A Randomized Double-blind, Parallel-Group, Virtual Study to Evaluate the Effectiveness and Safety of Two Digital Therapeutics in Late Adolescents and Adults for the Prevention of Episodic Migraine
Phase: NA
Conditions: Migraine, Episodic Migraine, Headache, Headache, Migraine
Sponsor: Click Therapeutics, Inc.

Click Therapeutics, Inc. 
 Clinical Study Protocol Amendment 3 
CT-132 
 
CT-132-R-001 
 
CONFIDENTIAL 
1 
 
May 2024 
 
 
 
 
 
Protocol 
Product Name/Number: 
CT-132 
Protocol Number: 
CT-132-R-001 
 
Study Phase: 
Pivotal 
Brief Title: 
Randomized Study of a Digital Therapeutic (CT-132) for the 
Prevention of Episodic Migraine 
Protocol Title: 
A Randomized Double-blind, Digital-Controlled, Parallel-Group, 
Virtual Study to Evaluate the Effectiveness and Safety of a Digital 
Therapeutic (CT-132) as Adjunctive Therapy in Late Adolescents 
and Adults for the Prevention of Episodic Migraine   
Version: 
Approval Date: 
Protocol Amendment 3 
08 May 2024 
Medical Monitor 
Medical monitor contact information will be provided separately. 
 
 
 
 
 
 
This document is a confidential communication of Click Therapeutics, Inc. This document may not be used, 
divulged, published, or otherwise disclosed without the consent of Click Therapeutics, Inc. This study will be 
performed in compliance with Good Clinical Practices and applicable regulatory requirements. 
80 White Street, 3rd Floor 
New York, New York 10013 
 

Click Therapeutics, Inc. 
 Clinical Study Protocol Amendment 3 
CT-132 
 
CT-132-R-001 
 
CONFIDENTIAL 
2 
 
May 2024 
 
 
Approval Signatures 
 
Protocol Number: 
CT-132-R-001 
Version: 
Protocol Amendment 3 
Issue Date: 
08 May 2024 
 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5/9/2024
5/8/2024

Click Therapeutics, Inc. 
 Clinical Study Protocol Amendment 3 
CT-132 
 
CT-132-R-001 
 
CONFIDENTIAL 
3 
 
May 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5/8/2024
5/8/2024

Click Therapeutics, Inc. 
 Clinical Study Protocol Amendment 3 
CT-132 
 
CT-132-R-001 
 
CONFIDENTIAL 
13 
 
May 2024 
 
TABLE OF CONTENTS 
 
1. 
PROTOCOL SUMMARY .................................................................................................16 
1.1. 
Synopsis ................................................................................................................................15 
1.2. 
Schedule of Activities and Assessments ...............................................................................22 
2. 
INTRODUCTION ..............................................................................................................24 
2.1. 
Study Rationale .....................................................................................................................24 
2.2. 
Background ...........................................................................................................................24 
2.2.1. 
Migraine ................................................................................................................................24 
2.2.2. 
CT-132 ..................................................................................................................................25 
2.3. 
Benefit/Risk Assessment ......................................................................................................26 
2.3.1. 
Risk Assessment ...................................................................................................................26 
2.3.2. 
Benefit Assessment ...............................................................................................................26 
2.3.3. 
Overall Benefit: Risk Conclusion .........................................................................................26 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................27 
4. 
STUDY DESIGN.................................................................................................................29 
4.1. 
Overall Design ......................................................................................................................29 
4.1.1. 
Screening Period (Day -42 to Day -29) ................................................................................30 
4.1.2. 
Run-In Period (Day -28 to Day -1) .......................................................................................30 
4.1.3. 
Baseline Virtual Visit (Day 1) ..............................................................................................30 
4.1.4. 
Double-Blind Intervention Period (Day 1 - Week 12)..........................................................31 
4.1.5. 
Follow-Up Period (Up to 1 week) ........................................................................................31 
4.2. 
Scientific Rationale for Study Design ..................................................................................31 
4.3. 
Justification for Dose ............................................................................................................32 
4.4. 
End of Study Definition ........................................................................................................32 
5. 
STUDY POPULATION .....................................................................................................33 
5.1. 
Inclusion Criteria ..................................................................................................................33 
5.2. 
Exclusion Criteria .................................................................................................................34 
5.3. 
Lifestyle Considerations .......................................................................................................35 
5.4. 
Screen Failures ......................................................................................................................35 
5.5. 
Criteria for Temporarily Delaying ........................................................................................35 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ................................36 
6.1. 
Study Interventions Administered ........................................................................................36 
6.1.1. 
CT-132 ..................................................................................................................................36 
6.1.2. 
Control ..................................................................................................................................37 
6.1.3. 
Medical/Investigational Devices ...........................................................................................37 
6.2. 
Preparation/Handling/Accountability/Disposition................................................................37 

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6.3. 
Measures to Minimize Bias: Randomization and Blinding ..................................................37 
6.4. 
Study Intervention Adherence ..............................................................................................38 
6.4.1. 
Study App Adherence Monitoring ........................................................................................39 
6.5. 
Dose Modification ................................................................................................................39 
6.6. 
Continued Access to Study Intervention after the End of the Study ....................................39 
6.7. 
Treatment of Overdose .........................................................................................................39 
6.8. 
Concomitant Therapy ...........................................................................................................39 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ............................................40 
7.1. 
Discontinuation of Study Intervention ..................................................................................40 
7.2. 
Participant Discontinuation/Withdrawal from the Study ......................................................40 
7.3. 
Lost to Follow-up..................................................................................................................40 
8. 
STUDY ASSESSMENTS AND PROCEDURES .............................................................42 
8.1. 
Study Assessments ................................................................................................................42 
8.1.1. 
Migraine Patient Journey Questionnaire ...............................................................................42 
8.1.2. 
Monthly Migraine Days (MMD) ..........................................................................................42 
8.1.3. 
Identify Chronic Migraine (ID-CM) .....................................................................................42 
8.1.4. 
Migraine-Specific Quality-of-Life (MSQ ) ..........................................................................42 
8.1.5. 
Migraine Disability Assessment Scale (MIDAS) .................................................................42 
8.1.6. 
42 
8.1.7. 
42 
8.1.8. 
43 
8.1.9. 
43 
8.1.10. Patient Global Impression of Change (PGI-C) .....................................................................43 
8.2. 
Study App Engagement Assessments ...................................................................................43 
8.3. 
Safety Assessments ...............................................................................................................43 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting ...................................................................................................................43 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .................................44 
8.4.2. 
Method of Detecting AEs and SAEs ....................................................................................44 
8.4.3. 
Follow-up of AEs and SAEs .................................................................................................44 
8.4.4. 
Regulatory Reporting Requirements for SAEs .....................................................................44 
8.4.5. 
Pregnancy ..............................................................................................................................45 
8.4.6. 
Reporting of Investigational Device Complaints ..................................................................45 
8.5. 
Pharmacokinetics ..................................................................................................................45 
8.6. 
Genetics and/or Pharmacogenomics .....................................................................................45 
8.7. 
Biomarkers ............................................................................................................................45 
8.8. 
Immunogenicity Assessments...............................................................................................45 

