Conditions: Atrial Fibrillation
Keywords: atrial fibrillation ventricular rate control rapid ventricular rate etripamil
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 69
Healthy volunteers: no

Brief summary:
Many patients with atrial fibrillation (AF) experience persistent tachycardia with episodes of rapid ventricular rate despite chronic treatment to reduce ventricular rate. The objectives of this study were to demonstrate the superiority of a nasal spray of etripamil over placebo in reducing ventricular rate in patients with AF; and to evaluate the safety and efficacy of etripamil nasal spray in participants with AF.

Detailed description:
This was a multi-center, randomized, double-blind, placebo-controlled study to evaluate the effects of etripamil nasal spray in participants with AF. This study included Screening, the Treatment Period (Screening and Treatment Period occur on the same day) and safety follow-up procedures.

Each participant received placebo or 70 mg of etripamil intranasally; treatment were randomized in a 1:1 ratio, to yield 50 evaluable participants with AF in 2 groups of 25.

Participants with AF were selected by the Investigator. The screening procedures included obtaining informed consent, a review of inclusion/exclusion criteria, a complete physical examination, and recording of any concomitant medications.

After screening procedures were complete, eligible participants were randomized to receive etripamil or placebo. Heart rate was measured continuously via Holter Electrocardiogram (ECG) from at least 10 minutes prior to dosing to 6 hours after study drug administration. Participants had to exhibit a rapid ventricular rate (≥110 bpm measured during 1 minute) on the Holter report prior to drug administration in order to receive the study drug. Beyond 60 minutes after study drug administration, medical care was offered in accordance with the standard of care and the participant was discharged from the clinic, while still wearing the Holter device.

Participants underwent a safety follow-up assessment and return the Holter device approximately 24 hours post-dose. Participants were contacted by phone 7 days post-dosing for safety follow-up.

Arms:
arm 1: Administration of placebo at the emergency department for an episode of atrial fibrillation arm 2: Administration of 70 mg etripamil at the emergency department for an episode of atrial fibrillation

Interventions: intervention 1: Etripamil intervention 2: Placebo
Intervention descriptions: intervention 1: The formulation of etripamil nasal spray consists of MSP-2017 (etripamil), water, acetic acid, disodium ethylene-diamine-tetra-acetic acid (EDTA), and sulfuric acid. The dose of etripamil to be evaluated in this study is 70 mg. intervention 2: The formulation of placebo nasal spray consists of water, sodium acetate, disodium, disodium ethylene-diamine-tetra-acetic acid (EDTA), and sulfuric acid to reproduce the same pH as the etripamil formulation.

Protocol document:
Prot_000.pdf: 
Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 1 of 62 
CLINICAL STUDY PROTOCOL 
 
Multi-Centre, Placebo-Controlled, Phase 2 Study of 
Etripamil Nasal Spray (NS) for the Reduction of Ventricular 
Rate in Patients with Atrial Fibrillation  
 
The ReVeRA-201 Trial 
 
Investigational Product: Etripamil (MSP-2017) 
Protocol Number: MSP-2017-5001 
EudraCT Number: 2022-001854-49 
 
 
 
 
 
 
 
 
 
 
Sponsor:  Milestone Pharmaceuticals Inc. 
1111 Dr. Frederik-Philips Blvd., Suite 420 
Saint-Laurent, QC H4M 2X6, Canada 
Telephone: +1-514-336-0444 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written consent of Milestone 
Pharmaceuticals Inc. except to the extent that disclosure would be required by law and for the purpose of evaluating 
and/or conducting a clinical study for Milestone Pharmaceuticals Inc. You are allowed to disclose the contents of 
this document only to your Institutional Review Board or Independent Ethics Committee and study personnel 
directly involved with conducting this protocol. Persons to whom the information is disclosed must be informed that 
the information is confidential and proprietary to Milestone Pharmaceuticals Inc. and that it may not be further 
disclosed to third parties. 
 
 
Version Number: 
1.0 
Original Protocol : 28 JUNE 2019 
 
2.0 
Amendment 1 : 31 JULY 2019 
 
3.0 
Amendment 2 : 19 JUNE 2020 
 
4.0 
Amendment 3 : 20 NOVEMBER 2020 
 
5.0 
Amendment 4 : 09 SEPTEMBER 2021 
 
6.0 
Amendment 5 : 06 JULY 2022  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 2 of 62 
STUDY PROTOCOL 
 
COMPOUND NAME/NUMBER: 
 
Etripamil (MSP-2017) 
PROTOCOL NUMBER: 
 
MSP-2017-5001  
EUDRACT NUMBER 
2022-001854-49 
DEVELOPMENT PHASE: 
 
Phase 2 
PROTOCOL TITLE: 
Multi-Centre, Placebo-Controlled, Phase 2 Study of 
Etripamil Nasal Spray (NS) for the Reduction of Ventricular 
Rate in Patients with Atrial Fibrillation 
SHORT TITLE :  
 
ReVeRA-201: Etripamil in Atrial Fibrillation Phase 2 
PROTOCOL VERSION: 
 
FINAL Version 6.0  
PROTOCOL DATE: 
 
 06 JULY 2022  
CONTRACT RESEARCH 
ORGANIZATIONS: 
Montreal Health Innovation Coordinating Centre (MHICC) 
5000 Bélanger St. 
Montreal, Quebec  H1T 1C8, Canada 
 
JSS Medical Research Inc. 
9400 Henri-Bourassa Boulevard West 
Montreal, Quebec, H4S 1N8, Canada 
 
This study will be performed in compliance with Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. 
 
 


Milestone Pharmaceuticals
Confidential
Clinical Study Protocol
The ReVeRA-201 Trial
MSP-2017-5001
Version : FINAL 6.0, 06 JULY 2022
Page 3 of 62
APPROVAL SIGNATURES
PROTOCOL NUMBER:
MSP-2017-5001
PROTOCOL VERSION:
FINAL 6.0, 06 JULY 2022
PROTOCOL TITLE:
Multi-Centre, Placebo-Controlled, Phase 2 Study of Etripamil Nasal 
Spray (NS) for the Reduction of Ventricular Rate in Patients with 
Atrial Fibrillation (The ReVeRA-201 Trial)
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.
David Bharucha, MD
Chief Medical Officer
Milestone Pharmaceuticals Inc.
Date
Francis Plat, MD
Chief Scientific Officer
Milestone Pharmaceuticals Inc.
Date
Cameron Szakacs, PhD
Senior Director, Drug Development Milestone 
Pharmaceuticals Inc.
Date
Guy Rousseau, PhD
Senior VP Regulatory Affairs
Milestone Pharmaceuticals Inc.
Date


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 4 of 62 
 
STUDY CONTACT AND DETAILS 
 
SERIOUS ADVERSE EVENT 
REPORTING 
 
Montreal Health Innovations Coordinating Centre (MHICC) 
E mail: ReVeRA-SAFETY@mhicc.org  
Telephone: +1-514-264-2631 (24/7 medical assistance) 
 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
 
Denis Roy, M.D., F.R.C.P., F.H.R.S. 
Montreal Heart Institute (MHI)  
E-mail: Denis.Roy@icm-mhi.org 
Telephone: +1-514-376-3330, ext.3200 
 
SPONSORED BY: 
Milestone Pharmaceuticals Inc. 
1111 Dr. Frederik-Philips Blvd., Suite 420 
Saint-Laurent, QC H4M 2X6, Canada 
Telephone: +1-514-336-0444 
 
CONTRACT RESEARCH 
ORGANIZATIONS: 
 
 
Montreal Health Innovations Coordinating Centre (MHICC) 
5000 Bélanger St. 
Montreal, Quebec, H1T 1C8, Canada 
 
JSS Medical Research Inc. 
9400 Henri-Bourassa Boulevard West 
Montreal, Quebec, H4S 1N8, Canada 
SPONSOR MEDICAL 
DIRECTOR : 
 
Silvia Shardonofsky, MD 
Telephone: +1-514-336-0444, ext. 235 
E-mail: sshardonofsky@milestonepharma.com  
 
INVESTIGATORS: 
 
 
A current list of clinical Investigators will be maintained in the 
Trial Master File (TMF) 
 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 5 of 62 
 
INVESTIGATOR AGREEMENT 
 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Milestone Pharmaceuticals Inc. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to Milestone 
Pharmaceuticals Inc. and that it may not be further disclosed to third parties. I understand that the 
study may be terminated, or enrollment suspended at any time by Milestone Pharmaceuticals Inc., 
with or without cause, or by me if it becomes necessary to protect the best interests of the study 
patients. 
I agree to conduct this study in full accordance with my governing Regulatory Authority (Health 
Canada, European Medicines Agency (EMA), Regional/Country Authority) Regulations, 
Institutional Review Board/Ethic Committee Regulations and International Council for 
Harmonization Guidelines for Good Clinical Practices. 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
 
 
______________________________________________ 
Site Name/City/Country 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 6 of 62 
TABLE OF CONTENTS 
 
