the SoA (Section 1.2) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. All ECGs will be obtaining after the patient has been resting in semi-supine position 
for at least 10 minutes. For each timepoint, 3 ECG recordings should be taken at about 
5 minute intervals. All ECGs will be performed on equipment provided by the Sponsor (or 
designee) and reviewed by site personnel and a core/central laboratory.  
8.2 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA. 
8.2.1 
Speech Fluency 
Speech fluency will be measured using the MLGSSS, the total MLGSSS score, and the SSI-4.  
8.2.2 
Overall Functioning 
Overall functioning will be assessed using the SDS.  
8.2.3 
Severity of Patient’s Illness 
The severity of a patient’s illness will be assessed using the PGI-S, PGI-C, CGI-C, and 
QIDS-16 rating scales.  
8.2.4 
Acceptability Assessment 
The patient’s assessment of acceptability will be assessed using the MSQ.  
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8.3 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.3.1 
Clinical Safety Laboratory Assessments 
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the visits indicated in the SoA. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date and time of collection will be recorded on the appropriate eCRF. 
The clinical chemistry, hematology and urinalysis will be performed at a central laboratory. 
Sample tubes and sample sizes may vary depending on laboratory method used and routine 
practice at the site. 
The laboratory variables provided in Table 3 will be measured.  
Table 3 
Laboratory Safety Assessments 
Laboratory 
Tests 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
% Reticulocytes 
PT-INR 
aPTT at screening only 
 
WBC count with: 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Urea 
Potassium 
Total cholesterol 
Triglycerides 
AST/ SGOT 
Total and 
conjugated 
bilirubin 
GGT 
 
Creatinine 
Sodium 
Chloride 
Magnesium 
Phosphates 
ALT/ SGPT 
Total Protein 
Albumin 
Creatine 
phosphokinase 
 
Glucose (fasting) 
Calcium 
Alkaline phosphatase 
Plasma 
Prolactin 
Routine 
Urinalysis 
• 
Each site should be supplied with a bottle of urinalysis test strips. Urine 
only sent to central lab for analysis if blood or protein is abnormal and 
explanation for the positive dipstick result not available. 
Other Screening 
Tests 
• 
Urine drug screen (to include at minimum: amphetamines, 
methamphetamines, barbiturates, cocaine, opiates, cannabinoids, 
buprenorphine, methadone and benzodiazepines) 
• 
 Serology: HIV-1, HIV-2 and Hepatitis B and Hepatitis C 
• 
All study-required laboratory tests will be performed by a central laboratory 
ALT, alanine aminotransferase; aPTT, activated thromboplastin time; AST, aspartate aminotransferase; GGT, 
gamma-glutamyl transferase; HIV, human immunodeficiency virus; INR, international normalized ratio; PT, 
prothrombin time; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum 
glutamic-pyruvic transaminase; WBC, white blood cell. 
The investigator must review the laboratory report, document this review, and record any 
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clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
patient’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study treatment should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified, and the sponsor notified. 
All protocol-required laboratory tests must be conducted in accordance with the laboratory 
manual and the SoA. 
If laboratory values from non-protocol specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the investigator (eg, SAE or AE or dose modification), then the results must be 
recorded in the source notes. 
8.3.2 
Other Safety Assessments 
NOE-105 is considered to be a CNS-active treatment. 
Patients being treated with NOE-105 should be monitored appropriately and observed closely 
for SIB or any other unusual changes in behavior, especially at the beginning and end of the 
course of treatment, or at the time of dose changes, either increases or decreases. Patients who 
experience signs of suicidal ideation or behavior, should undergo a risk assessment. All factors 
contributing to SIB should be evaluated and consideration should be given to discontinuation 
of the study treatment. 
When informed consent has been given, families and caregivers of patients being treated with 
NOE-105 should be alerted about the need to monitor patients for the emergence of unusual 
changes in behavior, as well as the emergence of suicidal ideation and behavior and to report 
such symptoms immediately to the study investigator. 
Baseline assessment of suicidal ideation and behavior/ treatment emergent suicidal ideation 
and behavior will be monitored during the study using the C-SSRS. 
Planned time points for C-SSRS assessments are provided in the SoA (Section 1.2). 
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8.4 
Adverse Events and Serious Adverse Events 
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
8.4.1 
Adverse Events of Special Interest 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
   
 
.  
8.4.2 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
AEs will be collected from time of signature of the ICF, throughout the treatment period and 
including the follow-up period. 
SAEs will be recorded from the time of signing of the ICF. 
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If the investigator becomes aware of an SAE with a suspected causal relationship to the IP that 
occurs after the end of the clinical study in a patient treated by him or her, the investigator 
shall, without undue delay, report the SAE to the sponsor. 
8.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
Noema retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Adverse event variables 
The following variables will be collected for each AE; 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
Maximum intensity, intensity, or changes in intensity 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP (yes or no) 
• 
Action taken with regard to IP 
• 
Select the appropriate as required: AE caused patient’s withdrawal from study (yes or no) 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
 
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8.4.4 Causality Collection 
The investigator should assess causal relationship between IP and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the investigational product?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B 4.3.  
8.4.5 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since you were last asked?’ or 
revealed by observation will be collected and recorded in the eCRF. When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
8.4.6 Adverse Events Based on Examinations and Tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the CSR.  
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, 
ECG assessments should therefore only be reported as AEs if they fulfil any of the SAE 
criteria, are the reason for discontinuation of treatment with the IP or are considered to be 
clinically relevant as judged by the investigator (which may include but not limited to 
consideration as to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, eg, dose adjustment or drug interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
should use the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
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8.4.7 
Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate Noema representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated Noema representative will work with the investigator to ensure that all the 
necessary information is provided to the Noema Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
Noema representatives of any follow-up information on a previously reported SAE within one 
calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware of 
it. 
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated Noema representative. 
If the EDC system is not available, then the investigator or other study site staff reports an 
SAE to the appropriate Noema representative by telephone. 
The Noema representative will advise the investigator/study site staff how to proceed.  
For further guidance on the definition of an SAE, see Appendix B 2. 
The reference document for definition of expectedness/listedness is the IB for the Noema 
drug.  
8.4.8 
Pregnancy 
All pregnancies in female partners and outcomes of pregnancy should be reported to Noema 
except if the pregnancy is discovered before the study patient has received any study 
intervention. 
8.4.9 
Medication Error 
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate Noema representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it. 
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The designated Noema representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-
Threatening) or 5 (other serious initial and follow up) calendar days if there is an SAE 
associated with the medication error (see Section 8.4.7) and within 30 days for all other 
medication errors. 
The definition of a Medication Error can be found in Appendix B 3.  
8.5 
Overdose 
For this study, any dose of NOE-105 greater than 15 mg within a 24 hour time period will be 
considered an overdose. 
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE and Accountability modules in the eCRF. 
• An overdose without associated symptoms is only reported on the Accountability 
eCRF.  
 
If an overdose on a Noema study intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate Noema representatives immediately, 
but no later than 24 hours of when he or she becomes aware of it. 
The designated Noema representative works with the investigator to ensure that all relevant 
information is provided to the Noema Patient Safety data entry site within one or 5 calendar 
days for overdoses associated with an SAE (see Section 8.4.7) and within 30 days for all 
other overdoses. 
8.6 
Human Biological Samples 
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix D. 
8.6.1 
Pharmacokinetics 
Not applicable.  
8.6.2 
Immunogenicity Assessments 
Not applicable.  
8.6.3 
Pharmacodynamics 
Not applicable.  
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8.7 
Human Biological Sample Biomarkers 
Not applicable. 
8.7.1 
Collection of Optional Biomarker Samples 
Not applicable. 
8.7.2 
Other Study Related Biomarker Research 
Not applicable. 
8.8 
Optional Genomics Initiative Sample 
Not applicable. 
8.9 
Health Economics or Medical Resource Utilization and Health 
Economics 
Not applicable. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The null hypothesis is that there is no difference in the change from baseline at the end of 
6 weeks of treatment in total MLGSSS score (items 1 to 6) between the placebo and NOE-105 
groups. The alternative hypothesis is that there is a difference. 
9.2 
Sample Size Determination 
As the primary endpoint for this study is a modified version of the SSS which has not been 
used before, the sample size estimation is based on the original SSS as it is believed to be a 
reasonable approximation. Maguire et al (2004) examined the effect of olanzapine vs placebo 
on stuttering and found an approximately 22% change from baseline at Week 12 in SSS in the 
active group (SD of 25%) against a change from baseline of less than 1% in the placebo group 
(Maguire et al 2004).  
For the sample size estimation for this study, the common SD is assumed to be the SD 
observed in the active group (25%) in the historical study. Assuming a treatment effect of 
22% change from baseline to end of treatment (in the active group as compared to the 
placebo), and a two-sided type I error rate of 0.05, a sample size of 54  patients (27 active, 
27 placebo) will give over 89% power in this study.  
Allowing for a dropout rate of 10% following randomization, a total of 60 patients are planned 
to be randomized. Additionally, to allow for a 10% drop out rate during the placebo run-in 
period a total of 67 patients should be enrolled. 
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Enrolled 
Estimated 67 patients 
Randomly assigned 
Estimated 60 patients 
 
Note: “Enrolled” means a patient’s, or their legally acceptable representative’s, agreement to 
participate in the clinical study following completion of the informed consent process and who 
are eligible to enter run-in. Patients who are screened for the purpose of determining eligibility 
for the study, but do not join the placebo run-in phase, are considered “screen failures”.  
9.3 
Populations for Analyses 
The following populations are defined: 
Table 4 
Populations for Analysis 
Population/Analysis set 
Description 
Enrolled  
All patients who sign the ICF 
Randomized 
Randomly assigned to study treatment 
Full analysis set 
Randomized to study treatment when eligible (using eligibility criteria 
assessments taken prior to randomization), who take at least one dose of 
study treatment and have at least one MLGSSS available post-
randomization. 
Secondary full analysis set 
Randomized to study treatment whether eligible or ineligible, who take at 
least one dose of study treatment and have at least one MLGSSS available 
post-randomization. 
Safety analysis set 
Randomized to study treatment and take at least one dose of study 
treatment. 
Per protocol analysis set 
All patients in the FAS who take all planned doses of study treatment, have 
MLGSSS available at both baseline and at Week 6 (Relative Day 43) and 
have no major protocol deviations. 
ICF, Informed consent form; MLGSSS, Maguire-Leal-Garibaldi Self-rated Stuttering Scale; FAS, full analysis 
set. 
 