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8.9. 
Health Economics .................................................................................................................45 
9. 
STATISTICAL CONSIDERATIONS ..............................................................................46 
9.1. 
Statistical Hypotheses ...........................................................................................................46 
9.2. 
Sample Size Determination ..................................................................................................46 
9.3. 
Analysis Sets .........................................................................................................................46 
9.4. 
Statistical Analyses ...............................................................................................................47 
9.4.1. 
General Considerations .........................................................................................................47 
9.4.2. 
Participant’s Disposition .......................................................................................................48 
9.4.3. 
Demographics and Baseline Characteristics .........................................................................48 
9.4.4. 
Primary Endpoint ..................................................................................................................48 
9.4.5. 
Secondary Endpoints ............................................................................................................49 
9.4.6. 
Multiplicity Control ..............................................................................................................49 
9.4.7. 
Exploratory Endpoints ..........................................................................................................50 
9.4.8. 
Safety Analysis .....................................................................................................................50 
9.5. 
Interim Analysis ....................................................................................................................50 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..........................................................................................................51 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..............................51 
10.1.1. Regulatory and Ethical Considerations .................................................................................51 
10.1.2. Financial Disclosure..............................................................................................................51 
10.1.3. Informed Consent Process ....................................................................................................52 
10.1.4. Data Protection......................................................................................................................52 
10.1.5. Committees Structure............................................................................................................52 
10.1.6. Dissemination of Clinical Study Data...................................................................................52 
10.1.7. Data Quality Assurance ........................................................................................................52 
10.1.8. Source Documents ................................................................................................................53 
10.1.9. Study and Site Start and Closure ..........................................................................................53 
10.1.10. Publication Policy .................................................................................................................54 
10.2. 
Appendix 2: Clinical Laboratory Tests .................................................................................55 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...............................................................55 
10.3.1. Definition of SAE .................................................................................................................56 
10.3.2. Recording and Follow-Up of AE and/or SAE ......................................................................57 
10.3.3. Reporting of SAEs ................................................................................................................59 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ................................................................59 
10.5. 
Appendix 5: Genetics............................................................................................................59 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ..........................................................................................................................60 

Click Therapeutics, Inc. 
 Clinical Study Protocol Amendment 3 
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10.7. 
Appendix 7: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies ..........................................................60 
10.7.1. Definition of Medical Device AE and ADE .........................................................................60 
10.7.2. Definition of Medical Device SAE, SADE and USADE .....................................................60 
10.7.3. Recording and Follow-Up of AE and/or SAE ......................................................................61 
10.7.4. Reporting of SADEs .............................................................................................................63 
10.8. 
Appendix 8: Country-specific Requirements .......................................................................63 
10.9. 
Appendix 9: Abbreviations and Definitions .........................................................................63 
10.10. 
Appendix 10: Protocol History .............................................................................................66 
11. 
References ............................................................................................................................70 
 
LIST OF IN-TEXT TABLES 
 
Table 1: 
Study Endpoints .......................................................................................................28 
Table 2: 
Study Interventions ..................................................................................................30 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1: 
Study Design Schema ...............................................................................................30 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Product Number 
CT-132 
Protocol 
Number 
CT-132-R-001 
Brief Title: 
Randomized Study of a Digital Therapeutic (CT-132) for the Prevention of Episodic 
Migraine 
Protocol Title 
A Randomized Double-blind, Digital-Controlled, Parallel-Group, Virtual Study to 
Evaluate the Effectiveness and Safety of a Digital Therapeutic (CT-132) as 
Adjunctive Therapy in Late Adolescents and Adults for the Prevention of Episodic 
Migraine 
Development 
Phase 
Pivotal 
Indication 
CT-132 is a prescription digital therapeutic (PDT) indicated for the preventive 
treatment of episodic migraine in late adolescents and adults 18 years of age or older.  

Click Therapeutics, Inc. 
 Clinical Study Protocol Amendment 3 
CT-132 
 
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CONFIDENTIAL 
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Introduction and 
Study Rationale 
CT-132 is a novel PDT being developed by Click Therapeutics. CT-132 is a mobile 
application that provides an interactive, software-based intervention for the 
preventive treatment of episodic migraine in late adolescents and adults. 
The purpose of this study is to evaluate the effectiveness and safety of CT-132 
relative to a Digital Control in a randomized controlled trial with an adequate sample 
size of participants diagnosed with episodic migraine. If demonstrated to be 
efficacious, CT-132 would offer an important addition to currently available 
treatment options. 
Objective 
To evaluate the effectiveness and safety of CT-132 in reducing the number of 
monthly migraine days (MMDs), compared with a Digital Control, among late 
adolescents and adults with episodic migraine. 
Criteria for 
Evaluation 
All effectiveness endpoints are evaluated as a comparison between the treatment 
group and the control group. 
A participant’s baseline MMDs and MHDs will be the total number of migraine 
days recorded during the 28-day run-in period. The Week 12 MMDs and MHDs will 
be the total number of migraine days recorded over the previous 28 days (Weeks 9-
12). 
 
Primary Effectiveness Endpoint 
 
Change in the number of MMDs from baseline (28-day run-in period) to 
Week 12 (previous 28 days, Week 9 through Week 12). 
Secondary Effectiveness Endpoints 
 
Proportion of participants who have at least a 50% reduction from baseline 
(28-day run-in period) in the number of MMDs to Week 12 (previous 28 
days, Week 9 through Week 12).  
 
Change from baseline (28-day run-in period) in the number of MMDs 
recorded over the previous 28 days at Week 4 and at Week 8. 
 
Change from baseline (28-day run-in period) in the mean number of MMDs 
over 12 weeks. 
 
Change in the number of headaches with at least moderate severity from 
baseline (28-day run-in period) to Week 12 (previous 28 days, Week 9 
through Week 12). 
 
Change from baseline (28-day run-in period) in the Migraine-Specific 
Quality-of-Life Questionnaire v2.1 (MSQ) total score over the previous 28 
days at Week 4, Week 8, and Week 12. 
 
Change from baseline (28-day run-in period) in the Migraine Disability 
Assessment (MIDAS) to Week 12 (previous 28 days, Week 9 through Week 
12). 
 
Change from baseline (28-day run-in period) to Week 12 (previous 28 days, 
Week 9 through Week 12) in the number of migraines with use of an acute 
medication. 

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 
Change in the number of MHDs from baseline (28-day run-in period) to 
Week 12 (previous 28 days, Week 9 through Week 12). 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monthly headache days (MHDs) 
o Change from baseline (28-day run-in period) in the number of MHDs 
recorded over the previous 28 days at Week 4 and at Week 8 
o Proportion of participants who have at least a 50% reduction from 
baseline (28-day run-in period) in the number of MHDs at Week 12 
(previous 28 days, Weeks 9 through Week 12) 
o Change from baseline (28-day run-in period) in the mean number of 
MHDs over 12 weeks.  
 
Patient Global Impression of Change (PGI-C) score at Week 12 
 
Shift from High Frequency Episodic Migraine (HFEM) at baseline (28-day 
run-in period) to Very Low Frequency Episodic Migraine (VLFEM) or Low 
Frequency Episodic Migraine (LFEM) at Week 12 (previous 28 days, Week 
9 through Week 12)  
 
Safety Endpoints 
 
Frequency and severity of AEs, serious AEs, and discontinuation from the 
study due to AEs 
 
Frequency and severity of AEs related to the worsening of migraine 
 
 
Study Design 
This is a randomized double-blind, digital-controlled, parallel-group, virtual study to 
assess the effectiveness and safety of CT-132 in late adolescents and adults for the 
prevention of migraine in comparison to a Digital Control. 

Click Therapeutics, Inc. 
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The study consists of an up-to-14-day screening period, a 28-day run-in period, a 12-
week double-blind intervention period, and an up-to-7-day follow-up period for 
safety assessments. 
 