1. 
SYNOPSIS ............................................................................................................................ 10 
2. 
LIST OF ABBREVIATIONS................................................................................................ 17 
3. 
INTRODUCTION ................................................................................................................. 19 
3.1 
Background .................................................................................................................. 19 
3.2 
Clinical Experience ...................................................................................................... 20 
3.2.1 Phase 1 Pharmacokinetics Studies ................................................................... 20 
3.2.2 Phase 2 Proof of Concept Study in PSVT ........................................................ 21 
3.2.3 NODE-301 Part 1 Phase 3 Efficacy and Safety Study ..................................... 24 
3.2.4 NODE-302 Phase 3 Open Label Extension Study ........................................... 25 
3.2.5 NODE-301 Part 2, the RAPID study ............................................................... 26 
3.2.6 NODE-303 Phase 3 Open Label Safety Study ................................................. 26 
3.3 
Rationale for the Study................................................................................................. 27 
3.4 
Summary of Potential Risks and Benefits .................................................................... 27 
4. 
OBJECTIVES ........................................................................................................................ 28 
4.1 
Primary Objective ........................................................................................................ 28 
4.2 
Secondary Objectives ................................................................................................... 28 
5. 
STUDY DESIGN .................................................................................................................. 28 
5.1 
Overall Study Design and Plan .................................................................................... 28 
5.2 
Discussion of Study Design ......................................................................................... 28 
5.3 
Rationale for Dosing .................................................................................................... 29 
6. 
STUDY POPULATION ........................................................................................................ 30 
6.1 
Selection of Study Population and Diagnosis .............................................................. 30 
6.2 
Study Entry Criteria ..................................................................................................... 30 
6.2.1 Inclusion Criteria .............................................................................................. 30 
6.2.2 Exclusion Criteria............................................................................................. 30 
6.3 
Patient Completion / Discontinuation / Withdrawal .................................................... 31 
7. 
TREATMENTS ..................................................................................................................... 32 
7.1 
Identification of Investigational Product ...................................................................... 32 
7.2 
Labeling and Packaging ............................................................................................... 32 
7.2.1 Labeling............................................................................................................ 32 
7.2.2 Packaging ......................................................................................................... 33 
7.2.3 Distribution ...................................................................................................... 33 
7.3 
Treatments Administered ............................................................................................. 33 
7.4 
Randomization and Unblinding Procedure .................................................................. 33 
7.5 
Drug Storage and Accountability ................................................................................. 34 
7.6 
Prior and Concomitant Therapies................................................................................. 34 
8. 
STUDY PROCEDURES ....................................................................................................... 35 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 7 of 62 
8.1 
Study Periods, Visits, and Procedures.......................................................................... 35 
8.1.1 Screening Procedures ....................................................................................... 35 
8.1.2 Treatment Procedures....................................................................................... 35 
8.1.3 Follow-Up Period ............................................................................................. 36 
8.2 
Assessments ................................................................................................................. 37 
8.2.1 Efficacy ............................................................................................................ 37 
8.2.1.1 
12-Lead ECG Recordings .................................................................... 37 
8.2.1.2 
Holter ECG Recording ......................................................................... 37 
8.2.1.3 
Treatment Satisfaction Questionnaire for Medication (TSQM-9) ....... 37 
8.2.2 Safety 37 
8.2.2.1 
Adverse Events ..................................................................................... 37 
8.2.2.2 
Clinical Laboratory Safety Assessments .............................................. 38 
8.2.2.3 
Clinical Examinations .......................................................................... 38 
9. 
ADVERSE EVENTS............................................................................................................. 38 
9.1 
Definitions .................................................................................................................... 38 
9.1.1 Adverse Events................................................................................................. 38 
9.1.2 Adverse Drug Reaction .................................................................................... 39 
9.1.3 Unexpected Adverse Event/Adverse Drug Reaction ....................................... 39 
9.1.4 Serious Adverse Events/Drug Reaction ........................................................... 39 
9.1.5 Serious Unexpected Suspected Adverse Reaction (SUSAR) .......................... 40 
9.1.6 Treatment-Emergent Adverse Events .............................................................. 40 
9.1.7 Adverse Events of Special Interest .................................................................. 40 
9.2 
Management of Adverse Events .................................................................................. 41 
9.2.1 Collection of Adverse Events........................................................................... 41 
9.2.2 Evaluation of Adverse Events .......................................................................... 42 
9.2.2.1 
Severity of Adverse Events ................................................................... 42 
9.2.2.2 
Seriousness ........................................................................................... 42 
9.2.2.3 
Outcome at the Time of Last Observation............................................ 42 
9.2.2.4 
Adverse Event Relationship to the Study Drug .................................... 42 
9.2.3 Documentation ................................................................................................. 43 
9.2.4 Follow-up of Adverse Events........................................................................... 44 
9.2.5 SAE Reporting ................................................................................................. 44 
9.2.5.1 
Serious Adverse Events ........................................................................ 44 
9.2.5.2 
Adverse Drug Reactions ....................................................................... 45 
9.2.5.3 
Nonserious Adverse Events .................................................................. 45 
9.3 
Special Considerations ................................................................................................. 45 
9.3.1 Pregnancy ......................................................................................................... 45 
9.3.2 Overdose .......................................................................................................... 46 
10. STATISTICS ......................................................................................................................... 46 
10.1 Study Endpoints ........................................................................................................... 46 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 8 of 62 
10.1.1 Efficacy Endpoints ........................................................................................... 46 
10.1.2 Safety Endpoints .............................................................................................. 48 
10.2 Sample Size Determination .......................................................................................... 48 
10.3 Analysis Populations .................................................................................................... 48 
10.4 Statistical Analyses ...................................................................................................... 48 
10.4.1 Efficacy Analyses............................................................................................. 48 
10.4.1.1 Primary Efficacy Analysis .................................................................... 49 
10.4.1.2 Secondary Efficacy Analyses ............................................................... 49 
10.4.2 Safety and Tolerability Analyses ..................................................................... 50 
10.4.2.1 Adverse Events ..................................................................................... 50 
10.4.3 Interim Analyses .............................................................................................. 50 
11. INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL .................................. 50 
11.1 Ethical Conduct of the Study ....................................................................................... 50 
11.2 Institutional Review Board/Independent Ethics Committee ........................................ 50 
11.3 Informed Consent ......................................................................................................... 51 
11.4 Study Monitoring Requirements .................................................................................. 51 
11.5 Data Collection............................................................................................................. 52 
11.6 Disclosure of Data ........................................................................................................ 52 
11.7 Retention of Records .................................................................................................... 52 
11.8 Data Protection ............................................................................................................. 52 
11.9 Audits and Inspections ................................................................................................. 53 
11.10 Publication Policy ........................................................................................................ 53 
11.11 Financial Disclosure ..................................................................................................... 53 
12. STUDY ADMINISTRATIVE INFORMATION .................................................................. 53 
12.1 Protocol Amendments .................................................................................................. 53 
12.2 Protocol Authors .......................................................................................................... 54 
13. FINAL CLINICAL STUDY REPORT ................................................................................. 54 
14. REFERENCES ...................................................................................................................... 55 
APPENDICES .............................................................................................................................. 56 
A. SCHEDULE OF ASSESSMENTS........................................................................................ 57 
B. STUDY DRUG ADMINISTRATION INSTRUCTIONS .................................................... 58 
C. TREATMENT SATISFACTION QUESTIONNIARE FOR MEDICATION (TSQM-9) ... 59 
D. REGULATIONS AND GOOD CLINICAL PRACTICE GUIDELINES ............................ 62 
 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 9 of 62 
 
LIST OF TABLES AND FIGURES 
List of Tables 
Table 1. Summary of Induced, Sustained Paroxysmal Supraventricular Tachycardia to Sinus 
Rhythm Conversion Within 15 Minutes After Study Drug Administration 
22 
 
List of Figures 
Figure 1. Kaplan-Meier Plot of Conversion 15 Minutes After Study Drug Administration ..... 23 
Figure 2. Mean Change in Systolic Blood Pressure (mmHg) Over Time ................................. 24 
Figure 3. Study Design Schematic ............................................................................................. 29 
 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 10 of 62 
1. SYNOPSIS  
PRODUCT 
NAME/NUMBER 
Etripamil (MSP-2017) 
PROTOCOL 
NUMBER 
MSP-2017-5001 
DEVELOPMENT 
PHASE 
Phase 2 
PROTOCOL TITLE 
Multi-Centre, Placebo-Controlled, Phase 2 Study of Etripamil Nasal Spray 
(NS) for the Reduction of Ventricular Rate in Patients with Atrial 
Fibrillation 
SHORT TITLE 
ReVeRA-201: Etripamil in Atrial Fibrillation Phase 2 
INDICATION 
Atrial Fibrillation  
OBJECTIVES 
Ventricular rate control without conversion of atrial fibrillation (AF) into 
sinus rhythm is one treatment option recommended in the guidelines.1  
Many patients with AF experience persistent tachycardia with episodes of 
rapid ventricular rate despite chronic treatment to reduce ventricular rate.  
Primary: 
1. The primary objective of this study is to demonstrate the superiority 
of etripamil NS over placebo in reducing ventricular rate in patients 
with AF. 
Secondary: 
1. The secondary objective is to evaluate the safety and efficacy of 
etripamil NS in patients with AF. 
STUDY 
POPULATION 
The study will randomize approximately 50 evaluable patients with AF in 
the Efficacy Population. Enrollment will continue until the target sample 
size is reached.  
STUDY ENTRY 
CRITERIA 
Inclusion Criteria: 
A patient will be eligible for study participation if they meet all of the 
following criteria: 
1. Aged 18 years and over 
2. Has provided written informed consent 
 