The primary analysis will be on the Full Analysis Set. Analyses using the Secondary Full 
Analysis Set and Per Protocol Analysis Set will be secondary. The safety evaluation will be 
performed on the Safety Analysis Set. 
Membership of subjects in each analysis set will be determined at a planned blinded data 
review meeting (BDRM), prior to any analysis. 
9.4 
Statistical Analyses 
The SAP will be finalized prior to data base lock, and will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses. Any differences to the protocol defined analysis 
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below will be highlighted within the SAP and also referenced in the final CSR.  
Data will be analyzed and reported using SAS® version 9.4 or later. 
9.4.1 
Descriptive Statistics 
Continuous variables will be summarized using the following statistics: number of available 
data, number of missing values, mean, standard deviation, median, Q1, Q3, minimum and 
maximum values. When relevant, CIs will be computed for the mean. 
Categorical variables will be summarized by frequency counts, and percentages for each 
category. Generally, percentages will be calculated using the number of available data as the 
denominator (ie, not including missing values).  
9.4.2 
Inferential Statistics and Significance Testing 
Between group comparisons will be performed using appropriate two-sided hypothesis tests at 
the 5% two-sided significance level, except if specified otherwise. 
An overall, family-wise false-positive rate of 5% for the secondary efficacy endpoints will be 
maintained, in that no significance of secondary endpoints will be claimed unless the primary 
statistical analysis is significant at the 5% level.   
In addition, the testing of the secondary endpoints will be conducted in a hierarchical fashion, 
in that once a null hypothesis is not rejected, all subsequent secondary hypothesis tests will be 
considered to be exploratory. The secondary endpoints in hierarchical order are: 
Key Secondary:  
1. 
Change from baseline to end point in SDS 
Other Secondaries: 
1. 
CGI-C rating at end point 
2. 
PGI-C rating at end point 
3. 
PGI-S rating at end point 
4. 
Change from baseline to endpoint in clinician-rated SSI-4 
For continuous variables the difference in means, the standard error and the 95% two-sided CI 
will be presented. An ANCOVA model will be used to evaluate the change from baseline, with 
treatment group and baseline included in the model. Multiple imputation will be used where 
appropriate for the data and clinical question of interest.  
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Methods for checking statistical model assumptions and alternative methods of analysis if the 
assumptions are not fulfilled will be described in the SAP. 
Baseline will be the last measurement taken before randomization. For some patients 
randomization will be on Day 1, while for others this will be on Day 15 or Day 29. For the 
questionnaires this is likely to be those taken on the day of randomization (pre-randomization) 
while for safety assessments this is likely to be the measurements taken at screening visit. 
9.4.3 
General Considerations 
9.4.3.1 
Participant Accountability 
The number of patients screened, receiving at least one dose of placebo in placebo run-in 
period, randomized, receiving at least one dose of study treatment, having been titrated to the 
maximum dose, being on randomized treatment for at least 6 weeks, discontinuing study 
treatment early (along with reasons for early discontinuation), withdrawing from study (along 
with reasons for withdrawal), and completing the study, and the numbers in each analysis set, 
will be summarized by treatment group. 
9.4.3.2 
Protocol Deviations 
Patient data will be reviewed for major protocol deviations prior to main analysis database 
lock at a planned BDRM, and decisions will be documented within the meeting minutes. At 
this meeting, patients will be reviewed for their inclusion/exclusion from the analysis sets. 
9.4.3.3 
Demographic and Baseline Characteristics 
Descriptive statistics of demographics (eg, age, race and ethnicity) will be presented by 
treatment group and across all patients. Medical history information will be listed. Other 
baseline characteristics will be defined in the SAP. 
9.4.3.4 
Compliance to Study Treatment 
Compliance will be summarized by treatment group, based on the number of capsules 
dispensed and returned. 
9.4.4 
Efficacy  
The primary analysis will examine the NOE-105 group against the placebo group.  
9.4.4.1 
Primary Estimand 
The primary endpoint is the change from baseline to the end of 6 weeks of treatment (Relative 
Day 43) in the total MLGSSS score, where baseline is defined as the last assessment prior to 
randomisation (Relative Day 1). The score will be obtained by summing the numerical 
response to each question at each timepoint. The score and change from baseline (last 
measurement taken before randomization) in score will be summarized at each timepoint 
using the Full analysis set.  
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The main analysis will use an ANCOVA model, with treatment group and baseline score 
included in the model. and will estimate the change from baseline at the end of 6 weeks of 
treatment for each treatment group as well as the treatment difference. 
The main analysis will address the intercurrent event attribute of the primary estimand, 
relating to events which will be analysed using the treatment policy strategy, by utilising copy 
reference multiple imputation to handle missing values. 
Two sensitivity analyses will be employed to further assess the handling of missing values. 
These will include the use of an MMRM model and a jump to reference multiple imputation 
approach.  
Further supplemental analyses may also be included to further support the conclusions of the 
primary estimand.  
9.4.4.2 
Supportive Primary Estimand  
The supportive primary endpoint is the change from baseline to the end of treatment of up to 
10 Weeks in the total MLGSSS score, where baseline is defined as the last assessment prior to 
randomisation (Relative Day 1). An ANCOVA model will also be used for this estimand with 
a missing at random multiple imputation apply to sporadically missing data.  
9.4.4.3 
Secondary Estimand(s) 
The scores at baseline (the last measurement taken before randomization) and at end point will 
be summarized along with the change from baseline at end point for the SDS and the SSI-4. 
Analysis will be performed, in a similar manner to the primary estimand, where the difference 
in change from baseline in score between NOE-105 and placebo will also be estimated using 
an ANCOVA model including treatment and baseline score. Full detail will be provided within 
the SAP. 
The CGI-C, PGI-C, and PGI-S will be summarized by frequency and analyzed using a 
Wilcoxon Rank Sum test and a win odds ratio will also be presented. The MSQ will be 
summarized by frequency and percentage of patients providing each response.Safety 
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class, preferred term, and treatment 
group for the number of AEs reported and the number and percentage of patients reporting 
each AE. A listing of AEs, including onset and resolution dates, severity, relationship to 
treatment, action taken, and outcome will be provided. 
Physical examinations and the C-SSRS questionnaire will be listed. 
Other safety endpoints will be summarized by treatment group, as absolute value and change 
from baseline at each visit; including hematology, biochemistry, urinalysis, ECG, vital signs, 
and QIDS-16, the details of which will be provided in the SAP. 
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9.5 
Interim Analyses  
No interim analysis will be carried out.  
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
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Appendix A Regulatory, Ethical, and Study Oversight 
Considerations 
A 1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study patients. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
A 1.1 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
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A 1.2 
Informed Consent/Assent Process 
The investigator or his/her representative will explain the nature of the study to the patient or 
their legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent/assent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC 
or study center. 
The patient record must include a statement that written informed consent/assent was obtained 
before the patient was enrolled in the study and the date the written consent/assent was 
obtained. The authorized person obtaining the informed consent/assent must also sign the ICF. 
Patients must be re-consented/assented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the patient or their legally authorized representative. 
A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within 7 days from the previous ICF signature date. 
A 1.2.1 
Data Protection 
Patients will be assigned a unique identifier by the sponsor. Any patient records or datasets 
that are transferred to the sponsor will contain the identifier only; patient names or any 
information which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient who will be required to give consent for their data to be used as 
described in the informed consent.  
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
A 1.3 
Dissemination of Clinical Study Data 
The results of the study will be reported within 1 year from the end of the clinical trial. 
Irrespective of the outcome, Noema Pharma will submit to the regulatory database a summary 
of the results of the clinical study within 1 year from the end of the clinical trial. This shall be 
accompanied by a summary written in a manner that is understandable to laypersons. 
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A 1.4 
Data Quality Assurance 
Patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). Data recorded 
electronically by the patient and/or their caregiver will be uploaded into CRF by the site staff 
at each visit.  
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for at least 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
A 1.5 
Source Documents 
The investigator/institution should maintain adequate and accurate source documents and 
study records that include all pertinent observations on each of the study center’s patients. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original entry, 
and should be explained if necessary (eg, via an audit trail). 
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Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site for 
15 years. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification (SDV) to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of patients are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
A 1.6 
Study and Site Start and Closure 
A 1.6.1 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first site open and will be the study start date. 
A 1.6.2 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study treatment development 
For site termination: 
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• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate or no patient recruitment (evaluated after a reasonable amount of time) of 
patients by the investigator 
• Total number of patients included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the patient and 
should assure appropriate participant therapy and/or follow-up. 
A 1.7 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
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Appendix B AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
B 1 
Definition of AE  
B 1.1 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study treatment, whether or not considered related to the 
study treatment. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study treatment. 
 
B 1.2 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected treatment – treatment 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 
B 1.3 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
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• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
B 2 
Definition of SAE 
An SAE is defined as any serious AE that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
patient 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 were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the patient has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
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e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the patient or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment for 
allergic bronchospasm, blood dyscrasias, convulsions or development of treatment 
dependency or treatment abuse. 
 