Study Design Schema 
 
 
 
Screening Period (Day -42 to -29) 
All participants will enter a screening period of up to 14 days to determine eligibility. 
Eligible participants must report having had at least four migraine days per month in 
the three months prior to the Screening Visit (a month is defined as 28 days). 
 
Prior to entering the screening period, participants will be asked to download the 
App (separate from the Study App) in order to provide consent to the 
trial and complete trial assessments, including self-administered scales. 
 
Run-In Period (Day -28 to -1) 
After completing the study onboarding activities, eligible participants will be 
contacted to schedule a remote video call to verify their identity and their migraine 
medication prescriptions. Once reviewed and verified, participants will be introduced 
to the Study App by downloading and installing the application onto their personal 
iPhone or Android smartphone. Only the eDiary component of the Study App will be 
activated. The eDiary contains items from the Migraine Disability Index (MIDI). 
 
Participants will then enter a 28-day run-in period during which they will enter daily 
headache information within the Study App to establish their baseline MMDs and 
determine Study App adherence and performance. Adherence to the onboarding 
requirements will be assessed by the investigator prior to randomization at the 
baseline visit. 
 
Baseline Virtual Visit (Day 1) 

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After completing the 28-day run-in period, the participant will be contacted for a 
Baseline Visit to review and confirm eligibility. Participants will be considered 
eligible for study entry based on all of the following criteria: 
 
Continuing to meet all other inclusion and no exclusion criteria, based on 
investigator assessment. 
 
Understanding of and adherence to the onboarding requirements and Study 
App (at 80% or greater adherence).  
 
Reporting within the Study App between 4-14 migraine days (inclusive) 
during the 28-day run-in period. 
 
Agreeing to complete the 12-week study intervention in good faith at the 
time of baseline virtual visit. 
Eligible participants will then be randomly assigned in a 1:1 ratio (CT-132: Digital 
Control) and the assigned full therapeutic app will be activated. Assessments and 
activities during this period will be performed remotely by telemedicine technology 
visits according to the SoA (Section 1.2). 
 
Double-Blind Intervention Period (12 Weeks) 
During the 12-week intervention period, the Study App will deliver either CT-132 or 
the Digital Control. Participants may use their prescribed medication to treat episodic 
migraine (including changes in medication or dosage) as needed while continuing to 
use the Study App on their regular schedule. Assessments and activities during this 
period will be performed remotely according to the Schedule of Activities and 
Assessments (Section 1.2). 
 
Follow-Up Period (Up to 1 week) 
Within one week of completion of the 12-week intervention period or withdrawal 
from the study, participants will complete the follow-up activities according to the 
Schedule of Activities and Assessments (Section 1.2). 
Planned Number 
of Participants 
Approximately 558 participants will be randomized in this study. 
Study Centers 
This will be a fully virtual study. Participants living in the United States will be 
enrolled and followed remotely through telemedicine visits. 
Study Entry 
Criteria 
Inclusion Criteria  
A participant will be eligible for entry into the study if all of the following criteria are 
met: 
1. Willing and able to provide written informed consent to participate in the study, 
attend study visits, and comply with study-related requirements and assessments. 
2. Lives in the United States. 
3. Adult or late adolescent, 18 years of age or older at the time of informed consent. 

Click Therapeutics, Inc. 
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4. Fluent in written and spoken English, confirmed by ability to read and understand 
the informed consent form. 
5. The following will be physician-reviewed: Participant has at least a 1-year history 
of migraine (with or without aura) consistent with a diagnosis according to the 
International Classification of Headache Disorders, 3rd Edition. 
i. Age of onset of migraines prior to 50 years of age 
ii. Migraine attacks, on average, lasting 4-72 hours if untreated 
 
iii. Per participant report, 4 or more migraine days per month within the last 
3 months prior to the Screening Visit (a month is defined as 28 days) 
iv. Four to fourteen migraine days during the run-in period 
6. Is currently managing migraines with ≥1 prescription acute treatment and/or 
prescription first or second-line preventive medications, as assessed by a 
physician. 
7. Is the sole user of an iPhone with an iPhone operating system (iOS) 14 or later or a 
smartphone with an Android operating system (OS) 11 or later and is willing to 
download and use the Study App required by the protocol. 
8. Is willing and able to receive SMS text messages and push messages on their 
smartphone. 
9. Is the owner of, and has regular access to, an email address. 
10. Has regular access to the Internet via cellular data plan and/or wifi. 
 
Exclusion Criteria 
A participant will not be eligible for study entry if any of the physician-reviewed 
criteria are met: 
 
1. History of basilar migraine or hemiplegic migraine. 
2. Active chronic pain syndromes, such as fibromyalgia, chronic pelvic pain, or 
complex regional pain syndrome (CRPS). 
3. Other pain syndromes (including trigeminal neuralgia), psychiatric conditions 
(such as major depressive episode, bipolar disorder, major depressive disorder, 
schizophrenia), dementia, or significant neurological disorders (other than 
migraine) that, in the Investigator’s opinion, might interfere with study 
assessments. 
4. History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 
months (48 weeks) or having met DSM-V criteria for any significant substance use 
disorder within the past 12 months (48 weeks) from the date of the screening visit. 
5. History of use of analgesics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs] 
or acetaminophen, including opioids) or butalbital on ≥ 15 days per month during 
the 3 months (12 weeks) prior to the Screening Visit or during the run-in period. 

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6. Currently taking a prescription anti-calcitonin gene-related peptide (CGRP) 
medication for either episodic or chronic migraine. 
7. Post-traumatic headache, persistent post-traumatic headache, or post-concussion 
syndrome. 
8. Other significant episodic or chronic medical condition(s) that in the opinion of the 
Investigator, may confound the interpretation of findings to inform PDT 
development. 
9. Failure to adhere with or inability to complete Study App inputs and onboarding 
activities during the run-in period. Participants who are not adherent during the 
run-in period are not eligible for study entry. 
10. Previous enrollment in any digital therapeutics pilot or pivotal study for a migraine 
indication. 
11. Participation in any other investigational clinical study while participating in this 
clinical study. 
 
Test Product and 
Mode of 
Administration 
Eligible participants will download and install the required Study App onto their own 
smartphone at the start of the run-in period. Participants will complete onboarding 
requirements during the run-in period and will be randomized to either CT-132 or 
Digital Control at the Baseline Visit (Day 1). 
Study Duration 
Participation in the study will last for approximately 19 weeks:  
 
Screening Period: Up to 2 weeks 
 
Run-In Period: 4 weeks 
 
Intervention Period: 12 weeks 
 
Follow-up Period: Up to 1 week 
Sample Size 
Approximately 558 participants are planned to be randomized in this study.   
Statistical 
Analysis 
Let μ1 and μ2 be the change from baseline in the MMD at the CT-132 and Digital 
Control arm, respectively. The null hypothesis for the primary endpoint is that the 
two are equal and the alternative hypothesis is that they are different.  
An Analysis of Covariance (ANCOVA) model will be used to test this hypothesis, 
where the dependent variable is the change from baseline to Week 12 in MMD for 
each participant. A participant’s baseline MMD will be the total number of migraine 
days recorded during the 28-day run-in period. The Week 12 MMD will be the total 
number of migraine days recorded over the previous 28 days (Weeks 9-12).  
The model will adjust for the following covariates: treatment arm, baseline MMD, 
and baseline use of concomitant medications for prevention of migraine. Analysis 
will be conducted on the Intent-to-Treat (ITT) analysis set. Multiple imputations 
under Missing At Random will be used to account for early termination or missing 
daily reports. Further details will be described in the SAP. 
No adjustment for multiplicity is planned for the secondary endpoints.  
 