 
1 January, CT et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation, Journal of 
the American College of Cardiology (2014) 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 11 of 62 
3. Patients with episodes of paroxysmal, persistent or permanent AF, 
presenting with AF and a ventricular rate ≥110 bpm measured over 
1 minute 
4. Patients should receive appropriate antithrombotic therapy as per 
the applicable guidelines for AF management (e.g. Canadian 
Cardiovascular Society (CCS) / European Society of Cardiology 
(ESC) guidelines).  
a. Etripamil (a calcium channel blocker) is intended for acute 
rate control only.2  If rhythm control is desired (outside of 
the present protocol), anticoagulation as per guidelines may 
start after the administration of study drug.  
Exclusion criteria: 
A patient will be excluded from the study if they meet any of the following 
criteria: 
1. Has evidence of atrial flutter (ECG) at presentation 
2. Has a history of stroke, transient ischemic attack or peripheral 
embolism within the last 3 months  
3. Has received by IV route any of the following within one hour 
before study drug administration: flecainide, procainamide, 
digoxin, beta-blocker, or calcium channel blocker  
4. Has signs and symptoms of severe congestive heart failure at 
presentation (e.g. tachypnea, oxygen desaturation <90% unless due 
to known pulmonary disease, pulmonary rales, sign of peripheral 
hypoperfusion) 
5. Hemodynamic instability, with systolic blood pressure <90 mmHg 
or diastolic blood pressure <60 mmHg 
6. Known uncorrected severe aortic or mitral stenosis 
7. Hypertrophic cardiomyopathy with outflow tract obstruction 
8. Has a history of second- or third-degree atrioventricular block 
9. Regular rhythm suggesting a complete AV block 
 