B 3 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for a Noema study drug that either causes harm to the patient or has the 
potential to cause harm to the patient.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error: 
• 
Occurred 
• 
Was identified and intercepted before the participant received the drug 
• 
Did not occur, but circumstances were recognized that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the patient 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet  
• 
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature  
• 
Wrong patient received the medication (excluding IVRS/IWRS errors) 
• 
Wrong drug administered to patient (excluding IIVRS/IWRS errors) 
 
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Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IVRS/IWRS – including those which lead to one of the 
above listed events that would otherwise have been a medication error  
• 
Patient accidentally missed drug dose(s) eg, forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Patient failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if a Noema product  
 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
B 4 
Recording and Follow-Up of AE and/or SAE 
B 4.1 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to the Sponsor/CRO in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested 
by Sponsor/CRO.  In this case, all patient identifiers, with the exception of the patient 
number, will be redacted on the copies of the medical records before submission to 
Sponsor/CRO. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 
B 4.2 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:  
• Mild: An event that is easily tolerated by the patient, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
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• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
B 4.3 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.  The AE must be characterized as related or 
unrelated: 
• “Related” conveys that there are facts, evidence, and/or arguments to suggest a 
causal relationship for the individual case. 
• “Unrelated” is used if there is not a reasonable possibility that the study treatment 
caused the AE. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• The investigator will also consult the IB. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the Sponsor/CRO.  However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor/CRO. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
B 4.4 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor/CRO to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
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• If a patient dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the Sponsor’s representative with a copy of any 
post-mortem findings including histopathology.  
• New or updated information will be recorded in the originally submitted documents. 
The investigator will submit any updated SAE data to the Sponsor’s representative within 24 
hours of receipt of the information. 
B 5 
Reporting of SAEs 
B 5.1 
SAE Reporting to the Sponsor/CRO via an Electronic Data Collection 
Tool 
• The primary mechanism for reporting an SAE to the Sponsor/CRO will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the Medical monitor by telephone. 
• Contacts for SAE reporting can be found in the Investigator Study File. 
 
B 5.2 
SAE Reporting to Sponsor/CRO via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the back-up method to 
transmit this information to the Sponsor/CRO. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• Contacts for SAE reporting can be found in Investigator Study File. 
 
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Appendix C Contraceptive and Barrier Guidance 
C 1 
Contraception Guidance 
Male patients with female partners of childbearing potential 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
• Agree to use a male condom plus partner use of a contraceptive method with a failure rate 
of <1% per year as described in Table 5 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant 
In addition, male patients must refrain from donating sperm for the duration of the study and 
for 90 days after study completion or the last dose of study treatment. 
Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration. 
 
Table 5 
Highly Effective Contraception Methods 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Intrauterine device (IUD) 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male patient can come from the site personnel’s review of the 
patient’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent  
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the patient. 
• 
Condom with spermicide 
Male condom plus spermicide to be used from Day 1 until 90 days after the end of the study. Note: male 
condoms are not reliable as a sole contraception method.   
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
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b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception for this study. 
Male condom and female condom should not be used together (due to risk of failure from friction). 
 
C 2 
Collection of Pregnancy Information: 
Female partner of male patient: 
The investigator will collect pregnancy information on any female partner of a male patient 
who becomes pregnant while participating in this study.  
Information will be recorded on the pregnancy notification form and submitted to the sponsor 
within 24 hours of learning of a patient’s partner’s pregnancy. The information will include 
the anticipated date of birth or termination of the pregnancy at the time of the initial report.   
The female partner of the male patient will be followed to determine the outcome of the 
pregnancy (after obtaining the necessary signed informed consent from the female partner). 
The investigator will collect follow-up information on the female partner of the male patient 
and the neonate and the information will be forwarded to the sponsor.  
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
While the investigator is not obligated to actively seek this information in former study 
patients, he or she may learn of an SAE through spontaneous reporting.  
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Appendix D Handling of Human Biological Samples 
D 1 
Chain of Custody 
A full chain of custody is maintained for all samples throughout their life cycle. 
The Investigator at each site keeps full traceability of collected biological samples from the 
patients while in storage at the site until shipment or disposal (where appropriate). 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
Noema will keep oversight of the entire life cycle through internal procedures, monitoring of 
study sites, auditing or process checks, and contractual requirements of external laboratory 
providers. 
If required, Noema will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is sooner. 
D 2 
Withdrawal of Informed Consent/Assent for Donated 
Biological Samples 
If a patient withdraws consent/assent to the use of donated biological samples, the samples 
will be disposed of/destroyed, and the action documented. If samples are already analyzed, 
Noema is not obliged to destroy the results of this research. 
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation. 
The Investigator: 
• 
Ensures patient’s withdrawal of informed consent/assent to the use of donated samples is 
notified immediately to Noema. 
• 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented. 
• 
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent/assent immediately and that samples are disposed of/destroyed, the action 
documented, and the signed document returned to the study site. 
• 
Ensures that the patient and Noema are informed about the sample disposal. 
 
Noema ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent/assent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
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D 3 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
 
Exempt – Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content. 
 
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Appendix E Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis 
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.  
E 1 
Reconsent/Reassent of Study Patients During Study Interruptions 
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits. Reconsent/reassent should be obtained for the alternative means 
of carrying out visits and assessments and should be obtained prior to performing the 
procedures described in Sections E 2 to E 6. Local and regional regulations and/or guidelines 
regarding reconsent of study patients should be checked and followed. Reconsent/reassent 
may be verbal if allowed by local and regional guidelines (note, in the case of verbal 
reconsent/reassent the ICF should be signed at the patient’s next contact with the study site). 
Visiting the study sites for the sole purpose of obtaining reconsent/reassent should be avoided.  
E 2 
Rescreening of Patients to Reconfirm Study Eligibility 
Additional rescreening for screen failures due to study disruption can be performed in 
previously screened patients. The investigator should confirm this with the designated study 
physician.  
In addition, during study disruption there may be a delay between confirming eligibility of a 
patient and either enrollment in the study or commencement of dosing with IP. If this delay is 
outside the screening window specified in Section 1.2, the patient will need to be rescreened 
to confirm eligibility before commencing study procedures. This will provide another 
opportunity to rescreen a participant in addition to that detailed in Section 5.4. The procedures 
detailed in Section 1.2 must be undertaken to confirm eligibility. 
E 3 
Home or Remote Visit to Replace On-site Visit (where applicable) 
A qualified HCP from the study site or TPV service will visit the patient’s home or other 
remote location as per local SOPs, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified HCP will be expected to collect information per the clinical study 
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protocol.  
E 4 
Telemedicine Visit to Replace On-site Visit (where applicable) 
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices. 
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow AEs, concomitant medication, review compliance of at-home PRO 
assessments, and healthcare resource utilization to be reported and documented. Scheduled 
blood sample collection will be performed when the patient can attend a subsequent site visit.   
E 5 
At-home or Remote Location IP Administration Instructions 
If a site visit is not possible, at-home or remote location administration of IP may be 
performed, within local regulation/guidance. The option of at-home or remote location IP 
administration ensures patient safety in cases of a pandemic where patients may be at 
increased risk by traveling to the site/clinic. This will also minimize interruption of IP 
administration during other study disruptions, eg, site closures due to natural disaster.  
A qualified HCP from the study site or TPV service may administer the IP at the patient’s 
home or other remote location according to the CSP, and if allowed by local SOPs, as 
applicable. All necessary supplies and instructions for administration and documentation of IP 
administration will be provided. Additional information related to the visit can be obtained via 
a telemedicine or home visit. 
E 6 
Data Capture During Telemedicine or Home / Remote Visits 
Data collected during telemedicine visits will be collected from the patient by a HCP. 
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Appendix F Amendment History 
Version 2.0 Amendment 2 US (01 September 2022)  
This is a substantial amendment as it contains changes to the dose adjustment 
recommendations in the case of AEs and inclusion/exclusion criteria.  
 
Overall Rationale for the Amendment:  
The primary rationale for this amendment is to refine the dose adjustment recommendations in 
the case of AEs, the addition of an additional screening for drugs of abuse and to update the 
exclusion criteria to exclude the use of antipsychotic drugs. 
 
Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Throughout 
Correction of minor typographical 
errors. 
Correction of previous minor errors. Non-substantial 
Protocol personnel details The address and contact details for 
the principal investigator were 
removed.  
These details were removed as not 
required and to protect personal 
information. 
Non-substantial 
Synopsis 
Intervention Groups and 
Duration 
The term ‘double blind’ when 
describing escalation of placebo 
was removed.  
This term was removed due to being 
an unnecessary term as it is 
previously stated that all dosing is 
blinded. . 
Non-substantial 
Section 1.2 
Schedule of Activities 
Time window for visits from Day 1 
to Day 71 inclusive amended to + 3 
days.  
This was amended to ensure that 
patients are not scheduled for visits 
too early.  
Substantial 
The duration of the screening 
period was amended to:  
- Week -4 to Week -1 for patients 
who are not receiving prior 
medications used to treat stuttering. 
- Week -4 to Week -2  for patients 
who are receiving prior 
medications used to treat stuttering. 
This was amended to allow patients 
who are not receiving prior 
medications used to treat stuttering 
and who have successfully 
completed all screening procedures 
to be randomized sooner.  
Substantial 
IP administration at Day 71 (EoT) 
was removed. 
This was included previously in error Substantial 
The note against IP administration 
stating ‘If there is no clinic visit or 
if the clinic visit is scheduled for 
later in the day IP can be taken in 
the morning at home’ was 
removed. 
This text was removed as not 
required since instructions are 
provided in Section 6.2. 
Non-substantial 
Section 2.2.1.2 
NOE-105 clinical studies 
When describing safety data in 
patients with schizophrenia the 
following text was added ‘As a 
daily dose of 4 mg risperidone is 
associated with a high incidence of 
dystonia, it is unclear whether these 
events were related to NOE-105 or 
the underlying risperidone.’  
This text was added to provide 
context around the clinical data. 
Non-substantial 
Section 3 
Objectives and endpoints 
The objective ‘To evaluate the 
effect of NOE-105 on change in 
mood as rated by the patient’ was 
moved from the list of secondary 
The assessment of the change in 
mood was added as a safety measure 
and had been previously added to the 
secondary endpoints section in error.  
Non-substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
endpoints to the list of safety 
endpoints. 
Section 4.3 
Justification for dose 
The reference to Section 6.6 for 
details of dose escalation was 
replaced by Section 6.1.1. 
This change was made to correct a 
previous error. 
Non-substantial 
Section 5.1 
Inclusion criteria 
Inclusion criterion number 1 was 
amended to raise the upper range of 
the age of patients to 55 years.   
The upper age limit was increased to 
be more reflective of the wider 
population. 
Substantial 
Inclusion criterion number 4 was 
amended to read ‘Patient reported 
global stuttering experience rated 
as “moderate” at screening and 
baseline’. 
This was amended to clarify that this 
criterion is based upon the patient’s 
own judgment.  
Non-substantial 
Inclusion criterion number 5 was 
amended to read “Patients must 
discontinue all medications used to 
treat stuttering for at least 14 days 
prior to receiving treatment. With 
the exception of antipsychotic 
therapies (see exclusion criterion 
number 13), other psychotropic 
drugs will be allowed provided 
they have been stable for at least 14 
days prior to receiving treatment 
and are expected to remain stable 
for the duration of the study”. Bold 
indicates new text. 
This was added to clarify that, whilst 
other psychotropic drugs are 
allowed, patients must not continue 
to use antipsychotic drugs for the 
duration of the study due to the 
potential of antipsychotic drugs to 
interfere with both tolerability and 
efficacy of NOE105. This is also in 
line with the newly added exclusion 
criterion number 20.  
Substantial 
Inclusion criterion number 6 was 
amended to require a BMI of 19 to 
35.  
The BMI range was widened to be 
more reflective of the wider 
population whilst still excluding 
extreme values.  
Substantial 
Section 5.2 
Exclusion criteria 
Exclusion criterion number 13 (Use 
of antipsychotic drug therapy 
within 14 days weeks prior to 
receiving treatment until the EoT 
visit) was added. 
The use of antipsychotic drug 
therapy has the potential to interfere 
with both the tolerability and 
efficacy of NOE-105 and should, 
therefore, be avoided.  
Substantial 
Exclusion criterion 16 (formerly 
15) has been amended as follows 
‘Positive urine drug screen for 
cannabinoids, cocaine, or 
nonprescribed opiates’. Bold 
indicates new text.  
This addition was made to specify 
which drugs are excluded since 
patients who are on stable stimulants 
due to ADHD or patients on stable 
benzodiazepines should not be 
excluded. 
Substantial 
Section 5.3.1 
Dietary Restriction 
It was added that ‘It is important to 
remind patients that any use of 
cannabis or cannabis products may 
have a direct impact on the study 
outcome including NOE 105 safety 
and efficacy’. 
The use of cannabis or cannabis 
products should be avoided as this 
has the potential to interfere with the 
safety and efficacy of NOE105.  
Substantial 
Section 5.3.2 
Caffeine, alcohol, and 
tobacco 
It was added that ‘There are no 
restrictions on consumption of 
caffeine or tobacco’. 
This was added to provide clarity. 
Non-substantial 
Section 6.3 
Measures to minimize bias: 
This section was amended to state 
that details of the randomization 
This was amended to correct an 
administrative error. 
Non-substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Randomization and 
blinding 
process are provided in the 
Pharmacy Manual instead of the 
IVRS/IWRS user manual.  
Section 6.6 
Dose modification 
This section was updated to allow 
investigators the option to resume 
dosing at the previously well 
tolerated dose in the case of 
significant intolerance. Patients 
who resume dosing at the 
previously well tolerated dose 
should remain on that dose until the 
end of the study. 
This was added to allow down-
titration for any significant 
intolerance.  
Substantial 
Section 7.1 
Discontinuation of study 
intervention 
This section was updated to 
confirm that patients should attend 
an EoT visit add the full title of that 
visit.  
This change of language was made 
to provided additional clarity.  
Non-substantial 
Section 8.1.1 
Medical History and 
Physical Examinations 
It was clarified that the cut-off for 
recording an abnormality as 
medical history in the eCRF is the 
signing of the ICF.  
To provided further clarity on how to 
distinguish medical history from an 
adverse event 
Non-substantial 
Section 8.3.1 
Clinical Safety Laboratory 
Assessments 
Alcohol screening was removed. 
Alcohol screening is not required in 
this study and was previously 
included in error. 
Substantial 
Appendix A.1.5 
Source documents 
Reference to the Study Reference 
Manual was removed.  
This was amended to correct an 
administrative error. 
Non-substantial 
Appendix B.5.1 
SAE reporting to the 
sponsor/CRO via an 
electronic data collection 
tool. 
Reference to the Study Reference 
Manual was replaced with 
Investigator Study File.  
This was amended to correct an 
administrative error. 
Non-substantial 
Appendix B.5.2 
SAE reporting to the 
sponsor/CRO via paper 
data collection tool. 
Reference to the Study Reference 
Manual was replaced with 
Investigator Study File.  
This was amended to correct an 
administrative error. 
Non-substantial 
EoT, end of treatment; IP, investigational product. 
 
Version 2.0 Amendment 1 US (13 May 2022)  
This is a substantial amendment as it contains changes that introduce an additional secondary 
efficacy endpoint (QIDS-16) and will directly affect the study participants.  
 
Overall Rationale for the Amendment:  
The primary rationale for this amendment is the addition of an additional secondary endpoint 
to complement the MLGSSS primary endpoint. 
 
Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Throughout 
Minor typographical and editorial 
changes were made.  
To correct previous typographical errors 
and to provide clarification. 
Non-substantial 
The term “participant” (when used in 
the context of taking part in the study) 
was replaced with the term “patient”. 
This was made to ensure consistency 
throughout the document.  
Non-substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Abbreviated terms and definitions are 
newly included in the list of 
abbreviations 
New abbreviations included, consistent 
with the amended text. 
Non-substantial 
Cross references were denoted with 
blue text 
This was added to adhere to the Sponsor’s 
new protocol template. 
Non-substantial 
Synopsis 
Changes were made to the synopsis in 
line with those made in the body of the 
protocol.  
Changes were made to the synopsis to 
reflect the changes made to the body of 
the protocol to ensure consistency.  
Substantial 
Section 1.2 
Schedule of Activities 
Time windows were updated to read  
rather than +. 
This was updated to correct typographical 
errors. 
Non-substantial 
The MLGSSS assessment was added to 
the placebo run-in.   
The addition of the Maguire-Leal-
Garibaldi self-rated stuttering scale 
(MLGSSS) at the run-in visit was made to 
enable the assessment of placebo effect 
prior to randomization. 
Substantial 
It was added that medical history will 
include stuttering and psychiatric 
conditions 
This was updated to provide additional 
clarity. 
Non-substantial 
It was updated to state that the end of 
treatment visit will be completed as 
soon as possible after the last dose of 
study medication rather than after 
completion of study medication 
This was updated to provide additional 
clarity. 
Non-substantial 
Assessments of serology clinical 
laboratory assessments were added to 
the screening visit in SoA. 
Serology at screening added as previously 
omitted in error from the SoA. 
Non-substantial 
Assessment of IP accountability was 
added at all clinic visits following 
randomization. 
The assessment of drug accountability 
was added to ensure compliance is 
monitored. 
Non-substantial 
It was added that vital signs, 12-lead 
ECG, clinical chemistry, hematology, 
urinalysis, and urine drug screen will be 
performed at Day 71/EoT. 
These assessments had been previously 
omitted in error. 
Substantial 
The note for administration of IP was 
updated to state that ‘If there is no clinic 
visit or if the clinic visit is scheduled for 
later in the day IP can be taken in the 
morning at home’ 
This was added to provide clarity. 
Non-substantial 
Adverse events and concomitant 
medications monitoring was added from 
screening.  
This was to allow assessment of baseline 
characteristics.  
Substantial 
Section 1.2 
Schedule of Activities 
Section 3 
Objectives and Endpoints 
Section 8.2.3 
Severity of Patient’s 
Illness 
Section 9.4.4.2 
Secondary Endpoint(s) 
QIDS-16 assessment of mood was 
added. 
To evaluate the effect of NOE-105 on 
change in mood as rated by the patient 
Substantial 
Section 1.2 
Schedule of Activities 
The term “neurological” was removed. Neurological examinations were 
previously included in error and removed 
for consistency throughout the document.  
Substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Section 9.4.5 
Safety 
Section 2.1 
Study Rationale and 
Section 4.2 
Scientific Rationale for 
Study Design 
The term “serious motor, 
extrapyramidal, and metabolic 
antipsychotic side effects” was added. 
This term was added to more clearly 
describe the common side effects of other 
treatments used for stuttering. 
Non-substantial 
Section 2.2 
Background 
Update of background with addition of 
a reference. 
Updated to provide additional informationNon-substantial 
Section 2.3.1 
Risk Assessments 
The term ‘family’ was replaced by 
‘household’. 
This change was made in the event that 
patients do not live with family.  
Non-substantial 
The number of patients with 
schizophrenia previously treated was 
updated from 26 to 59. 
This change was made to correct a 
typographical error. 
Non-substantial 
Section 3 
Objectives and Endpoints 
Safety assessments were added. 
Safety assessments had been omitted 
from this list previously in error. 
Non-substantial 
“To evaluate the effect of NOE-105 on 
change in mood as rated by the patient 
using QIDS-16” was added 
To evaluate the effect of NOE-105 on 
change in mood as rated by the patient 
Substantial 
Section 4.1 
Overall Design 
It was confirmed that patients will be 
randomized to NOE-105 or placebo 1:1. 
Updated to provide additional clarity. 
Non-substantial 
It was confurmed that the follow-up 
examination will be performed 28 ( 7) 
days after the last dose of study 
medication.  
This was added to ensure consistency 
with the SoA. 
Non-substantial 
Section 4.2 
Scientific Rationale for 
Study Design 
The rationale for the endpoints, placebo 
control, 7-day run-in, variable 
randomization and parallel group design 
was added. 
Details were added to provide additional 
rationale for the study design. 
Non-substantial 
The dose previously administered to 
patients with schizophrenia was 
amended from 1 mg to 15 mg. 
This change was made to correct a 
previous typographical error. 
Non-substantial 
Section 5.1 
Inclusion criteria 
Criterion 2 was updated to ‘Patients 
who satisfy DSM-5 criteria for 
childhood onset fluency disorder and 
are suitable for pharmacotherapy’ as 
opposed to ‘requires pharmacotherapy’. 
This change was made to provide a more 
relevant term for COFD. 
Non-substantial 
Section 5.3.2 
Caffeine, Alcohol, and 
Tobacco 
The time period to restrict consumption 
of alcohol was confirmed to be from 
screening until the end of treatment. 
This change was made to provide clarity. Non-substantial 
Section 6.3 
Measures to Minimize 
Bias: Randomization and 
Blinding 
It was clarified that ‘patients who 
continue to meet all entry criteria will 
enter the treatment phase and will be 
randomized via an IVRS/IWRS to 
receive one of two treatments (NOE-
105 or placebo) on Day 1, Day 15, or 
Day 29.’ 
This additional detail was added to 
provide clarity. 
Non-substantial 
The term ‘variable duration’ regarding 
the placebo run-in period was removed.  
The placebo run-in is of fixed duration 
and orginal wording was included in 
error. 
Substantial 
Section 6.4 
Study Intervention 
Compliance 
It was added that drug accountability 
will be recorded in the eCRF. 
This change was made to confirm the 
study procedures. 
Non-substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Section 6.5 
Concomitant Therapy 
It was added that the recording of 
concomitant therapy should commence 
from the start of screening rather than 
from the time of enrolment. 
This change was made to provide 
additional clarity. 
Non-substantial 
Section 6.6 
Dose Modification 
The following was amended ‘In case of 
serious events of any dystonia, 
including severe events that necessitate 
pharmacological intervention’ and ‘In 
the event of dystonia that could threaten 
the airway the participant will 
discontinue participation in the study:  
patient should complete EOT and FU 
visits per protocol’ (new text in bold) 
This wording was amended to provide 
additional clarity. 
Non-substantial 
Section 6.7.1 
Participant Level 
Stopping Criteria 
The following was amended 
‘Discontinuation from study in case of 
severely abnormal clinical laboratory 
test abnormalities in unscheduled 
assessments’ (new text in bold) 
This wording was amended to provide 
additional clarity. 
Non-substantial 
Section 7.1 
Discontinuation of Study 
Intervention 
It has been added that discontinued 
patients may be replaced to ensure 54 
evaluable patients. 
This was added in case of unexpectedly 
high discontinuation rates. 
Substantial 
Section 8.1.1 
Medical History and 
Physical Examinations 
It was added that ‘Relevant medical 
history should be obtained from the 
patient at screening, including stuttering 
and psychiatric conditions.’ 
This was added to provide clarity. 
Non-substantial 
Section 8.1.2 
Vital signs 
The assessment of weight and height 
(screening only) were added. 
Respiratory rate was removed. 
Assessment of weight as part of the vital 
signs assessments was added to ensure 
patients are monitored for weight 
changes. Respiratory rate was removed as 
this is not required. 
Substantial 
Section 8.3.1 
Clinical Laboratory Tests 
It was confirmed that alcohol can be 
assessed using an alcohol breath test. 
This change was made to document a 
change in process. 
Non-substantial 
It was confirmed that clinically 
significant results obtained from non-
protocol required laboratory 
assessments will be recorded in the 
patient’s source notes. 
This was added to provide clarity. 
Non-substantial 
The recording of laboratory test results 
in the eCRF was removed. 
Since the laboratory tests will be centrally 
assessed the results will be provided 
centrally. 
Non-substantial 
Section 8.5 
Overdose 
The reference to Overdose eCRF page 
was removed. 
This was removed to correct a previous 
error as there is no specific overdose 
eCRF page. 
Non-substantial 
Section 9.2 
The definition of an enrolled patient 
was updated. 
This was updated to provide additional 
clarity.  
Non-substantial 
Section 9.4.2 
Inferential Statistics 
Section 9.4.4.1 
Primary Endpoint(s) 
Section 9.4.4.2 
Secondary Endpoints 
The definition of baseline was updated 
to the last measurement taken before 
randomization. 
The definition was updated for 
clarification. 
Substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Section 9.4.4.1 
Primary Endpoint(s) 
The number of questions in the 
MLGSSS assessment was removed. 
The number was removed since not all 
questions form part of the primary 
endpoint. 
Non-substantial 
Section 9.4.5 
Safety 
Urinalysis and ECG were added to list 
of assessments. 
These were previously omitted in error. 
Substantial 
Appendix E4 
Telemedicine visits to 
replace on-site visit 
(where applicable) 
The term ‘and skin biopsy’ was 
removed. 
This term was previously included in 
error. 
Non-substantial 
CGI-C, clinical global impression of change; COFD, childhood onset fluency disorder; C-SSRS, Columbia-
suicide severity rating scale; ECG, electrocardiogram; eCRF, electronic case report form; IB, Investigator’s 
Brochure; IDMB, independent data monitoring board; MLGSS, Maguire-Leal-Garibaldi Self-rated Stuttering 
Scale; MSQ, medication satisfaction questionnaire; PGI-C, patient global impression of change; PGI-S, patient 
global impression of severity; QIDS-16, quick inventory of depressive symptomology, SoA, schedule of 
activities.  
 
 
Version 1.0 Amendment 1 Australia (05 May 2022)  
This is a substantial amendment as it contains changes that will directly affect the study 
patients.  
 
Overall Rationale for the Amendment:  
The primary rationale for this amendment is provide additional safety measures to mitigate the 
risk of dystonia with NOE105. 
 