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Study Day and Visit Window 
Screening/Run-In 
Intervention Period 
Follow-Up 
Screeningb 
Run-In 
Baseline 
Week 4 
Week 8 
Week 12/ET 
Week 13 
Days -42 to -29 Days -28 to -1 
Day 1 
+ 5 days 
Day 29 
± 3 days 
Day 57 
± 3 days 
Day 85 
± 3 days 
Days 86c to 92 
Study Visit Numbera 
n/a 
1 
2 
3 
4 
5 
6 
Study App Deactivation 
 
 
 
 
 
Xg 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 
 DOSE-Nonadherence measure = Domains of Subjective Extent Nonadherence measure; ET = 
Early Termination; ID-CM = Identify Chronic Migraine; MIDAS = Migraine Disability Assessment Scale; MSQ = Migraine-Specific Quality-of-Life 
Questionnaire; 
 PGI-C = Patient Global Impression of Change scale; 
 
a. 
All study visits are virtual and conducted via telemedicine. 
b. Screening Visit may occur up to fourteen (14) days before the run-in period. 
c. 
Follow-Up activities, to include revealing the trial hypothesis, to occur within one week of the final intervention period visit. This is at least one day after the 
Week 12 visit (between Day 86 and Day 92) or at least one day, but no more than seven days, after an Early Termination visit. 
d. Only the eDiary component of the Study App is used by the participant to complete run-in period activities. The run-in period consists of 28 days of data. 
However, per Study App design, participants may enter Day 28 data until Day 30. The Baseline Visit window will begin after Day 30. 
e. 
The full Study App is used every day by the participant during the indicated period. 
f. 
Adherence checks occur at baseline to confirm eligibility and as needed throughout the intervention period when a participant does not perform Study App 
Activities for 3 calendar days per Section 6.4. 
g. After completion of the intervention period (Day 84), the Study App will become inert. After Day 84, or upon study withdrawal, participants will not have 
continued access to the content provided by the Study App. 

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CONFIDENTIAL                                                 25    
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2. 
INTRODUCTION 
CT-132 is a novel prescription digital therapeutic (PDT) being developed by Click Therapeutics, 
Inc. CT-132 is a software-as-a-medical device (SaMD) mobile application that provides an 
interactive, software-based intervention for the preventive treatment of episodic migraine in late 
adolescents and adults. 
2.1. 
Study Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2. 
Background 
2.2.1. 
Migraine 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

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references to CT-132 or Digital Control should be made to the participant; both should only be 
referred to as the Study App. 
The activities and assessments during the 2-week screening period, the 4-week run-in period, the 
12-week double-blind intervention period, and the 1-week follow-up period will be completed 
according to the Schedule of Activities and Assessments (SoA; Section 1.2). Trial staff will 
implement procedures remotely. Participants will be assessed based on validated standard 
clinician-rated and participant-rated outcome scales for migraine at screening, the intervention 
period, and the follow-up period. Participants will also be evaluated for safety throughout the 
duration of the trial. 
4.1.1. 
Screening Period (Day -42 to Day -29) 
All participants will enter a screening period of up to 14 days to determine eligibility.  Eligible 
participants must report having had at least four migraine days per month in the three months 
prior to the Screening Visit (a month is defined as 28 days). 
 
Prior to entering the screening period, participants will be asked to download the 
 
App (separate from the Study App) in order to provide consent to the trial and complete trial 
assessments, including self-administered scales. 
4.1.2. 
Run-In Period (Day -28 to Day -1) 
After completing the study onboarding activities, eligible participants will be contacted to 
schedule a remote video call to verify their identity and their migraine medication prescriptions. 
Once reviewed and verified, participants will be introduced to the Study App by downloading 
and installing the application onto their personal iPhone or Android smartphone.  Only the 
eDiary component of the Study App will be activated. The eDiary contains items from the 
Migraine Disability Index (MIDI). 
 
Participants will then enter a 28-day run-in period during which they will enter daily headache 
information within the Study App to establish their baseline MMD and determine their 
adherence to and interest in the Study App. Adherence to the onboarding requirements will be 
assessed by the investigator prior to randomization at the baseline visit. Activities and 
assessments during this period will be performed remotely between the study personnel and the 
participant. 
 
The run-in period consists of 28 days of data. However, participants may enter data at Day 28 
through Day 30. The Baseline Visit window will begin after Day 30. 
4.1.3. 
Baseline Virtual Visit (Day 1) 
After completing the 28-day run-in period, eligible participants will have 3 days to complete 
baseline activities. Participants will attend a Baseline Visit via a telephone call to review and 
confirm eligibility. Participants will be considered eligible for study entry based on all of the 
following criteria: 

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 Continuing to meet all other inclusion and no exclusion criteria, based on investigator 
assessment. 
 Understanding of and adherence to the onboarding requirements and the Study App 
 
 
 Reporting within the Study App between 4-14 migraine days (inclusive) during the 28-
day run-in period. 
 Agreeing to complete the 12-week study intervention in good faith at the time of 
baseline virtual visit. 
 
Eligible participants will then be randomly assigned in a 1:1 ratio (CT-132:Digital Control). 
The Study App downloaded during the run-in period will be utilized to deliver the full 
therapeutic app. Participants will continue to utilize the eDiary component in the Study App 
throughout the study.  
The process for activating and accessing the full therapeutic application during the Baseline Visit 
will be the same for CT-132 digital intervention and the Digital Control.  The randomization 
process electronically unlocks one of two experiences in the Study App: the CT-132 
investigational therapy or the Digital Control. Study staff will complete the randomization 
process by giving the participant a code to proceed in the Study App. This code serves as a 
gatekeeper to confirm that the randomization process has been completed correctly and that the 
participant may continue in the study. This randomization process is designed in a way to 
minimize unblinding risk for the participant and the study staff. Participants are considered 
enrolled upon randomization. 
4.1.4. 
Double-Blind Intervention Period (Day 1 - Week 12) 
During the 12-week intervention period, the Study App will deliver either CT-132 or the Digital 
Control. The Study App will instruct participants to perform tasks daily. Participants may use 
their prescribed medication to treat episodic migraine, as needed, while continuing to use the 
Study App on their regular schedule. Assessments and activities during this period will be 
performed remotely according to the Schedule of Activities and Assessments. (SoA; Section 1.2)  
4.1.5. 
Follow-Up Period (Up to 1 week) 
After the end of Week 12, the Study App will become inert and no longer provide treatment. 
Within one week of completion of the 12-week intervention period or withdrawal from the study, 
participants will complete activities according to the Schedule of Activities and Assessments. 
(SoA; Section 1.2)  
At the conclusion of a participant’s participation in the study, study staff will inform the 
participant of the trial hypothesis (i.e., that one digital therapeutic was hypothesized to be more 
beneficial in preventing episodic migraine), but there was a need for a trial to confirm. Study 
staff will be provided with language to use for this notification. 