 
2  Andrade, JG et al., The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive 
Guidelines for the Management of Atrial Fibrillation. Canadian Journal of Cardiology 2020 Dec; 36(12): 1847-1948. 
See Section 9.1.1 Acute Rate Control. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 12 of 62 
10. Has a history or evidence of torsades de pointes, sick sinus 
syndrome, or Brugada syndrome  
11. Evidence of Acute Coronary Syndrome within the last 12 months 
except if patient was successfully revascularized 
12. Positive pregnancy test result at screening, and females of 
childbearing potential who do not agree to use adequate method of 
contraception for the duration of the study.  
13. Has evidence of any clinically significant acute or chronic condition 
of the nasal cavity (e.g., rhinitis or deviated septum) which could 
interfere with administration of the study drug in either or both 
nasal cavities  
14. Has a history of sensitivity to verapamil 
15. Has previously participated in a clinical study for etripamil 
16. Has a history of sensitivity to any components of the investigational 
product 
17. Signs of alcohol or drug intoxication at the time of presentation 
which, in the opinion of the Investigator, would impact the validity 
of study results   
18. Is currently participating in another drug or device study, or has 
received an investigational drug or device within 30 days of 
Screening 
19. Has evidence of clinically significant cardiovascular, endocrine, 
gastrointestinal, hematologic, hepatic, immunologic, neurologic, 
oncologic, pulmonary, psychiatric, or renal disease or any other 
condition which, in the opinion of the Investigator, would 
jeopardize the safety of the patient or impact the validity of study 
results  
STUDY DESIGN 
This is a multi-center, randomized, double-blind, placebo-controlled study 
to evaluate the effects of etripamil NS in patients with AF. This study 
includes Screening, the Treatment Period and Follow-up procedures.  Each 
patient will receive Placebo or 70 mg etripamil NS; treatment will be 
randomized in a 1:1 ratio, to yield 50 evaluable patients with AF in 2 groups 
of 25 (Efficacy Population).   
Screening and treatment procedures should be done at the same visit.  
Informed consent must be obtained prior to any study procedures. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
MSP-2017-5001 
Version : FINAL 6.0, 06 JULY 2022 
Page 13 of 62 
Screening Procedures: 
Patients with AF will be selected by the Investigator. The screening 
procedures will include obtaining informed consent, a review of 
inclusion/exclusion criteria, a complete physical examination, and 
recording of any concomitant medications.   
Treatment Procedures: 
After screening procedures are complete, eligible patients will be 
randomized to receive etripamil NS or placebo.  Heart rate will be measured 
via Holter ECG 10 minutes prior to and immediately before drug 
administration; patients must exhibit a rapid ventricular rate (≥110 bpm 
measured during 1 minute) prior to drug administration in order to be dosed. 
Blinded study drug will be administered during Holter ECG monitoring, 
which will be conducted for at least 10 minutes prior to and for 6 hours after 
administration. Investigators will record adverse events and concomitant 
medications.   
Study drug will be administered by clinical site staff. Patient must be seated 
for drug administration and should not perform any physical activity within 
1-hour post-dose. Patient will be asked to complete the TSQM-9
questionnaire. Patient can be discharged 1 hour after drug administration.
Follow-up Procedures: 
Patients will undergo a safety follow-up assessment and return the Holter 
device approximately 24 hours post-dose. The use of telemedicine is 
encouraged. Patients will also be contacted by phone 7 days post-dosing for 
safety follow-up.   
INVESTIGATIONAL 
PRODUCT 
The formulation of etripamil NS will consist of MSP-2017 (etripamil), 
water, acetic acid, disodium ethylene-diamine-tetra-acetic acid (EDTA), 
and sulfuric acid. The dose of etripamil to be evaluated in this study is 
70 mg.  
REFERENCE 
PRODUCT 
The formulation of placebo will consist of water, sodium acetate, disodium, 
EDTA, and sulfuric acid to reproduce the same pH as the etripamil 
formulation. 
TREATMENT 
REGIMENS 
Patients will receive a total of 200 µL of etripamil NS 70 mg or placebo 
(i.e., 100 µL in each nostril via the Aptar Pharma Nasal Spray Bidose 
System). The devices will be prefilled and packaged.  Instructions on device 
usage are provided in Appendix B.   
PRINCIPAL 
INVESTIGATOR 
Denis Roy, MD 
PLANNED STUDY 
SITES 
This study will be conducted at approximately 20 sites in Canada and in the 
Netherlands 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 14 of 62 
EFFICACY 
ENDPOINT 
Ventricular rate reduction 
CRITERIA FOR 
EVALUATION 
Efficacy Variables: 
Efficacy variables will be obtained from the Holter recordings measured by 
a central core laboratory. In case of conversion to sinus rhythm, only heart 
rate measurements prior to sinus conversion will be used to derive efficacy 
variables. 
The primary efficacy variable will be: 
• The maximum reduction in ventricular rate, measured on Holter 
monitoring, within 60 minutes from drug administration.  
The secondary efficacy variables will include: 
• Elapsed time from drug administration to nadir (lowest average heart 
rate) in the 60 minutes post drug administration. 
• Percentage of patients achieving ventricular rate of <100 bpm in the 
60 minutes post drug administration. 
o Elapsed time from drug administration to ventricular rate 
<100 bpm 
o Duration of ventricular rate <100 bpm in the 60 minutes post 
drug administration 
• Percentage of patients with 10% reduction from baseline ventricular 
rate in the 60 minutes post drug administration. 
o Elapsed time from drug administration to 10% reduction from 
baseline ventricular rate 
o Duration of 10% reduction from baseline ventricular rate in the 
60 minutes post drug administration 
• Percentage of patients with 20% reduction from baseline ventricular 
rate in the 60 minutes post drug administration. 
o Elapsed time from drug administration to 20% reduction from 
baseline ventricular rate 
o Duration of 20% reduction from baseline ventricular rate in the 
60 minutes post drug administration 
• Percentage of patients cardioverting into sinus rhythm  in the 60 
minutes post drug administration. 
o Elapsed time from drug administration to cardioversion into 
sinus rhythm 
• Area under the curve (AUC) of heart rate over the 60 minutes and the 
360 minutes post drug administration 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 15 of 62 
• Patient satisfaction with treatment, as measured by the Treatment 
Satisfaction Questionnaire for Medication (TSQM-9). 
Safety Variables: 
• Safety variables will include clinical adverse events (AEs), vital signs, 
and findings from electrocardiographic 
analysis (ventricular 
arrhythmia such as premature ventricular contractions, non sustained 
ventricular tachycardia any AV block) 
STATISTICAL 
METHODS 
Efficacy analyses: 
The efficacy analyses will compare placebo-treated patients versus 
etripamil-treated patients. Efficacy endpoint analyses will include 
summaries, both over time and as comparisons between placebo and 
etripamil. Continuous efficacy data will be presented with n, minimum, 
maximum, median, mean, and standard deviation, whereas discrete efficacy 
data will be summarized with frequency counts and percentages.  
Primary efficacy analysis 
The primary efficacy analysis will compare the maximum reduction in 
ventricular rate in placebo-treated patients versus etripamil-treated patients. 
This comparison will be done using an analysis of covariance (ANCOVA) 
adjusting for baseline ventricular rate.  
Secondary efficacy analyses  
The secondary efficacy analyses performed on the secondary efficacy 
parameters will use ANCOVA methods for continuous variable, Chi-Square 
or Fisher exact tests for percentages and Kaplan-Meier methods for elapsed 
times.   
Safety analyses: 
Safety data will be summarized with descriptive statistics. Continuous 
safety data will be presented with n, minimum, Q1, Q3, maximum, median, 
mean, and standard deviation, whereas discrete safety data will be 
summarized with frequency counts and percentages. 
SAMPLE SIZE 
DETERMINATION 
The primary efficacy variable for this study is the maximal reduction of 
ventricular rate after study drug administration. Accounting for a two-
sided test with a type I error rate of α=0.05, 25 patients per group will 
provide 93% power to detect a 20 bpm absolute difference in ventricular 
rate from baseline value  between active drug and placebo, assuming a 
standard deviation of 20 bpm.  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 16 of 62 
STUDY AND 
TREATMENT 
DURATION 
Patients will receive a single dose of either etripamil NS 70 mg or Placebo.  
Screening and Treatment procedures should occur at the same visit. Safety 
follow-up will be performed on the next day, preferably via telemedicine. 
Patients will also be contacted by phone 7 days after dosing. Total duration 
of participation is 1 week. Enrollment in the study will continue until 
enough patients are randomized to provide at least 50 patients in the 
Efficacy Population, including at least 25 patients in each treatment arm.   
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 17 of 62 
2. LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AF 
Atrial Fibrillation 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AV 
Atrioventricular 
BDS 
Bidose System 
BPM 
Beat Per Minute 
CCS 
Canadian Cardiovascular Society 
CFR 
Code of Federal Regulations 
CMS 
Cardiac Monitoring System 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylene-Diamine Tetra-Acetic Acid 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IN 
Intranasal 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive Web Randomization System 
MFD 
Maximum Feasible Dose 
MHICC 
Montreal Health Innovations Coordinating Centre 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 18 of 62 
mITT 
Modified Intent to Treat 
NS 
Nasal Spray 
NSVT 
Non-Sustained Ventricular Tachycardia 
OAC 
Oral Anticoagulant 
PAF 
Paroxysmal Atrial Fibrillation 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PSVT 
Paroxysmal Supraventricular Tachycardia 
SAP  
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SR 
Sinus Rhythm 
TEAE 
Treatment-Emergent Adverse Event 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 19 of 62 
3. INTRODUCTION 
3.1 
Background  
Etripamil (also referred to as MSP-2017 in study documents), an L-type calcium channel 
antagonist and short-acting verapamil analog, is currently being developed by Milestone 
Pharmaceuticals Inc. (hereinafter Milestone) for the treatment of paroxysmal supraventricular 
tachycardia (PSVT), and other arrhythmias.  
Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, with an irregular and 
often rapid heart rate that increases the risk of stroke and heart failure.  
Prevalence estimates range from four to six million patients suffering from atrial fibrillation in the 
United States. Approximately 25% of these have Paroxysmal Atrial Fibrillation (PAF), another 
25% have persistent atrial fibrillation, and 50% have permanent atrial fibrillation.  
For most patients, current treatment for AF consists of anti-coagulant therapy, either warfarin or 
novel oral anti-coagulants (e.g., Pradaxa®, Xarelto®, Eloquis®) to reduce the risk of blood clot 
embolization and stroke; those who cannot take these stronger blood thinners may be prescribed 
aspirin at 325 mg a day, but aspirin has only been shown to be somewhat efficacious in a very 
small and specific population. With regard to the abnormal heart rate that occurs during AF, there 
are two strategies. One strategy focuses on controlling the heart rate during AF to reduce or 
eliminate symptoms, while the other takes aim at terminating AF and maintaining sinus rhythm. 
Multiple clinical studies have demonstrated that there is no difference in outcome whether a rate 
or rhythm control strategy is pursued (e.g., AF-CHF 1 AFFIRM 2). The major unmet needs are for 
more efficacious and safer rhythm-control drugs as well as rate-control drugs with a faster onset 
of action to bring down the heart rate. 
Rhythm control drugs such as amiodarone, dronedarone, flecainide, ibutilide are modestly 
effective in converting atrial fibrillation into normal sinus rhythm but are often associated with 
toxicity and can cause life-threatening pro-arrhythmic effects.3  Rate-control drugs include calcium 
channel blockers (diltiazem and verapamil) and beta blockers (e.g., metoprolol, atenolol), and their 
goal is to minimize symptoms associated with an increased ventricular rate, improve cardiac 
output, and prevent tachycardia-associated cardiomyopathy.4  Based on data from both the Phase 
1 and Phase 2 studies, etripamil has demonstrated its ability to prolong conduction through the 
atrioventricular (AV) node, which is key to reducing the ventricular rate during AF. This makes 
etripamil an excellent candidate for use in controlling the ventricular rate in a subset of patients 
with AF. 
Patients who present to the emergency room in AF with a rapid heart rate are almost universally 
treated with an intravenous calcium channel blocker or beta blocker to provide a rapid reduction 
in ventricular rate to control symptoms and improve cardiac output.5 Intravenous (IV) rate-control 
drugs for immediate rate-control, however, are limited to use in the acute setting and therefore 
cannot be self-administered by patients in the outpatient setting when symptoms begin. Oral rate-
control drugs can be taken at home, but do not provide immediate ventricular rate-control due to 
the delayed 30 to 90-minute onset of action by the oral route.  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 20 of 62 
3.2 
Clinical Experience 
3.2.1 Phase 1 Pharmacokinetics Studies 
A Phase 1 study (MSP-2017-1096) evaluated the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of etripamil, with the aim of determining the maximum tolerated dose or 
maximum feasible dose (MFD) of 2 different formulations administered via the intranasal (IN) 
route in healthy, adult male subjects. All etripamil doses were generally well tolerated, and there 
was no difference in the safety profile and PK between the 2 etripamil formulations (MSP-2017A 
and MSP-2017B). The study of formulation A was stopped at 60 mg, and formulation B was 
studied at 105 mg and 140 mg. Pharmacokinetic analyses demonstrated rapid absorption and 
elimination following IN administration of etripamil (across the dose range tested), and a dose 
proportional systemic exposure (area under the curve and maximum plasma concentration for 
MSP-2017 and its inactive metabolite [MSP-2030]) following administration of up to 140 mg of 
MSP-2017. The 140 mg dose was the MFD because neither the concentration (350 mg/mL) nor 
the volume (200 µL) of solution administered in each nostril could be increased. 
MSP-2017-1205 (NODE-102) study was a randomized, double-blind, placebo-controlled, single 
dose, 4-way crossover, single dose Phase I study to assess the PK, PD, and safety and tolerability 
of etripamil nasal spray (NS) at three dose levels and placebo in healthy Japanese and non-Japanese 
adults. The primary objective was to assess the safety and tolerability of etripamil in healthy 
Japanese and non-Japanese volunteers. The secondary objectives were to assess the PK and PD of 
etripamil in healthy Japanese and non-Japanese volunteers and the exploratory objectives were to 
assess the PK and PD of etripamil in healthy male and female volunteers. 
A maximum of 24 participants, 12 Japanese and 12 non-Japanese, were planned and enrolled in 
the study and 23 completed the study (1 Japanese subject discontinued prematurely due to the 
development of an adverse event). After signing the informed consent form (ICF), potential 
participants underwent screening procedures within 28 days of Day 1. Participants were admitted 
to the clinical unit on Day -1 and screening procedures were repeated to confirm their eligibility. 
Participants fasted overnight for at least 10 hours. On Day 1, participants were randomized to 1 of 
3 treatment sequences (Placebo-70 mg-35 mg, 35 mg-Placebo-70 mg, or 70 mg-35 mg-Placebo) 
and received either a single intranasal dose of etripamil or placebo followed by a 2-week washout 
period between doses. Etripamil NS up to 105 mg was administered using the Phase 3 formulation 
Aptar Bi-dose nasal spray device (i.e., up to 3 sprays of 100 μL of 350 mg/mL etripamil 
formulation in each nostril). After the third period, all participants received a dose of 105 mg 
etripamil. The total study duration was approximately 3 months, including the screening and 
follow-up. Blood for PK assessments was collected before each dose and at 0.5, 1.5, 3, 5, 7, 10, 
15, 25, 50, 90, 360, 720, and 1440 minutes after dosing. Urine for PK analysis was collected before 
dosing and over the intervals of 0-2 hours, 2-4 hours, 4-6 hours, 6-12 hours, and 12-24 hours after 
dosing. Vital signs and electrocardiograms (ECGs) were measured at the corresponding PK time 
points. 
Slightly more Japanese participants experienced a Treatment-Emergent Adverse Event (TEAE) 
compared with non-Japanese participants and there were more TEAEs at the 105 mg dose 
compared with the 35 mg and 70 mg doses. However, at the 35 mg and 70 mg doses, the percentage 
of participants with TEAEs was within the range of values associated with placebo treatment. The 
most frequent TEAEs (>10%) were increased lacrimation, burning nose sensation, and rhinorrhea, 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 21 of 62 
occurring at all doses (including placebo). Each of these was considered by the investigator as 
related to treatment. Most TEAEs were mild or moderate in intensity, except 1 instance of burning 
nose sensation (non-Japanese participant at 105 mg etripamil dose) which was severe. There were 
no serious adverse events. One Japanese participant discontinued due to TEAEs (tearing, facial 
burning sensation, rhinorrhea). There were no trends in clinical laboratory changes and there were 
no TEAEs due to changes in clinical laboratory values. There were no meaningful changes in vital 
signs. Changes in ECGs were generally transient and judged to be not clinically significant by the 
Investigator.  
In both Japanese and non-Japanese participants, etripamil exposure increased in a dose-
proportional manner between 35 mg and 70 mg, while exposure at the highest dose of 105 mg was 
similar to what was seen at 70 mg. 
3.2.2 Phase 2 Proof of Concept Study in PSVT 
NODE-1 (MSP-2017-1109), a Phase 2 study, was conducted in the electrophysiology laboratory 
(EPL) as a proof-of-concept and dose response study in patients with documented history of PSVT. 
This Phase 2 study assessed the ability of etripamil to terminate an episode of PSVT induced in 
the EPL and was also designed to identify the dose(s) that will be taken in subsequent studies. The 
primary objective was to demonstrate the superiority of at least 1 dose of IN etripamil over placebo 
in terminating an episode of PSVT induced in the EPL. The secondary objectives were to establish 
a dose-related trend for etripamil, to determine the minimal effective dose of etripamil, and to 
evaluate the safety of etripamil in a clinical setting. 
During a pre-study visit, patients were randomly assigned to 1 of the 5 following study groups in 
a 1:1:1:1:1 ratio: placebo, or etripamil NS at 35, 70, 105, or 140 mg. Induction of PSVT was 
attempted using standard pacing and programmed stimulation methods. If PSVT could not be 
induced after a reasonable number of attempts, or could be induced but did not sustain for 5 
minutes, IV isoproterenol was infused. After a minimum of 5 minutes in induced, sustained PSVT, 
patients were administered double-blind study drug NS via 4 pre-filled Aptar Pharma Unit dose 
spray devices by EPL personnel using a double-dummy, multiple-dose design. Each device 
delivered 100 µL of either placebo or 35 mg of etripamil. The appropriate combination of active 
and placebo devices was used to deliver etripamil according to the dose (0, 35, 70, 105, or 140 mg) 
assigned at randomization and arranged so that all the active medication was administered prior to 
any placebo. 
In total, 199 patients were randomized into the double-blind study; 95 withdrew prior to dosing: 
70 due to inability to induce (n = 42) or sustain (n = 28) PSVT, 5 based on physician discretion, 
1 lost to follow-up, 1 due to withdrawal of consent, and 18 for other reasons. In total, 104 patients 
had PSVT induced and sustained for ≥5 minutes and were dosed with study drug. In the population 
of the 104 patients who received the study drug, 56.7% were females and the mean age was 
52.2 years. Isoproterenol was given to 46.2% of patients. The mean heart rate (HR) in PSVT at 
time 0 was 177 bpm in the placebo group and 168, 173, 180, and 155 bpm in the etripamil NS 35, 
70, 105, and 140 mg groups, respectively. Overall, 87% of patients who were induced into PSVT 
had atrioventricular nodal reentry tachycardia.  
Of the 104 patients in the Evaluable Population, 20 received etripamil NS 35 mg, 23 received 
etripamil NS 70 mg, 20 received etripamil NS 105 mg, 21 received etripamil NS 140 mg, and 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 22 of 62 
20 received placebo. The percentage of patients in whom PSVT converted to sinus rhythm (SR) 
within 15 minutes after study drug administration and in whom SR was maintained for at least 
30 seconds (primary efficacy endpoint) was 35%, 65%, 87%, 75%, and 95% in the placebo and 
etripamil NS 35, 70, 105, and 140 mg groups, respectively. Applying the pre-specified hierarchy 
for determining significance, the 3 highest etripamil doses of 140, 105, and 70 mg showed 
statistically significantly greater conversion rates compared with placebo (see Table 1). 
Table 1. 
Summary of Induced, Sustained Paroxysmal Supraventricular Tachycardia 
to Sinus Rhythm Conversion Within 15 Minutes After Study Drug 
Administration 
 