Section # and Name  
Description of Change  
Brief Rationale  
Substantial/ 
Non-
substantial  
Title Page 
The title of the study was amended to 
change the treatment duration from “6 to 
10 weeks” to “10 weeks”. 
The duration of treatment 
includes the entire double-
blind period which is 
10 weeks. 
Substantial 
Throughout 
Minor typographical and editorial changes 
were made.  
To correct previous 
typographical errors and to 
provide clarification. 
Non-
substantial 
The terms “subject” and “participant” 
(when used in the context of taking part in 
the study) were replaced with the term 
“patient”. 
This was made to ensure 
consistency throughout the 
document and to adhere to the 
Sponsor’s SOPs.  
Non-
substantial 
Abbreviated terms and definitions are 
newly included in the list of abbreviations 
New abbreviations included, 
consistent with the amended 
text. 
Non-
substantial 
Synopsis 
Changes were made to match those made 
in the body of the protocol. 
Changes were made to ensure 
consistency. 
Substantial 
Section 1.2 
Schedule of Activities  
Details of whether visits will be conducted 
in clinic or remotely were added. 
This addition was made to 
provide additional clarity 
regarding how assessments 
will be made.  
Non-
substantial 
It was updated to state that the end of 
treatment visit will be completed as soon 
This was updated to provide 
additional clarity. 
Non-
substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/ 
Non-
substantial  
as possible after the last dose of study 
medication rather than after completion of 
study medication.  
Additional clinic visits were added at Days 
8, 22, 36, 43, and 64, and remote visits at 
50, and 57.    
To mitigate the risk of 
intolerance, on site 
administration will take place 
for Dose 1, at each weekly 
dose increase, and at weekly 
intervals up to and including 
Week 8. In addition, 
MLGSSS will be conducted at 
weekly intervals throughout 
the study.  
Substantial  
C-SSRS assessment has been added to 
every in-clinic visit and the baseline 
assessment will be made a Week -1. 
In order to detect newly 
emerging suicidal ideation and 
behavior the C-SSRS will be 
assessed every week during 
study treatment.  
Substantial 
SAS assessments have been added at D1, 
D50, and Day 71/EoT. 
SAS has been added to 
investigate effects on motor 
function, coordination, and 
tremor.  
Substantial 
SSI-4 assessment to be performed at Days 
1 and 71 only. 
The number of assessments 
was reduced to optimize the 
frequency of scales to provide 
relevant information and limit 
the burden to the investigator 
and study patients. 
Substantial 
MLGSSS assessments to be performed 
every week during treatment. 
The increase in the frequency 
of assessments will allow for 
assessment of post-
randomization in patients who 
end treatment prematurely.  
Substantial 
PGI-S to be performed every week during 
treatment. 
The frequency of assessments 
was increased to allow for 
assessment of post-
randomization in patients who 
end treatment prematurely.  
Substantial 
PGI-C assessment to be performed at 
EoT/Day 71 and compared with the voice 
recording completed pre-dose on Day 1. 
PGI-S is added as an 
appropriate tool to assess 
stuttering providing a good 
insight into the conditions and 
patients’ perception of their 
condition.  
Substantial 
CGI-C assessment to be performed on 
EoT/Day 71 only. 
The clinical global assessment 
of change will use the 
investigator’s notes for the 
baseline assessment and 
assess change over the 
duration of treatment.  
Substantial 
SDS to be assessed on Days 1 and 
EoT/Day 71. 
The number of assessments 
was reduced to optimize the 
Substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/ 
Non-
substantial  
frequency of scales to provide 
relevant information and limit 
the burden to the investigator 
and study patients. 
Assessments of serology clinical 
laboratory assessments were added to the 
screening visit in SoA. 
Serology at screening added 
as previously omitted in error 
from SoA. 
Non-
substantial 
The note for administration of IP was 
updated to state that ‘If there is no clinic 
visit or if the clinic visit is scheduled for 
later in the day IP can be taken in the 
morning at home’. 
This was added to provide 
clarity. 
Non-
substantial 
Assessment of IP accountability was 
added at all clinic visits following 
randomization.  
The assessment of drug 
accountability was added to 
ensure compliance is 
monitored. 
Non-
substantial 
Section 1.2  
Schedule of Activities  
Section 4.1 
Overall Design 
It was added that eligibility assessment 
may include a video interview to confirm a 
minimal severity of moderate stuttering.   
To ensure recruitment of 
patients with moderate 
stuttering, an independent 
confirmation will be made for 
the first patients. 
Substantial 
Section 1.2 
Schedule of Activities 
Section 3 
Objectives and Endpoints 
Section 8.2.3 
Severity of Patient’s 
Illness 
Section 9.4.4.2 
Secondary Endpoint(s) 
QIDS-16 assessment of mood was added. This scale was added to 
capture psychological impacts 
of COFD. 
Substantial 
Section 1.2 
Schedule of Activities 
Section 8.1.1 
Medical history 
Physical/neurological examinations have 
been split into separate assessments. 
Neurological examination at Screening, 
D50, Day 71/EoT, and at follow-up has 
been added. Addition of stuttering and 
psychiatric conditions as relevant 
conditions to be documented as Medical 
History. 
In order to detect newly 
emerging neurological events, 
an additional neurological 
examination will be 
performed at Day 50. 
Substantial 
Section 2.1 
Study Rationale 
The term “language fluency” was replaced 
by “speech fluency”. 
This change was made to 
provide a more accurate 
description of the term. 
Non-
substantial 
Section 2.1 
Study Rationale and 
Section 4.2 
Scientific Rationale for 
Study Design 
The term serious motor, extrapyramidal, 
and metabolic antipsychotic side effects 
was added. 
This term was added to more 
clearly describe the common 
side effects of other 
treatments used for stuttering.  
Non-
substantial 
Section 2.2.1 
NOE-105 
The term “first line therapies” was 
replaced with currently used therapies”. 
There are no defined lines of 
treatment for COFD, so the 
original term was not 
accurate. 
Non-
substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/ 
Non-
substantial  
Section 2.2 
Background 
Update of background with addition of a 
reference and description of the 
males/females ratio in COFD. 
Updated to provide additional 
information. 
Non-
substantial 
Section 2.3 
Risk Assessment 
Details of additional mitigation measures 
in the event of dystonia were added. 
Measures were added to 
provide further directions to 
investigators on how to 
mitigate the risk of dystonia. 
Substantial 
Oral anti-cholinergic biperiden was added. This was added to correct a 
previous omission. 
Substantial 
Section 3 
Objectives and Endpoints 
The secondary endpoints PGI-C was 
added.  
PGI-C is added as an 
appropriate tool to assess 
overall wellbeing providing a 
good insight into the 
conditions and participant’s 
perception of the change in 
their overall well-being.  
Substantial 
Clarification of the CGI-C was made. 
The description of the SSI-4 was added as 
number of syllables stuttered and duration 
of hesitance. 
Updates to secondary 
endpoints were made to 
provide additional clarity. 
Non-
substantial 
The ordering of secondary endpoints was 
updated. 
The secondary endpoints were 
reordered according to 
importance. 
Non-
substantial 
Safety assessments were added.  
Safety assessments had been 
omitted from this list 
previously in error. 
Non-
substantial 
Section 4.1 
Overall Design 
The description of the run-in period and 
the treatment period were updated with 
clarification of when randomization will 
occur and that randomization will be 1:1.  
The description of the run-in 
period and treatment period 
have been updated to provide 
additional clarity.  
Non-
substantial 
The maximum dose level for NOE-105 of 
15 mg was added. 
It was reiterated that patients 
will have their dose of 
NOE-105 increased until they 
reach a dose of 15 mg or their 
maximum tolerated dose. 
Non-
substantial 
Section 4.2 
Scientific Rationale for 
Study Design 
The term “language fluency” was replaced 
by “speech fluency”. 
This change was made to 
provide a more accurate 
description of the term. 
Non-
substantial 
The rationale for the endpoints, placebo 
control, 7-day run-in, variable 
randomization and parallel group design 
was added. 
Details were added to provide 
additional rationale for the 
study design.  
Non-
substantial 
The dose previously administered to 
patients with schizophrenia was amended 
from 1 mg to 15 mg. 
This change was made to 
correct a previous 
typographical error.  
Non-
substantial 
Section 5.1 
Inclusion criteria 
Criterion 2 was updated to ‘Patients who 
satisfy DSM-5 criteria for childhood onset 
fluency disorder and are suitable for 
pharmacotherapy’ as opposed to ‘requires 
pharmacotherapy’. 
This change was made to 
provide a more relevant term 
for COFD. 
Non-
substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/ 
Non-
substantial  
Criterion 10 “Fluency in the language of 
the investigator, study staff and the 
informed consent” was removed.  
This criterion is no longer 
required since all patients and 
clinical staff are required to 
speak English which is 
included in Criterion 9. 
Substantial 
Section 5.3.2 
Caffeine, Alcohol, and 
Tobacco 
The time period to restrict consumption of 
alcohol was confirmed to be from 
screening until the end of treatment.  
This change was made to 
provide clarity.  
Non-
substantial 
Section 5.3.3 
Activity 
Watching television and reading were 
removed as examples of light recreational 
activities. 
These examples were 
removed since they imply that 
all activities should be 