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4.2. 
Scientific Rationale for Study Design 
The purpose of the proposed study is to evaluate the effectiveness and safety of CT-132 relative 
to a Digital Control in a randomized controlled trial with an adequate sample size of participants 
diagnosed with migraine and are taking first and second-line preventive medications. If 
demonstrated to be effective, CT-132 would offer an important addition to current first and 
second-line preventive migraine treatment options.   
Recent studies on Global Burden of Diseases, Injuries, and Risk Factors have reported headache, 
including migraine, as a major global public health concern and one of the main causes of 
disability worldwide, particularly in young adults and middle-aged women. A peak in prevalence 
and years of life lived with disability for migraine occurs between ages 35 and 39 years. In both 
sexes, the percentages of all years lived with disability (YLDs) is highest in the group aged 
15-49 years (migraine 8.2%) and has a high prevalence in individuals aged 50–69 years 
(migraine 4.2%).  (GBD 2016 Headache Collaborators, 2016)  
In children and early adolescents (aged under 18 years), attacks may last 2–72 hours (the 
evidence for untreated durations of less than two hours in children has not been substantiated). 
Migraine headache in children and early adolescents is more often bilateral than in adults or late 
adolescents; unilateral pain usually emerges in late adolescence or early adult life. (ICHD-3, 
2018) Due to this similar pathophysiology and clinical symptomology in late adolescence or 
early adult life, the Sponsor selected a study population including late adolescents and adults 
aged 18 years or older. The selected patient population is similar to the population studied in 
pivotal trials of Erenumab and Fremanezumab indicated for the preventive treatment of migraine 
in adults aged 18 years or older.  
Thus, as described in the device description, given the significant impact of migraine on daily 
activities, and the high incidence and prevalence in the population aged 18 years or older, it is 
clinically important that the product be evaluated and labeled for use in late adolescents and 
adults aged 18 years or older.  
In order to reduce bias, study participants will be blinded to the hypothesis and treatment 
assignment, and informed that they will receive one of the two digital interventions being 
studied. The use of a comparator Digital Control poses minimal risk as all participants are 
maintained on their background therapy of SoC. See Section 6.3 for further information. 
4.3. 
Justification for Dose 
Not applicable. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last contact, or the date of final contact attempt, 
for the last participant completing or withdrawing from the trial.  
For the purposes of this trial, participants who complete the trial assessments at Day 84 (Week 
12) will be defined as completers. 
 

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5. 
STUDY POPULATION 
 
Migraine prevalence peaks in middle life and is lower in adolescents and those older than age 60 
years. Migraine is also about three times more prevalent in females than males (Lipton, 2007). 
As guided by the FDA’s Industry Guidance for Evaluation and Reporting of Age, Race, and 
Ethnicity Specific Data in Medical Device Clinical Studies (FDA’s Industry Guidance, Sep 
2017), study enrollment will reflect current migraine prevalence trends and will enroll 
participants reflecting the characteristics of clinically relevant population.  
 
Eligible participants who are enrolled will be randomized and receive the Study App at Baseline. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
 
5.1. 
Inclusion Criteria 
A participant will be eligible for entry into the study if all of the following inclusion criteria are 
met: 
 
1. Willing and able to provide written informed consent to participate in the study, attend 
study visits, and comply with study-related requirements and assessments. 
2. Lives in the United States. 
3. Adult or late adolescent, 18 years of age or older at the time of informed consent. 
4. Fluent in written and spoken English, confirmed by ability to read and understand the 
informed consent form. 
5. The following will be physician-reviewed: Participant has at least a 1-year history of 
physician-diagnosed migraine (with or without aura) consistent with a diagnosis 
according to the International Classification of Headache Disorders, 3rd Edition 
(ICHD-3): 
i. Age of onset of migraines prior to 50 years of age 
ii. Migraine attacks, on average, lasting 4-72 hours if untreated 
iii. Per participant report, 4 or more migraine days per month within the last 
3 months prior to the Screening Visit (a month is defined as 28 days) 
iv. Four to fourteen migraine days during the run-in period 
6. Is currently managing migraines with ≥1 prescription acute treatment and/or 
prescription first or second-line preventive medications, as assessed by a physician. 
7. Is the sole user of an iPhone with an iPhone operating system (iOS) 14 or later or a 
smartphone with an Android operating system (OS) 11 or later and is willing to 
download and use the Study App required by the protocol. 

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8. Is willing and able to receive SMS text messages and push messages on their 
smartphone. 
9. Is the owner of, and has regular access to, an email address. 
10. Has regular access to the Internet via cellular data plan and/or wifi. 
 
5.2. 
Exclusion Criteria  
A participant will not be eligible for study entry if any of the following criteria are met: 
 
1. 
History of basilar migraine or hemiplegic migraine. 
2. 
Active chronic pain syndromes, such as fibromyalgia, chronic pelvic pain, or complex 
regional pain syndrome (CRPS). 
3. 
Other pain syndromes (including trigeminal neuralgia), psychiatric conditions (such as 
major depressive episode, bipolar disorder, major depressive disorder, schizophrenia), 
dementia, or significant neurological disorders (other than migraine) that, in the 
Investigator’s opinion, might interfere with study assessments. 
4. 
History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 
months (48 weeks) or having met DSM-V criteria for any significant substance use 
disorder within the past 12 months (48 weeks) from the date of the screening visit. 
5. 
History of use of analgesics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs] or 
acetaminophen, including opioids) or butalbital on ≥ 15 days per month during the 3 
months (12 weeks) prior to the Screening Visit or during the run-in period. 
6. 
Currently taking a prescription anti-calcitonin gene-related peptide (CGRP) 
medication for either episodic or chronic migraine. 
7. 
Post-traumatic headache, persistent post-traumatic headache, or post-concussion 
syndrome. 
8. 
Other significant acute or chronic medical condition(s) that, in the opinion of the 
Investigator, may confound the interpretation of findings to inform PDT development. 
9. 
Failure to adhere with or inability to complete Study App inputs and onboarding 
activities during the run-in period. Participants who are not adherent during the run-in 
period are not eligible for study entry. 
10. Previous enrollment in any digital therapeutics pilot or pivotal study for a migraine 
indication. 
11. Participation in any other investigational clinical study while participating in this 
clinical study. 
 
 

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5.3. 
Lifestyle Considerations 
Participants should have routine access to their smartphones for the duration of the trial. In 
addition, they should be able to attend remote telemedicine visits during the trial. Participants 
should refrain from using alcohol, recreational drugs, or prohibited medications during the times 
the Study App will be accessed.  
5.4. 
Screen Failures 
A screen failure is a participant from whom informed consent is obtained and is documented in 
writing (i.e., participant signs an informed consent form; ICF), but who is not randomized or 
assigned trial intervention. Investigators must account for all participants who sign the informed 
consent documentation. 
If a participant is found to not meet eligibility criteria for randomization into the study, the 
investigator will complete the required Electronic Case Report Form (eCRF) pages. The primary 
reason for screen fail will be recorded in the eCRF using the following categories: 
 Pretreatment AE or serious adverse event (SAE) as per investigator judgement 
 Did not meet eligibility criteria (inclusion and exclusion criteria) 
 Lost to follow-up 
 Voluntary withdrawal 
 Major protocol deviation 
 Study termination 
 Other (specify reason) 
Participant ID numbers assigned to participants who screen fail will not be reused. Individuals 
who do not meet the criteria for participation in this study (screen failure) may not be rescreened. 
5.5. 
Criteria for Temporarily Delaying 
Not applicable. 
 

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6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY 
6.1. 
Study Interventions Administered 
The CT-132-R-001 Study App will administer participants with one of two study interventions. 
Study interventions are CT-132 PDT and a comparator Digital Control (Table 2). 
 