Placebo 
(N = 20) 
MSP-2017 
35 mg 
(N = 20) 
MSP-2017 
70 mg 
(N = 23) 
MSP-2017 
105 mg 
(N = 20) 
MSP-2017 
140 mg 
(N = 21) 
Number (%) of patients converted to sinus 
rhythm within 15 minutes after study drug 
7 (35.0) 
13 (65.0) 
20 (87.0) 
15 (75.0) 
20 (95.2) 
Treatment comparisons 
Odds ratio (vs. placebo) 
NA 
3.45 
12.38 
5.57 
37.14 
95% CI of odds ratio (vs. placebo) 
NA 
(0.79, 
15.46) 
(2.28, 
82.26) 
(1.19, 
27.63) 
(3.84, 
1654.17) 
Fisher’s exact test p-value (vs. placebo) 
NA 
0.1128 
0.0006 
0.0248 
<0.0001 
CMH p-value (vs. placebo) 
NA 
0.0802 
0.0006 
0.0125 
<0.0001 
Cochran-Armitage test p-value (trend test) 
<0.0001 
CI = confidence interval; CMH = Cochran-Mantel-Haenszel; N = the number of patients in the Evaluable Population in the 
given group; NA = not available; vs. = versus. 
Source: Clinical Study Report MSP-2017-1109 
For the 3 etripamil doses with statistically significant conversion rates compared with placebo 
(70, 105, and 140 mg), mean times to conversion were all <3 minutes, with a shortest median time 
to conversion of 1.8 minutes in the etripamil NS 140 mg group. Only 7 (35%) patients had a 
successful conversion of PSVT within 15 minutes in the placebo group; therefore, 13 patients were 
censored at 15 minutes, and the median time to conversion is not available. The time to conversion 
for the 7 patients who converted within 15 minutes was more widely dispersed in the placebo 
group compared with the etripamil groups. 
Figure 1 shows the distribution of time to conversion for each patient reported as a Kaplan-Meier 
plot. Patients who did not convert within 15 minutes after study drug administration were censored 
at 15 minutes. 
 
 
 
 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 23 of 62 
Figure 1. 
Kaplan-Meier Plot of Conversion 15 Minutes After Study Drug Administration 
 
Note: Patients who did not convert within 15 minutes after study drug administration were censored at time 15. 
Source: Clinical Study Report MSP-2017-1109 
At least 1 adverse event (AE) considered related to the study drug, according to the Investigator 
assessment, was reported in 17 (85.0%) patients in the etripamil NS 35 mg group, 
18 (78.3%) patients in the 70 mg group, 15 (75.0%) patients in the 105 mg group, 
20 (95.2%) patients in the 140 mg group, and 4 (20.0%) patients in the placebo group. The 
incidence of AEs was not dose dependent.  
Most AEs were mild (44.2%) or moderate (24.0%) across all treatment groups. A total of 3 severe 
AEs were considered possibly related to etripamil; 1 patient who received etripamil NS 35 mg 
experienced facial flushing, shortness of breath, and chest discomfort; and 2 patients who received 
etripamil NS 105 mg had nausea and vomiting (1 patient) and a serious AE (SAE) of cough 
(1 patient). There were no AEs that led to study discontinuation or death. 
Adverse events that occurred with an incidence of >10% in any etripamil group and ≤10% in the 
placebo group were nasal discomfort, nasal congestion, oropharyngeal pain, rhinorrhea, cough, 
dysgeusia, increased lacrimation, vomiting, and nausea.  
Of note, 1 patient had an episode of second-degree AV block with hypotension beginning 
5 minutes after conversion to SR immediately following administration of etripamil NS 140 mg. 
Atrioventricular block resolved after 43 minutes, and ablation was subsequently performed. 
The mean systolic blood pressure (SBP) was decreased from the baseline measurements (before 
PSVT induction) to measurements done in PSVT before study drug administration (time 0). 
A decrease of 7 mmHg was statistically significant in the placebo group only (Figure 2). 
Compared with baseline, SBP measurements taken from 2 minutes to 16 minutes post-study drug 
administration demonstrated no decrease in mean SBP in the placebo and the etripamil NS 35 mg 
group, a minor change of 2 mmHg at 4 minutes post-dose in the etripamil NS 70 mg group, and 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 24 of 62 
decreases of 17 mmHg (p<0.05 versus baseline) 6 minutes post-dose in the etripamil NS 105 mg 
group, and 20 mmHg at 6 minutes and 8 minutes post-dose (p<0.05 versus baseline) in the 
etripamil NS 140 mg group. 
There was no decrease in mean SBP compared to baseline from 16 to 30 minutes post-study drug 
administration when all patients were back in normal SR. 
Figure 2. 
Mean Change in Systolic Blood Pressure (mmHg) Over Time 
 