sedentary and light exercise is 
permitted. 
Non-
substantial 
Section 6.1.1 
Investigational Products 
The unit dose strength of 7.5 mg NOE105 
was added.  
This was added to correct a 
previous omission.  
Non-
substantial 
It was updated that N0E-105 is supplied in 
blister wallets. 
This update was made to 
reflect changes in the 
packaging. 
Non-
substantial 
Details of the NOE105 titration scheme 
were updated and moved to this section. 
The titration scheme was 
amended to provide additional 
clarity. 
Non-
substantial 
Section 6.2 
Preparation/Handling/ 
Storage/Accountability 
It was added that on site administration 
will take place for Dose 1, at each weekly 
dose increase, and at weekly intervals up 
to and including Week 8 and patients will 
be required to stay under supervision for 
1 hour post dose. 
Additional on-site 
administration of NOE105 
was added to mitigate the risk 
of dystonia. 
Substantial 
Section 6.3 
Measures to Minimize 
Bias: Randomization and 
Blinding 
The term “flexible” was removed when 
describing the duration of the run-in period 
and patients were denoted as entering the 
treatment phase.  
The term flexible was 
removed as the run-in period 
is now a fixed duration of 7 
days.  
Non-
substantial 
The person responsible for breaking the 
code was changed to “The 
pharmacovigilance function assigned by 
the Sponsor”. 
This change was made to 
reflect an administrative 
change in personnel. 
Non-
substantial 
Section 6.4 
Study Intervention 
Compliance 
It was added that drug accountability will 
be recorded in the eCRF. 
This change was made to 
confirm the study procedures. 
Non-
substantial 
Section 6.5 
Concomitant Therapy  
It was added that the recording of 
concomitant therapy should commence 
from the start of screening rather than 
from the time of enrolment. 
This change was made to 
provide additional clarity. 
Non-
substantial 
Section 6.6 
Dose Modification 
Remote follow up of patients prior to dose 
escalation was removed as all dose 
increases will be performed at clinic visits. 
To mitigate the risk of 
dystonia, each weekly dose 
increase will be performed at 
the clinical site.  
Substantial 
Dose titration details were changed from 
tabular format to text format.  
Dose titration details were 
moved to Section 6.1.1.  
Non-
substantial 
It was clarified that investigators will have 
the option to maintain patients at the same 
dose without further titration. 
This was added to provide 
clarity. 
Substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/ 
Non-
substantial  
Specific details on how to modify the dose 
in case of dystonia were added.  
Since dystonia has been noted 
as a risk with NOE105, 
specific instructions on how to 
dose modify in the case of 
dystonia are provided. 
Substantial 
Section 6.7 
Stopping Criteria 
This is a new section providing details of 
the IDMB. The IDMB will recommend 
termination of the study if the risk of 
treatment with NOE-105 exceeds the 
potential benefit of treatment. The IDMB 
will analyze the data before 
recommending if the study should 
continue or be stopped. 
Details were added to provide 
greater clarity and to 
introduce the role of the 
IDMB. 
Substantial 
Section 6.7.1 
Participant Level 
Stopping Criteria 
This is a new section providing stopping 
criteria for an individual participant.  
Details were added to provide 
clarity on criteria which 
would result in termination of 
a participant in the study.  
Substantial 
Section 6.7.2 
Study Level Stopping 
Criteria 
This is a new section providing stopping 
criteria for the entire study. 
Details were added to provide 
clarity on criteria which 
would result in termination of 
the study. 
Substantial 
Section 7.1 
Discontinuation of Study 
Intervention 
It has been added that discontinued 
patients may be replaced to ensure 54 
evaluable patients. 
This was added in case of 
unexpectedly high 
discontinuation rates. 
Substantial 
Section 8.1.2 
Vital signs 
The assessment of weight and height 
(screening only) were added. Respiratory 
rate was removed.  
Assessment of weight as part 
of the vital signs assessments 
was added to ensure patients 
are monitored for weight 
changes. Respiratory rate was 
removed as this is not 
required.  
Substantial 
Section 8.1.3 
Electrocardiograms 
It is confirmed that ECGs will be obtained 
after the patient has been resting in semi-
supine position for at least 10 minutes. For 
each timepoint, 3 ECG recordings should 
be taken at about 5 minute intervals. All 
ECGs will be performed on equipment 
provided by the Sponsor (or designee) and 
reviewed by site personnel and a 
core/central laboratory.  
Information was updated to 
provide additional clarity and 
to confirm a change in process 
that all ECGs will be reviewed 
and analyzed centrally.  
Substantial 
Section 8.2.1 
Speech fluency 
SSI-4 was added as an assessment. 
This was added to correct a 
previous omission in this 
section. 
Non-
substantial 
The text “MLGSSS will be provided in the 
study manual” was removed. 
The MLGSSS will be 
provided in electronic form to 
the study patients. 
Non-
substantial 
Section 8.2.2 
Overall functioning 
The text “The SDS will be provided in the 
study manual” was removed. 
Due to a change in procedure 
the SDS will no longer be 
provided in the study manual. 
Non-
substantial 
Section 8.2.3 
Severity of patient’s 
illness 
The text “The PGI-S and CGI-C will be 
provided in the study manual” was 
Due to a change in procedure 
the PCI-S, PGI-C and CGI-C 
no longer be provided in the 
Non-
substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/ 
Non-
substantial  
removed. PGI-C and QIDS-16 
assessments were added. 
study manual. PGI-C has 
previously been omitted in 
error.  
Section 8.2.4 
Acceptability assessment 
The text “The MSQ will be provided in the 
study manual” was removed.  
Due to a change in procedure, 
the MSQ scales will no longer 
be provided in the study 
manual. 
Non-
substantial 
Section 8.3.1 
Clinical Safety 
Laboratory Assessments 
It was confirmed that all samples will be 
analyzed at a central laboratory. Urine 
samples will be tested using dipsticks and 
only sent to the central laboratory in case 
of abnormal values.  
This change was made to 
document a change in process. 
Non-
substantial 
It was confirmed that alcohol can be 
assessed using an alcohol breath test. 
This change was made to 
document a change in process. 
Non-
substantial 
It was confirmed that clinically significant 
results obtained from non-protocol 
required laboratory assessments will be 
recorded in the patient’s source notes.  
This was added to provide 
clarity. 
Non-
substantial 
Section 8.3.2 
Other Safety 
Assessments 
It was added that assessment of motor 
function, coordination, and tremor will 
performed using SAS. 
The SAS was added to 
investigate effects on motor 
function, coordination, and 
tremor. 
Substantial 
Section 8.4.1 
Adverse Events of 
Special Interest 
This is a new section providing details on 
AESI for NOE-105.  
This change was to provide 
the investigators with a 
summary of available data on 
dystonia, which is the AESI 
identified for NOE-105 in 
clinical trials, with reference 
to IB for further information. 
Substantial 
Section 8.5 
Overdose 
The reference to Overdose eCRF page was 
removed. 
This was removed to correct a 
previous error as there is no 
specific overdose eCRF page.  
Non-
substantial 
9.2 
Sample size 
determination 
9.3 
Populations for Analysis 
The definition patients enrolled was 
updated to state patients who sign the ICF. 
The definition was updated 
for clarity.  
Non-
substantial 
Section 9.4.4.1 
Primary Endpoint(s) 
The number of questions in the MLGSSS 
assessment was removed.  
The number was removed 
since not all questions form 
part of the primary endpoint. 
Non-
substantial 
Section 9.4.4.1 
Primary Endpoint(s) 
Section 9.4.4.2 
Secondary Endpoints 
The definition of baseline was updated to 
the last measurement taken before first 
dose of study treatment following 
randomization.  
The definition was updated 
for clarification. 
Substantial 
9.4.4.2 
Secondary endpoint(s) 
The endpoint CGI-C was added. 
This endpoint had previously 
been omitted in error.  
Substantial 
The secondary endpoint PGI-CQIDS-16 
was added. 
This scale was added to 
capture psychological impacts 
of COFD..   
Substantial 
Section 9.4.5 
Safety 
Urinalysis and ECG were added to list of 
assessments.  
These were previously 
omitted in error.  
Substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/ 
Non-
substantial  
Appendix A.1.4 
Data quality assurance 
The reference to participant diaries and 
questionnaires has been replaced by 
electronic data capture. 
The use of paper diaries and 
questionnaires has been 
replaced by electronic data 
capture methods.  
Substantial 
Appendix D.1 
Chain of Custody 
The paragraph “Samples retained for 
further use will be stored in ?????? 
biobanks and will be registered by the 
????? during the entire life cycle” was 
removed. 
This paragraph was removed 
to correct a previous error 
since there are no samples to 
be retained for further use in 
this study.  
Non-
substantial 
Appendix E4 
Telemedicine visits to 
replace on-site visit 
(where applicable) 
The term ‘and skin biopsy’ was removed.  This term was previously 
included in error.  
Non-
substantial 
CGI-C, clinical global impression of change; COFD, childhood onset fluency disorder; C-SSRS, Columbia-
suicide severity rating scale; IB, Investigator’s Brochure; IDMB, independent data monitoring board; MLGSS, 
Maguire- Leal-Garibaldi Self-rated Stuttering Scale; PGI-C, patient global impression of change; PGI-S, patient 
global impression of severity; QIDS-16, quick inventory of depressive symptomology, SAS, Simpson-Angus 
scale, SDS, Sheehan disability scale; SSI-4, Stuttering Severity Instrument – Fourth Edition. 
 