Table 2: 
Study Interventions  
 
 
CT-132 
Digital Control 
Type  
SaMD 
SaMD 
Dose Formulation 
PDT under development 
App 
Unit Dose Strength(s) 
N/A 
N/A 
Dosage Level(s) 
N/A 
N/A 
Route of Administration 
Digital 
Digital 
Use 
Experimental 
Comparator 
IMP and NIMP 
N/A 
N/A 
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Packaging and Labeling 
Digital 
Digital 
Current/Former Name(s) 
or Alias(es) 
N/A 
N/A 
PDT = prescription digital therapeutic; IMP = investigational medicinal product; N/A = not applicable; 
NIMP = non-investigational medicinal product; SaMD = software-as-a-medical device 
6.1.1. 
CT-132 
CT-132 is a prescription digital therapeutic intended to reduce monthly migraine days in 
individuals with episodic migraine. CT-132 consists of a mobile application that delivers 
therapeutic content and support throughout a 12-week treatment experience. CT-132 will only be 
accessible via prescription and is intended to be used only under the supervision of a clinician. 
CT-132 is a mobile application that provides an interactive, software-based intervention for the 
prevention of migraine in late adolescents and adults aged 18 years or older. 
 
 
 
 
 
  

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6.1.2. 
Control 
A Digital Control application will be used as a comparator group in this trial. The application 
will be a comparable digital experience with similar daily engagement levels for the prescribed 
period of time. 
6.1.3. 
Medical/Investigational Devices 
 
1. The sponsor-manufactured medical device provided for use in this study is CT-132 and 
Digital Control (both referred to as the Study App) manufactured by Click Therapeutics, 
Inc. 
2. Instructions for medical device use are provided in the CT-132-R-001 Study App 
Instructions. 
3. All device deficiencies (including malfunction, use error and inadequate labelling) will be 
documented and reported by the investigator throughout the clinical investigation (see 
Section 10.7) and appropriately managed by the sponsor. 
6.2. 
 
 
 
 
 
 
 
 
 
 
. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
 
Study using 
IVRS/IWRS 
All participants will be centrally assigned to randomized study 
intervention using an Interactive Web Response System (IWRS). The 
IWRS will be integrated into the electronic data collection (EDC) system.  

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Study team(s) will refer to the randomization information in the EDC 
system. 
The study intervention (Study App) will be downloaded, activated, and 
deleted at the study visits summarized in the SoA. 
Blind Break 
(IWRS) 
The IWRS will be programmed with blind-breaking instructions. In case 
of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participants’ intervention assignment is 
warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the 
sponsor prior to unblinding a participant’s intervention assignment unless 
this could delay emergency treatment of the participant. Once a 
participant’s intervention assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation and 
case report form, as applicable. 
Blinding 
Participants will be randomly assigned in a 1:1 ratio to receive either the 
CT-132 or Digital Control as study intervention through the Study App. 
Investigators and designated personnel will remain blinded to each 
participant’s assigned study intervention throughout the course of the 
study.  
To protect the blind between the participant and site staff, a small subset 
of virtual site staff will be designated as unblinded. The unblinded virtual 
site staff will perform regulatory and administrative duties as well as 
provide patient support as needed.  
The sponsor’s trial management team will not have access to unblinded 
data codes and safeguards will be implemented to ensure that sponsor 
cannot access blinding codes during the trial. 
Study Hypothesis 
Blind 
Study participants will be blinded to the effectiveness hypothesis of the 
study. Both treatment arms will be presented to the participant as possible 
treatments for migraine. No references to CT-132 or Digital Control will 
be made to the participant. This approach limits the risk of participant 
unblinding to treatment assignment and expected effectiveness.    
 
Assigned safety personnel may unblind the intervention assignment for any participant with an 
SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the participant’s intervention assignment, may be sent 
to investigators in accordance with local regulations and/or sponsor policy. 

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6.4. 
Study Intervention Adherence 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
6.5. 
Dose Modification 
Not applicable. 
6.6. 
Continued Access to Study Intervention after the End of the Study 
Not applicable. 
6.7. 
Treatment of Overdose 
Not applicable. 
6.8. 
Concomitant Therapy 
Participants will continue to use their prescribed first and second-line preventive and acute 
therapies for migraine management while enrolled in this study. Participants are not allowed to 
use prohibited medications throughout the duration of the study. 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will complete 
early termination assessments as per the SoA (Section 1.2). 
Events that could result in permanent discontinuation of study intervention include: 
 Nonadherence 
 Use of prohibited concomitant medications 
 Use of prohibited recreational medications 
 Investigator’s discretion 
The Study App on the discontinued participant's smartphone device will be disabled as described 
in Section 6.2. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
 
Study staff should make every effort to encourage participants to remain in the study and to 
continue to use the Study App. A participant may withdraw from the study at any time at their 
own request or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons. This is expected to be uncommon. 
A participant cannot withdraw consent for use of data already collected as part of the study. If 
the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
Participants who prematurely discontinue study participation must complete the early 
termination procedures as described in the SoA (Section 1.2). Participants who discontinue use 
of the Study App prematurely should ideally be observed until the end of the study as if they 
were still using the Study App. The Study App on the discontinued participant's smartphone 
device will be disabled as described in Section 6.2. For all participants, the reason for 
discontinuation (e.g., AEs) must be recorded in the eCRF. These data will be included in the 
study database and reported. 
Participants who are not actively using the Study App may be less motivated to adhere to the 
study visit schedule. Investigators and study staff should work to detect early signs of waning 
interest and encourage continued participation.  
 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to attend scheduled 
visits and is unable to be contacted by the study investigator or designee. 
The following actions must be taken if a participant fails to attend a required study visit: 

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 The investigator or designee must attempt to contact the participant and reschedule the 
missed visit as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the participant 
wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant. Study staff will conduct a minimum of 
3 communication attempts (via chat, SMS, email, or telephone). These contact attempts 
should be documented in the participant’s record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures, including their timing, are summarized in the SoA 
(Section 1.2). Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. Protocol waivers or exemptions are not allowed. 
Every effort should be made to ensure that the protocol required assessments and procedures are 
completed as described. All scales should be administered by individuals who have been 
appropriately trained. Study procedures are described in Section 4.1. Effectiveness and safety 
assessments are described below. 
8.1. 
Study Assessments 
The following effectiveness assessment scales are used in this trial at the times as provided in the 
SoA (Section 1.2). A description of the scales and the respective scoring algorithms for all 
endpoints will be provided in the Statistical Analysis Plan (SAP). 
8.1.1. 
Migraine Patient Journey Questionnaire 
The Migraine Patient Journey Questionnaire is a 4-item Click-generated self-report questionnaire 
to characterize migraine history.  
8.1.2. 
Monthly Migraine Days (MMD) 
Participants will record the number of days per month (defined as 28 days) a participant 
experiences migraine events within the Study App. 
8.1.3. 
Identify Chronic Migraine (ID-CM) 
The Identify Chronic Migraine (ID-CM) (Lipton, 2016) is a 12-item self-report standardized 
assessment designed to assess presence of self-report migraine diagnosis and subsequently 
categorizes respondents as meeting diagnostic criteria for either episodic or chronic migraine.  
8.1.4. 
Migraine-Specific Quality-of-Life (MSQ) 
The  Migraine-Specific Quality-of-Life Questionnaire version 2.1 (MSQ) (Rendas-Baum, 2013) 
is a 14-item questionnaire that measures the impact of migraine across three essential aspects of 
a patient’s health-related quality of life over the past 4 weeks. 
8.1.5. 
Migraine Disability Assessment Scale (MIDAS) 
The Migraine Disability Assessment (MIDAS) (Stewart, 1999) questionnaire is a brief, self-
report 7-item questionnaire designed to quantify headache-related disability over a 3-month 
period.  
8.1.6. 
 
 
  

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8.1.7. 
  
 
 
 
8.1.8. 
 
 
 
.  
‘  
8.1.9. 
 