Note: Baseline is defined as the average of the 20 and 10 minutes pre-dose measurements. Time 0 is defined as the average of the 
measurement during PSVT between 0 and 5 minutes before study drug administration. 
Source: Clinical Study Report MSP-2017-1109 
3.2.3 NODE-301 Part 1 Phase 3 Efficacy and Safety Study 
NODE-301 (MSP-2017-1138), was a Randomized, Double-Blind, Placebo-Controlled Phase 3 
safety and efficacy study of etripamil NS in patients with PSVT receiving the drug in an at-home 
setting.  The study was conducted in the United States and Canada.  Patients first received etripamil 
NS at the clinical site while in normal sinus rhythm during a Test Dose Visit.  Patients who showed 
an acceptable safety and tolerability profile in the Test Dose Visit were randomized in a 2:1 ratio 
to receive either etripamil NS or matching placebo.  They returned home and waited for a PSVT 
episode to occur, at which time they may have taken etripamil NS or placebo.  Each episode was 
documented by an ambulatory Cardiac Monitoring System (CMS) that was placed on the chest by 
the patient or caregiver when symptoms began and recorded at least 5 hours of continuous ECG.  
After taking etripamil NS or placebo for the treatment of one PSVT episode, a patient completed 
the NODE-301 study and was eligible for the open label extension study NODE-302. 
The NODE-301 Part 1 trial was an event-driven Phase 3 trial designed to evaluate the efficacy of 
self-administered etripamil for terminating PSVT episodes in the at-home setting. A total of 431 
subjects  received a test dose of etripamil 70 mg NS while in sinus rhythm and 198 subjects 
received study drug (138 etripamil 70 mg; 60 placebo) during a perceived episode of PSVT. A 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 25 of 62 
total of 156 adjudicated episodes included in the pivotal analysis; 107 (68.6%) subjects received 
etripamil and 49 (31.4%) subjects received placebo. Etripamil (70 mg) did not achieve its primary 
endpoint of time to conversion of PSVT to sinus rhythm compared to placebo over the 5-hour 
period following study drug administration. The hazard ratio (95% CI) at 5 hours was 1.086 (0.726, 
1.623); P value 0.12 in favor of etripamil.  The median time to conversion was 25 minutes [95% 
CI: 16, 43] for etripamil vs. 50 minutes [95% CI: 31,101] for placebo. A post hoc efficacy analysis 
of the NODE-301 Part 1 study demonstrated that within 30 minutes after drug administration, 
etripamil was highly effective, with a sinus rhythm conversion rate of 54% of etripamil subjects 
vs. 35% of placebo subjects, i.e., approximately a 19% absolute difference. These results are 
consistent with the rapid onset of action of etripamil and the PK/PD profile of the drug and are 
similar to those observed in Phase 2 (NODE-1). Overall, the prolonged 5-hour efficacy observation 
period likely confounded the results of the primary analysis of the Phase 3 clinical trial.  
There were no new or clinically relevant safety findings seen in NODE-301 Part 1 study. A total 
of 308 subjects had at least one AE. The maximum severity was mild (49.8%) or moderate 
(17.6%). The most commonly reported TEAEs occurring after study drug administration were 
nasal discomfort, nasal congestion, rhinorrhea, throat irritation and lacrimation. Severe TEAEs 
included throat irritation, drug hypersensitivity, rhinorrhea, epistaxis and hypotension, each 
reported in one subject. Fourteen serious adverse events were reported and were assessed by the 
Investigator as not related to the study treatment.  
Of note, two subjects experienced syncope 168 and 68 days after the test dose of etripamil. One 
subject reported “near-syncope” prior to etripamil administration. Therefore, none of these events 
were related to the drug administration.  
3.2.4 NODE-302 Phase 3 Open Label Extension Study 
NODE-302 (MSP-2017-1158) was an open label extension study for NODE-301.  This study is 
now closed and enrolled PSVT patients who had previously completed NODE-301, and followed 
them for multiple at-home administrations of 70 mg etripamil NS. Each episode was documented 
by an ambulatory CMS.  This study is currently in the reporting phase.  
One-hundred and sisty-nine patients were enrolled in the study and 105 patients received at least 
one dose of etrupamil 70 mg NS. There were no new or clinically relevant safety findings seen in 
the NODE-302 study. A total of 67 (63.8%) patients have had at least one AE. The maximum 
severity of TEAEs for most patients was mild (34.3%) or moderate (6.7%). Severe TEAEs were 
reported in 2 (1.9%) patients (rhinorrhea in 1 patient, and two episodes of epistaxis in 1 patient). 
There were 34 (32.4%) subjects who experienced an AE that was considered related to the study 
treatment by the Investigator.  
Ten SAEs were reported in 8 (7.6%) subjects. The most frequently reported SAE was 
supraventricular tachycardia (3 [2.9%] subjects), with all other SAEs reported by 1 (1.0%) subject 
each, including bradycardia, syncope, ataxia, troponin increased, and pancreatitis. All these SAEs 
were assessed by the Investigator as not related to the study treatment. The SAEs of syncope and 
ataxia occurred 50 days and 53 days following the most recent etripamil dose, respectively. 
The most commonly reported TEAEs (regardless of relationship to study drug) were nasal 
discomfort, nasal congestion, and rhinorrhea. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 26 of 62 
3.2.5 NODE-301 Part 2, the RAPID study  
NODE-301 is a multicenter, randomized, double-blind, placebo-controlled, efficacy, and safety 
study of etripamil NS 70 mg for the termination of spontaneous episodes of PSVT. This study 
consists of 2 parts:  
• NODE-301 Part 1 consisted of patients that were dosed with the double-blind study drug 
or had discontinued the study before the adjudication of the 150th positively adjudicated 
PSVT episode.  
• NODE-301 Part 2 (the RAPID Study, ongoing) consists of patients randomized into Part 1 
who were not dosed with the double-blind study drug or had not discontinued the study 
before the adjudication of the 150th positively adjudicated PSVT episode, and new patients 
enrolled into the study following the completion of Part 1.  
Based on the results of Part 1, patients in Part 2 of NODE-301 (RAPID) will be randomized to a 
dosing regimen that will permit a second 70 mg dose if symptoms still persist at 10 minutes after 
the first dose. The primary efficacy endpoint is defined as time to an adjudicated termination of a 
positively adjudicated episode of PSVT and conversion to sinus rhythm for at least 30 seconds 
within 30 minutes of start of study drug dosing. 
3.2.6 NODE-303 Phase 3 Open Label Safety Study 
The ongoing NODE-303 study is a multi-center, multi-national, open-label study designed to 
evaluate the safety of etripamil when self-administered by patients for spontaneous episodes of 
PSVT outside of the clinical setting. The NODE-303 design is intended to provide an assessment 
of etripamil NS safety in a use setting which closely mimics a real-world setting. Secondary 
objectives are to evaluate the efficacy of self-administered etripamil NS outside of the clinical 
setting, to evaluate the impact of etripamil NS on PSVT disease burden, and to evaluate the safety 
and efficacy of etripamil NS when used for multiple PSVT episodes.  
The study will enroll up to approximately 3000 patients to obtain a sufficient number of patients 
(in the overall development program) with a PSVT episode. Patients are diagnosed with PSVT by 
a medical professional and have reported having at least one previous episode of PSVT prior to 
study screening. Patients are provided with an ambulatory CMS to help document PSVT episodes. 
The CMS is self-applied by the patient when they feel the onset of PSVT symptoms. Patients then 
self-administer etripamil NS if a vagal maneuver is ineffective to resolve their symptoms.  The 
treatment regimen of etripamil to be evaluated  is an initial dose of etripamil NS 70 mg to be 
followed by a second dose 10 minutes later if the patient continues to experience PSVT symptoms. 
After each episode of PSVT for which etripamil NS was administered, the patient returns to the 
investigative site and has the option to continue in NODE-303 and manage subsequent episodes 
of PSVT with etripamil NS (treatment for up to a maximum of 4 perceived PSVT episodes).  
As of the cut-off date (10 December 2021), 369 subjects had self-administered at least one dose of 
Etripamil NS 70 mg of which 350 subjects took a single dose of etripamil NS 70 mg for all PSVT 
episodes and 19 subjects took 2x70 mg for at least one PSVT episode. As of the cut-off date, 207 
subjects were ongoing, 107 subjects discontinued from the study, and 55 subjects had completed 
the study after treating 4 PSVT episodes (the maximum in this study).  
Of these 350 patients who took a single dose of etripamil NS 70 mg for all PSVT episodes, 205 
(59%) had at least one AE and 147 (42%) had at least one TEAE (defined as AEs occurring <24 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 27 of 62 
hours after the administration of etripamil). The maximum severity of these TEAEs for most of 
the patients was mild (30%) or moderate (9%). Severe AEs were reported in 9 (3%) subjects. The 
most reported AEs were under Respiratory, thoracic and mediastinal disorder system organ class 
(SOC) followed by Nervous system disorders SOC. The most commonly reported TEAEs to date 
(regardless of relationship to study drug) were nasal discomfort (26%) and nasal congestion (11%). 
There were 11 (3.1%) subjects who reported SAEs that occurred at any time following the first 
dose of etripamil (death [unknown cause], acute coronary syndrome, coronavirus infection, 
papillary serous endometrial carcinoma, stress cardiomyopathy (Takotsubo cardiomyopathy), 
appendicitis, breast cancer, aortic valve stenosis, in 1 subject each, and acute myocardial infarction 
in 2 subjects, and sepsis and Crohn’s disease that were both reported in the same subject, of which 
only 1 SAE (stress cardiomyopathy) was treatment emergent. None of the SAEs were considered  
related to the study drug.  
3.3 
Rationale for the Study 
The primary objective of this study is to demonstrate the superiority of etripamil NS over placebo 
in reducing ventricular rate in patients with AF. 
The secondary objective of the study is to further evaluate the safety and efficacy of etripamil NS 
70 mg in patients with AF.   
Ventricular rate control without conversion of AF into sinus rhythm is one treatment option 
recommended in the guidelines for the management of AF.6 Many patients experience persistent 
tachycardia with episodes of rapid ventricular rate despite chronic treatment to reduce ventricular 
rate.  
Etripamil addresses an unmet medical need since there are currently no short-acting products 
available for patient self-administered treatment of episodes of atrial fibrillation. 
We believe that etripamil NS will provide symptomatic relief in patients who experience rapid 
ventricular rates during AF. This is a treatment option that patients will be able to self-administer 
in a non-acute setting to provide immediate ventricular rate control. The rapid onset of action and 
duration of effect afforded by etripamil nasal spray should provide patients with immediate 
symptom relief while waiting for AF to spontaneously resolve or waiting for adjunctive oral 
medications to take effect.  
3.4 
Summary of Potential Risks and Benefits 
The primary benefit of this study is that etripamil nasal spray may provide rapid symptom relief 
to patients with atrial fibrillation by decreasing the ventricular response rate.  
The potential risks of study participation include those associated with exposure to etripamil and 
the risks of medical evaluation. AEs associated with etripamil include nasal irritation, nasal 
discomfort, and throat irritation.  Potential adverse events which have been rare or not observed in 
studies to date include other cardiac arrhythmias, or AEs associated with drops in blood pressure 
(dizziness, headache).   
 