Version 2 (03 March 2022)  
This is a substantial amendment as it contains changes that will directly affect the study 
participants.  
 
Overall Rationale for the Amendment:  
The primary rationale for this amendment is provide additional safety measures to mitigate the 
risk of dystonia with NOE-105. 
 
Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Title Page 
The title of the study was amended to 
change the treatment duration from “6 
to 10 weeks” to “10 weeks”. 
The duration of treatment includes 
the entire double-blind period which 
is 10 weeks. 
Substantial 
Throughout 
Minor typographical and editorial 
changes were made.  
To correct previous typographical 
errors and to provide clarification. 
Non-substantial 
The terms “subject” and “patient” 
(when used in the context of taking part 
in the study) were replaced with the 
term “participant”. 
This was made to ensure consistency 
throughout the document.  
Non-substantial 
Abbreviated terms and definitions are 
newly included in the list of 
abbreviations 
New abbreviations included, 
consistent with the amended text. 
Non-substantial 
Synopsis 
Changes were made to match those 
made in the body of the protocol. 
Changes were made to ensure 
consistency. 
Substantial 
Section 1.3  
Schedule of Activities  
Details of whether visits will be 
conducted in clinic or remotely were 
added. 
This addition was made to provide 
additional clarity regarding how 
assessments will be made.  
Non-substantial 
Additional visits were added at Days 8, 
22, 36, 43, 50, 57, and 64.    
To mitigate the risk of intolerence, 
on site administration will take place 
for Dose 1, at each weekly dose 
Substantial  
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
increase, and at weekly intervals up 
to and including Week 8. In 
addition, MLGSSS will be 
conducted at weekly intervals 
throughout the study.  
C-SSRS assessment has been added to 
every in-clinic visit. 
In order to detect newly emerging 
suicidal ideation and behavior the 
C-SSRS will be assessed every week 
during study treatment.  
Substantial 
SSI-4 assessment to be performed at 
Days 1 and 71 only. 
The number of assessments was 
reduced to optimize the frequency of 
scales to provide relevant 
information and limit the burden to 
the investigator and study 
participants. 
Substantial 
MLGSSS assessments to be performed 
every week during treatment. 
The increase in the frequency of 
assessments will allow for 
assessment of post-randomization in 
participants who end treatment 
prematurely.  
Substantial 
PGI-S to be performed every week 
during treatment. 
PGI-S is added as an appropriate 
tool to assess stuttering providing a 
good insight into the conditions and 
participants’ perception of their 
condition.  
Substantial 
PGI-C assessment to be performed on 
Day 71 and compared with the voice 
recording completed on Day 1. 
The number of assessments was 
limited to last scheduled visit or 
upon treatment discontinuation.  
Substantial 
CGI-C assessment to be performed on 
Day 71 only. 
The clinical global assessment of 
change will use the investigator’s 
notes for the baseline assessment 
and assess change over the duration 
of treatment.  
Substantial 
SDS to be assessed on Days 1 and 71. 
The number of assessments was 
reduced to optimize the frequency of 
scales to provide relevant 
information and limit the burden to 
the investigator and study 
participants. 
Substantial 
AEs and concomitant medications to be 
assessed during the follow up period 
This update was made to correct a 
previous error. 
Substantial 
Section 1.3  
Schedule of Activities  
Section 4.1 
Overall Design 
It was added that eligibility assessment 
may include a video interview to 
confirm a minimal severity of moderate 
stuttering.   
To ensure recruitment of participants 
with moderate stuttering, an 
independent confirmation will be 
made for the first participants. 
Section 2.1 
Study Rationale 
The term “language fluency” was 
replaced by “speech fluency”. 
This change was made to provide a 
more accurate description of the 
term. 
Non-substantial 
Section 2.2.1 
NOE-105 
The term “first line therapies” was 
replaced with currently used therapies”. 
There are no defined lines of 
treatment for COFD, so the original 
term was not accurate. 
Non-substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Section 2.3 
Risk Assessment 
Details of additional mitigation 
measures in the event of dystonia were 
added. 
Measures were added to provide 
further directions to investigators on 
how to mitigate the risk of dystonia. 
Substantial 
Oral anti-cholinergic biperiden was 
added. 
This was added to correct a previous 
omission. 
Substantial 
Section 3 
Objectives and Endpoints 
The secondary endpoints PGI-C was 
added.  
PGI-C is added as an appropriate 
tool to assess stuttering providing a 
good insight into the conditions and 
participant’s perception of their 
condition.  
Substantial 
Clarification of the CGI-C was made. 
The description of severity of stuttering 
as number of syllables stuttered and 
duration of hesitance. 
Updates to secondary endpoints 
were made to provide additional 
clarity. 
Substantial 
The ordering of secondary endpoints 
was updated. 
The secondary endpoints were 
reordered according to importance. 
Non-significant 
Section 4.1 
Overall Design 
The description of the run-in period and 
the treatment period were updated.  
The description of the run-in period 
and treatment period have been 
updated to provide additional clarity. 
Non-substantial 
The maximum dose level for NOE-105 
of 15 mg was added. 
It was reiterated that participants 
will have their dose of NOE-105 
increased until they reach a dose of 
15 mg or their maximum tolerated 
dose. 
Non-substantial 
Section 4.2 
Scientific Rationale for 
Study Design 
The term “language fluency” was 
replaced by “speech fluency”. 
This change was made to provide a 
more accurate description of the 
term. 
Non-substantial 
Section 5.1 
Inclusion criteria 
Criterion 10 “Fluency in the language of 
the investigator, study staff and the 
informed consent” was removed.  
This criterion is no longer required 
since all participants and clinical 
staff are required to speak English 
which is included in Criterion 9. 
Substantial 
Section 5.5.3 
Activity 
Watching television and reading were 
removed as examples of light 
recreational activities. 
These examples were removed since 
they imply that all activities should 
be sedentary and light exercise is 
permitted. 
Substantial 
Section 6.1.1 
Investigational Products 
The unit dose strength of 7.5 mg 
NOE-105 was added.  
This was added to correct a previous 
omission.  
Non-substantial 
It was updated that both N0E-105 and 
placebo are supplied in blister wallets. 
This update was made to reflect 
changes in the packaging. 
Non-substantial 
Details of the NOE-105 titration scheme 
were updated and moved to this section. 
The titration scheme was amended 
to provide additional clarity. 
Non-substantial 
Section 6.2 
Preparation/Handling/ 
Storage/Accountability 
It was added that on site administration 
will take place for Dose 1, at each 
weekly dose increase, and at weekly 
intervals up to and including Week 8 
and participants will be required to stay 
under supervision for 3 hours post dose. 
Additional on-site administration of 
NOE-105 was added to mitigate the 
risk of dystonia. 
Substantial 
Section 6.3 
Measures to Minimize 
Bias: Randomization and 
Blinding 
The term “flexible” was removed when 
describing the duration of the run-in 
period.  
The term flexible was removed as 
the run-in period is now a fixed 
duration of 7 days.  
Non-substantial 
The person responsible for breaking the 
code was changed to “The 
This change was made to reflect an 
administrative change in personnel. 
Non-substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
pharmacovigilance function assigned by 
the Sponsor”. 
Section 6.6 
Dose Modification 
Remote follow up of participants prior 
to dose escalation was removed as all 
dose increases will be performed at 
clinic visits.     
To mitigate the risk of dystonia, 
each weekly dose increase will be 
performed at the clinical site.  
Substantial 
Dose titration details were removed 
from this section.  
Dose titration details were moved to 
Section 6.1.1.  
Non-substantial 
It was clarified that investigators will 
have the option to maintain participants 
at their previously tolerated dose 
without further titration. 
This was added to provide clarity. 
Substantial 
Specific details on how to modify the 
dose in case of dystonia were added.  
Since dystonia has been noted as a 
risk with NOE-105, specific 
instructions on how to dose modify 
in the case of dystonia are provided. 
Substantial 
Section 6.7 
Stopping Criteria 
This is a new section providing details 
of the IDMB. The IDMB will 
recommend termination of the study if 
the risk of treatment with NOE-105 
exceeds the potential benefit of 
treatment. The IDMB will analyze the 
data before recommending if the study 
should continue or be stopped. 
Details were added to provide 
greater clarity and to confirm the 
role of the IDMB. 
Substantial 
Section 6.7.1 
Participant Level 
Stopping Criteria 
This is a new section providing stopping 
criteria for an individual participant.  
Details were added to provide clarity 
on criteria which would result in 
termination of a participant in the 
study.  
Substantial 
Section 6.7.2 
Study Level Stopping 
Criteria 
This is a new section providing stopping 
criteria for the entire study. 
Details were added to provide clarity 
on criteria which would result in 
termination of the study. 
Substantial 
Section 8.1.3 
Electrocardiograms 
It is confirmed that ECGs will be 
obtained after the participant has been 
resting semi-supine position for at least 
10 minutes. For each timepoint, 3 ECG 
recordings should be taken at about 
5 minute intervals. All ECGs will be 
performed on equipment provided by 
the Sponsor (or designee) and reviewed 
by site personnel and a core/central 
laboratory. In addition, all ECGs will be 
analyzed at the central laboratory. 
Information was updated to provide 
additional clarity and to confirm a 
change in process that all ECGs will 
be reviewed and analyzed centrally.  
Non-substantial 
Section 8.2.1 
Speech fluency 
SSI-4 was added as an assessment. 
This was added to correct a previous 
omission in this section. 
Substantial 
The text “MLGSSS, the severity subset 
of the MLGSSS, and the SSI-4 will be 
provided in the study manual” was 
removed. 
The MLGSSS and the severity 
subset of the MLGSSS will be 
provided in electronic form to the 
study participants, and the SSI-4 
scales will be provided to the 
participant in a paper format and 
both will be filed in the trial master 
file. 
Non-substantial 
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Section # and Name  
Description of Change  
Brief Rationale  
Substantial/Non-
substantial  
Section 8.2.2 
Overall functioning 
The text “The SDS will be provided in 
the study manual” was removed. 
The SDS scale will be provided to 
the participant in an electronic 
format and will be filed in the trial 
master file. 
Non-substantial 
Section 8.2.3 
Severity of participant’s 
illness 
The text “The PGI-S and CGI-C will be 
provided in the study manual” was 
removed. 
The PCI-S, PGI-C and CGI-C will 
be provided to the participant in an 
electronic format and will be filed in 
the trial master file. 
Non-substantial 
Section 8.2.4 
Acceptability assessment 
The text “The MSQ will be provided in 
the study manual” was removed.  
The MSQ scales will be provided to 
the participant in an electronic 
format and will be filed in the trial 
master file. 
Non-substantial 
Section 8.3.1 
Clinical Safety 
Laboratory Assessments 
It was confirmed that samples will be 
analyzed at a central laboratory. Urine 
samples will be tested using dipsticks 
and urine only sent to the central 
laboratory in case of abnormal values.  
This change was made to document 
a change in process. 
Non-substantial 
Section 8.4.1 
Adverse Events of 
Special Interest 
This is a new section providing details 
on AESI for NOE-105.  
This change was to provide the 
investigators with a summary of 
available data on dystonia, which is 
the AESI identified for NOE-105 in 
clinical trials, with reference to IB 
for further information. 
Substantial 
9.2 
Sample size 
determination 
The number of participants in the study 
has been updated.  
The number of participants was 
updated to align with details in the 
table and to correct a previous error.  
Non-substantial 
9.4.4.2 
Secondary endpoint(s) 
The endpoint CGI-C was added. 
This endpoint had previously been 
omitted in error.  
Substantial 
The secondary endpoint PGI-C was 
added. 
PGI-C is added as an appropriate 
tool to assess stuttering providing a 
good insight into the conditions and 
participant’s perception of their 
condition.   
Substantial 
Appendix A.1.4 
Data quality assurance 
The reference to participant diaries and 
questionnaires has been replaced by 
electronic data capture. 
The use of paper diaries and 
questionnaires has been replaced by 
electronic data capture methods.  
Substantial 
Appendix D.1 
Chain of Custody 
The paragraph “Samples retained for 
further use will be stored in ?????? 
biobanks and will be registered by the 
????? during the entire life cycle” was 
removed. 
This paragraph was removed to 
correct a previous error since there 
are no samples to be retained for 
further use in this study.  
Non-substantial 
CGI-C, clinical global impression of change; COFD, childhood onset fluency disorder; C-SSRS, Columbia-
suicide severity rating scale; IB, Investigator’s Brochure; IDMB, independent data monitoring board; MLGSS, 
Maguire- Leal-Garibaldi Self-rated Stuttering Scale; MSQ, medication satisfaction questionnaire; PGI-C, patient-
reported clinical global impression of change; PGI-S, patient-reported clinical global impression of severity; 
SDS, Sheehan disability scale; SSI-4, Stuttering Severity Instrument – Fourth Edition. 
 
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ABBREVIATIONS 
Abbreviation 
Definition 
AE  
Adverse event  
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
ALT  
Alanine aminotransferase  
aPTT  
Activated partial thromboplastin time  
AST  
Aspartate aminotransferase  
AUC  
Area under the curve  
AUCinf 
Area under the curve to infinity 
AUCtau 
Area under the curve over the dosing interval 
BDRM 
Blinded data review meeting 
BL 
Baseline 
BMI 
Body mass index 
C 
Clinic (visit) 
cAMP 
Cyclic adenosine monophosphate  
CGI  
Clinical Global Impression 
CGI-C 
Clinical Global Impression of Change 
CONSORT 
Consolidated standards of reporting trials 
CPT  
Continuous performance test 
CRO  
Contract research organization  
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
D1, D2 
Dopamine 1, dopamine 2 receptor 
DMTS 
Delayed-match-to-sample 
DS 
Developmental stuttering 
ECG 
Electrocardiogram 
eCRF  
Electronic Case Report Form  
EDC  
Electronic data capture  
EFD 
Embryo fetal development 
EoT 
End of treatment 
EPS 
Extra pyramidal symptoms 
FDA 
Food and drug administration 
GABA 
γ-aminobutyric acid 
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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
HCP 
Health care professional 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV  
Human immunodeficiency virus  
HV 
Healthy volunteer 
IB  
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDMB 
Independent data monitoring board 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio  
IP 
Investigational Product 
IQ 
Intelligence quotient 
IRB 
Institutional Review Board 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system  
MAD  
Multiple Ascending Doses  
MedDRA 
Medical dictionary for regulatory activities 
MLGSSS 
Maguire-Leal-Garibaldi Self-rated Stuttering Scale 
mRNA 
Messenger ribonucleic acid 
MSN 
Medium spiny neuron 
MSQ 
Medication satisfaction questionnaire 
MTD 
Maximum tolerated dose 
NMDA 
N-methyl-D-aspartate 
NOAEL  
No observed adverse event level  
NOEL 
No observed event level  
OD 
Once daily 
OGTT 
Oral glucose tolerance test 
PDE10A 
Phosphodiesterase 10A 
PET 
Positron emission tomography 
PGI-C 
Patient global impression of change 
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Abbreviation 
Definition 
PGI-S 
Patient global impression of severity 
PI 
Principal investigator 
PK  
Pharmacokinetic  
PT 
Prothrombin time 
Q1, Q3 
First quartile, third quartile 
QIDS-16 
Quick inventory of depressive symptomology 
QIDS-C16 
Quick inventory of depressive symptomology, clinician version 
QIDS-SR16 
Quick inventory of depressive symptomology, self-report version 
R 
Remote (visit) 
RBC 
Red blood cell 
SAD  
Single ascending dose  
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
scPCP 
Subchronic phencyclidine 
SD 
Standard deviation 
SDS 
Sheehan disability scale 
SOP 
Standard operating procedure 
SOSS 
Self-ordered spatial search 
SSI-4 
Stuttering Severity Instrument – Fourth Edition 
SSS 
Self-rated stuttering scale 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Half-life 
tmax 
Time to maximum concentration 
TPV 
Third party vendor 
ULNR 
Upper limit of normal range 
US 
United States 
W 
Week 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
 
 
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11 
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