 
 
 
  
 
8.1.10. 
Patient Global Impression of Change (PGI-C) 
The Patient Global Impression of Change (PGI-C) is a self-reported, 7-point scale depicting a 
patient’s rating of overall improvement. PGI-C has been validated in a number of other episodic 
diseases against well-established measures of pain intensity, pain interference in daily life, and 
treatment effectiveness. (Perrot, 2019) 
 
8.2. 
Study App Engagement Assessments 
 
 
 
 
 
 
8.3. 
Safety Assessments 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.3.2. 
The definitions of device-related safety events, (adverse device effects [ADEs] and serious 
adverse device effects [SADEs]), can be found in Section 10.7.1 and Section 10.7.2, 
respectively.  
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 

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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until 
the follow-up visit at the time points specified in the SoA (Section 1.2). 
AEs will be divided into non-treatment-emergent AEs (non-TEAEs) and treatment-emergent 
AEs (TEAE). Non-TEAEs are those AEs that occurred prior to the first study treatment and 
TEAEs are those AEs with onset date/time at or after the first study treatment.  
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 

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An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file 
it along with other appropriate documentation (e.g., Investigator’s Brochure) and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.4.5. 
Pregnancy 
Pregnancy will not be excluded from participating in the study. However, because pregnancy is a 
major life event, the sponsor will track pregnancy status. Details of all pregnancies in female 
participants will be collected after the start of study intervention and until the end of Week 13. 
If a pregnancy is reported, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the female participant 
pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any female participant who becomes pregnant while participating in the study can continue in 
the study as planned. Prior to continuation of study intervention following pregnancy, the 
investigator must agree to monitor the outcome of the pregnancy and the status of the participant 
and her offspring. 
8.4.6. 
Reporting of Investigational Device Complaints 
An investigational device complaint (IDC) is any written, electronic, or oral communication by a 
HCP, consumer, participant, medical representative, regulatory agency, partner, or other third 
party that alleges Inadequacy of a medical device related to its identity, quality, durability, 
reliability, safety, or performance, such as malfunction, misuse or use error and inadequate 
labeling. 
For this study, all IDCs related to the Study App are reportable to the sponsor. 
8.4.6.1. 
Eliciting and Reporting Device Complaints 
During the study, possible or suspected Study App IDCs will be gathered by Click via Click’s 
technical support resource. Instructions for reporting IDCs can be found in the Study App 
Instructions. 
8.5. 
Pharmacokinetics 
Not applicable. 
8.6. 
Genetics and/or Pharmacogenomics 
Not applicable. 
8.7. 
Biomarkers 
Not applicable. 

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8.8. 
Immunogenicity Assessments 
Not applicable. 
8.9. 
Health Economics 
Not applicable. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary endpoint is the change from baseline in the number of MMD at Week 12. The null 
hypothesis for the primary endpoint is that there is no difference between the means of the 
treatment arms and the alternative hypothesis is that they are different.  
An Analysis of Covariance (ANCOVA) model will be used to test this hypothesis, where the 
dependent variable is the change from baseline to Week 12 in MMD for each participant. A 
participant’s baseline MMD will be the total number of migraine days recorded during the 28-
day run-in period. The Week 12 MMD will be the total number of migraine days recorded over 
the previous 28 days (Weeks 9-12).  
The model will adjust for the following covariates: treatment arm, baseline MMD, and baseline 
use of concomitant medications for prevention of migraine. Analysis will be conducted on the 
Intent-to-Treat (ITT) analysis set. Multiple imputations under Missing At Random will be used 
to account for early termination or missing daily reports. Further details will be described in the 
SAP.  
The null hypothesis will be rejected in favor of the alternative hypothesis if the two-sided p-
value is smaller than 0.05 and the result favors the CT-132 arm. 
No adjustment for multiplicity is planned for the secondary endpoints.  
9.2. 
Sample Size Determination 
Assuming a difference of 1.6 in the mean MMD between the two arms, and a common Standard 
Deviation (SD) of 5.8, 474 participants are required for the study (237 per arm) to ensure 85% 
power and using a two-sided alpha of 5%.  
Sample size was calculated using a two-sample t-test assuming equal variance. Assuming 15% 
drop out, at least 558 participants will be randomized in a 1:1 ratio to CT-132 or Digital Control. 
9.3. 
Analysis Sets 
 
For the purposes of analysis, the following analysis sets are defined: 
Analysis Set 
Description 
Consented 
All participants who signed the ICF. 
Enrolled 
All participants who signed the ICF and completed the run-in 
period. 
Intent-To-Treat (ITT) 
The ITT set includes all enrolled participants who were 
randomized, based on the assigned intervention in the 
randomization and recorded in the database, regardless of 
treatment by Study App intervention.  
This will be the main analysis set for all effectiveness analysis. 
 

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Modified Intent-to-Treat 
(mITT) 
 
 
 
 
 
 
 
 
 
 
Per Protocol (PP) 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
All randomized participants who were exposed to study 
intervention (completed at least one task). Participants will be 
analyzed according to the intervention they received. This 
analysis set will be used for all safety analyses. 
 
9.4. 
Statistical Analyses 
The SAP will be finalized prior to database lock and it 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 of the most important endpoints including primary and secondary 
endpoints. 

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9.4.1. 
General Considerations 
For continuous variables, summary tables will provide the number of observations [n], mean, 
standard deviation, median, minimum and maximum. For categorical variables, summary tables 
will provide the number of observations [n] and frequency of each category (including missing 
data). Tabulations will be presented by treatment and overall, when appropriate. 
Modeling and testing will be described for each endpoint.  
9.4.2. 
Participant’s Disposition 
The number of participants who were screened and enrolled to the study will be presented, as 
well as the reason for not being randomized. The number of participants who discontinue the 
study will be presented by reason for discontinuation. The number of participants in the ITT, 
mITT, PP, and safety analysis set will be presented. 
9.4.3. 
Demographics and Baseline Characteristics 
In order to assess the comparability of the two arms at baseline, demographic and baseline 
characteristics data will be summarized by treatment group. These summaries will be presented 
for the ITT set. If there is a difference of more than five participants in the total number of 
participants between the ITT and the safety, mITT and PP analysis sets, the summaries will be 
presented for these sets. 
9.4.4. 
Primary Endpoint 
The primary analysis will include the ITT set. 
The primary endpoint is change in the number of MMDs from baseline (28-day run-in period) to 
Week 12 (previous 28 days, Week 9 through Week 12). The primary endpoint will be analyzed 
using an ANCOVA model, where the dependent variable is the change from baseline to Week 12 
in MMD for each participant. A participant’s baseline MMD will be the total number of migraine 
days recorded during the 28-day run-in period. The Week 12 MMD will be the total number of 
migraine days recorded over the previous 28 days (Weeks 9-12).  
The model will adjust for the following covariates: treatment arm, baseline MMD, and baseline 
use of concomitant medications for prevention of migraine. Multiple imputations under Missing 
At Random will be used to account for early termination or missing daily reports. Details of 
imputation will be described in the SAP.  
Least Squares Means (LSMEANS) for the difference in the change from baseline between the 
two treatment arms will be presented as well as the associated 95% confidence interval and two-
sided p-value to test the null hypothesis of no difference. The study will be considered successful 
if the two-sided p-value will be ≤ 0.05. 
9.4.4.1. 
Sensitivity Analysis for Primary Endpoint 
The primary analysis will be repeated for the mITT and PP analysis sets. 
The SAP will define additional analyses to assess impact of missing data.   