A summary of the pharmacological properties and known potential risks of etripamil is provided 
in the current version of the Investigator’s Brochure (IB).  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 28 of 62 
4. OBJECTIVES 
4.1 
Primary Objective 
The primary objective of this study is to demonstrate the superiority of etripamil NS over placebo 
in reducing ventricular rate in patients with AF. 
4.2 
Secondary Objectives 
The secondary objective is to evaluate the safety and efficacy of etripamil NS in patients with AF. 
5. STUDY DESIGN 
5.1 
Overall Study Design and Plan 
This is a multi-center, randomized, double-blind, placebo-controlled study to evaluate the effects 
of etripamil NS in patients with AF. This study includes screening procedures, treatment 
procedures, and a follow-up period.  Patients will be randomized in a double-blind fashion to yield 
at least 50 evaluable patients in 2 groups of at least 25 patients each (Efficacy Population).  Each 
patient will receive a single dose of Placebo or 70 mg etripamil intranasally. 
Screening and treatment procedures should be performed at the same visit. Informed consent must 
be obtained prior to any study-specific procedures being completed. Patients will be contacted by 
phone (or other available telemedicine application) for follow-up the next day and 7 days after 
dosing (on-site follow-up visits may be performed as necessary) Total duration of participation is 
1 week. 
See Section 8 for a full description of the study procedures. 
5.2 
Discussion of Study Design 
In Phase 2 studies, etripamil has been shown to decrease heart rate and convert patients with PSVT 
to sinus rhythm.  A fast-acting calcium channel blocker such as etripamil is likely to reduce 
ventricular rate in patients with AF as well.  As ventricular rate control is one recommended option 
for treatment of patients with AF, etripamil could provide benefit to this patient population.   
This study is designed as a two-arm, double-blind, randomized, placebo-controlled, proof of 
concept study to evaluate if etripamil decreases ventricular rate in an AF population.   
The study design is depicted in Figure 3: 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 29 of 62 
Figure 3. 
Study Design Schematic 
 