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9.4.4.2. 
Subgroups 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.5. 
Secondary Endpoints 
 
Analysis of secondary endpoints will include the ITT set. 
 Proportion of participants that have at least 50% reduction from baseline (28-day run-in 
period) in the number of MMDs to Week 12 (previous 28 days, Week 9 through Week 
12).  The proportion of patients who have at least a 50% reduction in MMDs will be 
compared between the two treatment groups using the normal approximation for 
difference between two proportions, for each of the complete data sets. The results will 
be combined using Rubin’s rule. 
 Change from baseline (28-day run-in period) in the number of MMDs recorded over the 
previous 28 days at Week 4 and at Week 8 will be analyzed in the same manner as the 
primary endpoint.  
 Change from baseline (28-day run-in period) in the mean number of MMDs over 12 
weeks. The endpoint will be analyzed in the same manner as the primary endpoint.  
 Change in the number of headaches with at least moderate severity from baseline (28-
day run-in period) to Week 12 (previous 28 days, Week 9 through Week 12). An 
ANCOVA model will be used to analyze this endpoint. 
 Change from baseline (28-day run-in period) in the Migraine-Specific Quality-of-Life 
Questionnaire v2.1 (MSQ) total score over the previous 28 days at Week 4, Week 8, 
and Week 12. An ANCOVA model will be used to analyze this endpoint. 
 Change from baseline in the Migraine Disability Assessment (MIDAS) to Week 12. 
This endpoint will be analyzed using Wilcoxon rank-sum test. 

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 Change from baseline (28-day run-in) to Week 12 (previous 28 days, Week 9 through 
Week 12) in the number of migraines with use of an acute medication. An ANCOVA 
model will be used to analyze this endpoint. 
 Change in the number of MHDs from baseline (28-day run-in period) to Week 12 
(previous 28 days, Week 9 through Week 12). The endpoint will be analyzed in the 
same manner as the primary endpoint, using MHDs instead of MMDs. 
The SAP will elaborate on the analysis of other endpoints, covariates and handling of missing 
data. 
9.4.6. 
Multiplicity Control 
No multiplicity adjustment will be made to secondary endpoints, sensitivity analyses, and 
subgroups. 
9.4.7. 
Exploratory Endpoints 
Exploratory endpoints will be summarized descriptively by treatment arm. Further details will be 
described in the SAP. 
9.4.8. 
Safety Analysis 
All safety analysis will be conducted on the safety analysis set and will be descriptive. The SAP 
will elaborate on the safety analysis. 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory Activities 
(MedDRA) preferred team. The incidence of AEs and SAEs recorded through the study will be 
presented with the following categories: 
 Number of AE and number of participants with at least one AE 
 Number of SAE and number of participants with at least one SAE 
 Number of related AE (based on causality as assessed by the investigator) and number of 
participants with at least one related AE  
 Number of related SAE and number of participants with at least one related SAE 
 Number of AE leading to study discontinuation 
 Number of AE leading to death 
9.5. 
Interim Analysis 
No interim analysis is planned. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
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, Investigator Brochure and other relevant documents 
(e.g., 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 participants.  
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 
participants. 
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, pregnancies or other significant safety findings as 
required by IRB/IEC procedures 
 Providing oversight of the conduct of the study 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. 
10.1.2. 
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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10.1.3. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study to the 
participant or their legally authorized representative and answer all questions regarding 
the study. 
 Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
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 participant record, if applicable, must include a statement that written informed 
consent was obtained before the participant was enrolled in the study and the date the 
written consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
 Participants must be re-consented 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 participant or their legally authorized 
representative. 
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant 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 participant who will be required to give consent for their data to be used as 
described in the informed consent form. 
The participant must be informed that his/her participant 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. 
10.1.5. 
Committees Structure 
An independent Data Safety Monitoring Board is not planned. 
10.1.6. 
Dissemination of Clinical Study Data 
Research study results will be available on ClinicalTrials.gov and may be available through 
publication in peer-reviewed scientific journals. 
10.1.7. 
Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

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 Guidance on completion of CRFs will be provided separately. 
 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 (e.g., 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 Clinical Monitoring Plan (CMP). 
 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 (e.g., 
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. 
10.1.8. 
Source Documents 
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed by the investigator. 
 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 participant records must be available. 
 Definition of what constitutes source data can be found separately. 
 The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 Study monitors will perform ongoing source data verification 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 participants 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. 
 
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The first act of recruitment is the first informed consent signed and will be the study start date. 

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Study Termination 
The sponsor or designee reserves the right to terminate the study at any time, for any reason, at 
the sole discretion of the sponsor.  
The investigator may initiate study 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 may include but are not limited to: 
 
 For study termination: 
o Discontinuation of further study intervention development 
 
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 participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy 
 
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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CBT 
cognitive behavioral therapy 
CGRP 
calcitonin gene-related peptide 
 
 
CIOMS 
Council for International Organizations of Medical Sciences, International 
Ethical Guidelines 
CMP 
Clinical Monitoring Plan 
CRF 
case report form 
CRPS 
complex regional pain syndrome 
CT-132 
A novel prescription digital therapeutic that is being developed by Click 
Therapeutics that delivers an interactive, software-based intervention for 
prevention of migraine. 
DAS 
Defeatist Beliefs Subscale of the Dysfunctional Attitudes Scale 
DRE(s) 
disease-related event(s) 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DTx 
digital therapeutic 
eCRF 
electronic case report form 
EDC 
electronic data collection 
ET 
early termination 
 
 
GCP 
Good Clinical Practice Guidelines 
hCG 
human chorionic gonadotropin 
HFEM 
High Frequency Episodic Migraine 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICD-10 
International Classification of Diseases, Tenth Revision 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICH GCP 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, Good Clinical Practice 
Guidelines 
ID-CM 
Identify Chronic Migraine 

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IDC 
investigational device complaint 
IDFU 
Investigational Directions for Use 
IEC(s) 
Independent Ethics Committee(s) 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
iOS 
iPhone operating system 
IRB(s) 
Institutional Review Board(s) 
ITT 
intent-to-treat 
LFEM 
Low Frequency Episodic Migraine 
MDR 
medical device regulation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHD 
monthly headache day(s) 
MIDAS 
Migraine Disability Assessment 
MIDI 
Migraine Disability Index 
mITT 
modified intent-to-treat 
MMD 
monthly migraine day(s) 
MMRM 
Mixed Models Repeated Measures 
MSQ 
Migraine-Specific Quality-of-Life Questionnaire 
NIMP 
non-investigational medicinal product 
NSAID 
nonsteroidal anti-inflammatory drug 
PDT 
prescription digital therapeutic 
PGI-C 
Patient Global Impression of Change  
 
 
PMR 
progressive muscle relaxation 
PP 
per protocol 
QTLs 
Quality Tolerance Limits 
SADE 
serious adverse device effect 
SAE(s) 
serious adverse event(s) 
SaMD 
software-as-a-medical device 
SAP 
Statistical Analysis Plan 

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SDS 
Sheehan Disability Scale 
SMS 
short message service (the most common form of text messages) 
SoA 
Schedule of Assessments and Activities 
SoC 
standard of care 
TOC 
table of contents 
ULN 
upper limit of normal 
USADE/UADE 
unanticipated serious adverse device effect/ unanticipated adverse device 
effect 
VLFEM 
Very Low Frequency Episodic Migraine 
WHODAS 2.0 
WHO Disability Assessment Schedule 2.0 
YLD 
years lived with disability 
 
10.10. 
Appendix 10: Protocol History 
 
 
DOCUMENT HISTORY 
Document 
Date 
Protocol Amendment 3 
08 May 2024 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 

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11. 
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