5.3 
Rationale for Dosing 
The choice of the dose level of etripamil NS (70mg) was made according to the data obtained in 
Phase 1 and Phase 2 studies.  The selected dose is also being studied in the Phase 3 PSVT program, 
NODE-301 Part 1 and NODE-302 studies and in the ongoing Phase 3 NODE-301 Part 2 (RAPID) 
and NODE-303 studies that allow a second 70 mg dose if symptoms persist at 10 minutes after the 
first dose. 
In the Phase 1 study, etripamil 140 mg was determined to be the MFD with the current formulation 
based on the maximal concentration of etripamil and the required volume of administration (up to 
220 µL of the solution) in each nostril. The 4 highest doses tested in Phase 1 (30, 60, 105, and 
140 mg) produced an increase in the PR interval of the ECG that was consistent with the necessary 
PD effect required to convert reentry tachycardia involving the AV node to SR (see Section 3.2). 
Four doses (35, 70, 105, and 140 mg) were tested in the NODE-1 Phase 2 study. The 3 highest 
doses (70, 105, and 140 mg) were statistically significantly superior compared with placebo for 
terminating induced PSVT in the EPL within 15 minutes of dosing; in addition, the time to 
conversion of PSVT to SR was shorter with these doses compared with placebo. The Emax model 
of dose response indicates that these 3 doses are at the plateau of the dose response, whereas the 
35 mg dose is in the ascending portion of the curve (see Section 3.2.2). 
A drop in SBP versus baseline was observed with the 105 and 140 mg doses between 4 and 
10 minutes after etripamil administration, with mean reductions of 11.4% (105 mg), and 15.6% 
(140 mg) mmHg. These decreases were generally asymptomatic and quickly resolved.  Mean SBP 
did not drop following administration of etripamil 35 and 70 mg. 
Etripamil NS 70 mg satisfies the need to balance benefit and risk. The required delivery dose 
(70 mg) is well tolerated; efficacy (measured in PSVT termination rate) is at the plateau of the 
dose response curve; and the AE profile is acceptable, with no post-dose reductions observed in 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 30 of 62 
SBP.  Currently the 70 mg dose has the greatest amount of safety data available, with strong 
evidence that it is biologically active.   
For these reasons, etripamil NS 70 mg has been selected as the initial dose in patients with Atrial 
Fibrillation.  Initial studies to find the optimal dose in this patient population may be required if 
this proof of concept trial shows activity in this indication.   
6. STUDY POPULATION 
6.1 
Selection of Study Population and Diagnosis 
Enrollment will continue until enough patients are randomized to provide at least 50 evaluable 
patients in the Efficacy Population.  Patients must be diagnosed with AF by a medical professional 
and show evidence of current AF with ventricular rate ≥110 bpm at screening and prior to study 
drug administration.  
6.2 
Study Entry Criteria 
6.2.1 Inclusion Criteria 
A patient will be eligible for study participation if they meet all of the following criteria: 
1) Aged 18 and over 
2) Has provided written informed consent 
3) Patients with episodes of paroxysmal, persistent or permanent AF, presenting with AF and 
a ventricular rate ≥110 bpm measured over 1 minute  
4) Patients should receive appropriate antithrombotic therapy as per the applicable guidelines 
for AF management (e.g. Canadian Cardiovascular Society (CCS) / European Society of 
Cardiology (ESC) guidelines) 
a. Etripamil (a calcium channel blocker) is intended for acute rate control only.7 If 
rhythm control is desired (outside of the present protocol), anticoagulation as per 
guidelines may start after the administration of study drug.  
6.2.2 Exclusion Criteria 
A patient will be excluded from the study if they meet any of the following criteria: 
1) Has evidence of atrial flutter (ECG) at presentation 
2) Has a history of stroke, transient ischemic attack, or peripheral embolism within the last 3 
months  
3) Has received by IV route any of the following within one hour before study drug 
administration: flecainide, procainamide, digoxin, beta-blocker, or calcium chanel blocker  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 31 of 62 
4) Has signs and symptoms of severe congestive heart failure at presentation (e.g. tachypnea, 
oxygen desaturation <90% unless due to known pulmonary disease, pulmonary rales, sign 
of peripheral hypoperfusion)  
5) Hemodynamic instability, with systolic blood pressure <90 mmHg or diastolic blood 
pressure <60 mmHg 
6) Known uncorrected severe aortic or mitral stenosis 
7) Hypertrophic cardiomyopathy with outflow tract obstruction 
8) Has a history of second- or third-degree atrioventricular block 
9) Regular rhythm suggesting a complete AV block 
10) Has a history or evidence of torsades de pointes, sick sinus syndrome, or Brugada syndrome  
11) Evidence of Acute Coronary Syndrome within the last 12 months except if patient was 
successfully revascularized 
12) Positive pregnancy test result at screening, and females of childbearing potential who do 
not agree to use adequate method of contraception for the duration of the study  
13) Has evidence of any clinically significant acute or chronic condition of the nasal cavity 
(e.g., rhinitis or deviated septum) which could interfere with administration of the study 
drug in either or both nasal cavities  
14) Has a history of sensitivity to verapamil 
15) Has previously participated in a clinical study for etripamil 
16) Has a history of sensitivity to any components of the investigational product. 
17) Signs of alcohol or drugs intoxication at the time of presentation which, in the opinion of 
the Investigator, would impact the validity of study results;   
18) Is currently participating in another drug or device study, or has received an investigational 
drug or device within 30 days of Screening 
19) Has evidence of clinically significant cardiovascular, endocrine, gastrointestinal, 
hematologic, hepatic, immunologic, neurologic, oncologic, pulmonary, psychiatric, or 
renal disease or any other condition which, in the opinion of the Investigator, would 
jeopardize the safety of the patient or impact the validity of study results.   
6.3 
Patient Completion / Discontinuation / Withdrawal 
The end of study is defined as the date of the last visit of the last study participant.  Last study visit 
of the last study participant is the date of their last follow-up contact.  
All patients will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The Investigator should make every reasonable 
attempt to keep patients in the study; however, patients must be withdrawn from the study if they 
withdraw consent to participate.  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 32 of 62 
Investigators must attempt to contact patients who fail to respond to the 24-hour follow-up 
phone/video call in order to exclude the possibility of an AE being the cause of withdrawal. Should 
this be the cause, the AE must be documented, reported, and followed as described in Section 9.2. 
Milestone reserves the right to request the withdrawal of a patient because of protocol violations 
or other reasons. Any administrative or other reason for withdrawal must be documented and 
explained to the study participant. 
The investigator also has the right to withdraw patients from the study or discontinue study drug 
treatment at any time for apparent lack of therapeutic effect, or drug treatment that is intolerable 
or otherwise unacceptable to the patient, for intolerable or unacceptable AEs, intercurrent illness, 
noncompliance with study procedures, administrative reasons, or in the investigator’s opinion, to 
protect the patient’s best interest. 
Should a study participant decide to withdraw, all efforts will be made to complete and report the 
observations prior to withdrawal as thoroughly as possible. 
Study participants withdrawing from the study treatment should be followed as per protocol for 
the entire duration of the study unless the study participant explicitly withdraws consent for 
follow-up and refuses to provide further information.   
If a patient is withdrawn or discontinues treatment, the reason and the date of discontinuation will 
be recorded on the appropriate electronic case report form (eCRF), in addition to information on 
any ongoing adverse event.  
7. TREATMENTS 
7.1 
Identification of Investigational Product 
The formulation of etripamil is for intranasal administration and will consist of etripamil, water, 
acetic acid, disodium ethylene-diamine-tetra-acetic acid (EDTA), and sulfuric acid. The dose of 
etripamil to be evaluated in this study is 70 mg.  
The formulation of placebo will consist of water, sodium acetate, disodium EDTA, and sulfuric 
acid to reproduce the same pH as the etripamil formulation. 
The study drug is packaged a prefilled device, the Aptar Pharma Nasal Spray Bidose System 
(BDS). 
7.2 
Labeling and Packaging 
Clinical labeling, packaging, and distribution of the study drug will be performed by PCI Pharma 
Services. 
7.2.1 Labeling 
Study drug will be labeled according to the requirements of local law and legislation, as well as 
current Good Manufacturing Practice (GMP) and International Council for Harmonization (ICH) 
Good Clinical Practice (GCP) guidelines. In compliance with these regulations and guidelines, the 
label may include information such as the study protocol number, administration sequence, lot 
number, storage conditions, expiry date, Sponsor identification, or appropriate cautionary 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 33 of 62 
language for investigative material. Proof labels, detailing actual label text, will be available in the 
study files. 
7.2.2 Packaging 
The study drug distributor will package the study drug in kits, according to current GMP and ICH 
GCP guidelines. Drug kits will be packaged in accordance to the randomization list provided by 
an unblinded biostatistician, and identified by a unique kit ID number that will maintain treatment 
blinding, while allowing unblinded personel to identify the treatment it contains, if necessary.  
7.2.3 Distribution 
The sponsor will not supply an investigator/institution with the study drug until all required 
approvals from the institutional review board (IRB)/ Independent Ethics Committee (IEC) and 
competent authority are obtained. Study drug kits will be distributed to approved sites by PCI 
Pharma Services. 
7.3 
Treatments Administered 
Study drug will be administered at the clinical site by the Investigator or qualified designee. Each 
patient will receive a total of 200 µL of placebo or etripamil NS 70 mg (i.e., 100 µL in each nostril 
via the Aptar Pharma Nasal Spray Bidose System [BDS]). The devices will be prefilled and 
packaged.  Instructions for  use of the nasal spray are provided in the Appendix B.  Date and time 
of dosing will be recorded in the eCRF. 
If only one spray of the BDS is administered for any reason, it will be considered a partial dose.  
Missed and partial doses will be recorded in the eCRF. 
7.4 
Randomization and Unblinding Procedure 
Each randomized patient will be assigned to receive either placebo or 70 mg etripamil NS; 
treatment will be randomized in a 1:1 ratio to yield at least 50 evaluable patients with AF in 2 
groups of at least 25 each (placebo vs. etripamil NS). To ensure an adequate sample size, 
enrollment in the study will continue until each treatment group reaches the minimum of 25 
evaluable patients. Throughout the study, the Milestone Medical Monitor (or designated medical 
reviewer) will log into the Interactive Web Randomization System (IWRS) to indicate whether or 
not each randomized patient meets the criteria for inclusion in the Efficacy Population (see Section 
10.3).  
Upon confirmation of eligibility, site personnel will log in to the IWRS to obtain a blinded 
treatment assignment for the patient: the IWRS will specify which drug kit is assigned to which 
patient, without revealing the treatment group (etripamil or placebo).   The kit ID administered to 
each patient will also be recorded in the electronic data capture (EDC) system and in drug 
accountability documentation.  
The randomization list will be generated by an IWRS vendor, and will only be accessible to limited 
unblinded personnel, e.g. drug packaging vendor, IWRS vendor. Blinding is critical for the 
integrity of the study. However, in the event of a medical emergency where revealing the study 
medication is critical to the care of the patient, the investigator may need to break the code. Before 
breaking the blind, the investigator should have determined that the information is necessary.  It is 
recommended to contact the Montreal Health Innovations Coordinating Centre (MHICC) Medical 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 34 of 62 
Monitor or the Sponsor Medical Director before any unblinding. The unblinding will be done 
through the IWRS system. If the IWRS is not accessible, the investigator will contact the Milestone 
Medical Monitor. This unblinding and the reason will be clearly document by the principal 
investigator in the study source documents.  
7.5 
Drug Storage and Accountability 
Study drug will be stored at the clinical site at ambient room temperature (15°C to 30°C [59°F to 
86°F]) and will be protected from light in a secure area with access limited to authorized personnel. 
For more information on study drug stability, please refer to the Investigator Brochure. 
Used nasal spray devices should be maintained until study end to allow for full drug accountability 
to be conducted. 
Records will be maintained at each clinical site indicating the receipt and dispensation of all study 
drug supplies. The responsible pharmacist or designee at the investigational site must keep an 
accurate inventory of study drug shipments received and the amount of study drug used or not used 
by each patient. A full reconciliation of drug inventory will be performed at the end of the study, 
and the results of the inventory will be recorded in the drug accountability log. 
The final accountability of study drug (both used and unused kits) will be performed by the Clinical 
Research Associate (CRA) at the sites. The sites will be allowed to destroy used devices after CRA 
accountability. Unused study drug kits will be returned to PCI Pharma Services for destruction. If 
no study drug remains, this will be indicated in the drug accountability log. 
7.6 
Prior and Concomitant Therapies 
All concomitant medications and treatments used within 30 days of screening (including over-the-
counter medications and herbal supplements) will be recorded in the source document and on the 
appropriate eCRF. 
Patients who, prior to enrollment, have received any of the following drugs by IV route may be 
eligible to participate at least 1 hour after these drugs were administered : flecainide, procainamide, 
digoxin, beta-blocker, or calcium channel blocker. Time of administration of such prior treatments 
must be documented in the eCRF.  
After study drug administration, in case of clinical symptoms representing a safety risk for the 
patient, it is the investigator’s prerogative to use any additional treatment in accordance with the 
standard of care. 
The use of any drugs of abuse (such as marijuana or prescription opioids) which, in the opinion of 
the Investigator, would impact the validity of the study results is prohibited. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 35 of 62 
8. STUDY PROCEDURES 
Prospective study patients will be asked to sign the informed consent form before the 
commencement of any study-related assessments or procedures, including the cessation of 
prohibited concomitant therapy. 
For a summary of assessments and procedures throughout the study, refer to the schedule of 
assessments (Appendix A). 
8.1 
Study Periods, Visits, and Procedures 
8.1.1 Screening Procedures 
Prospective study patients will be asked to sign the informed consent form before the 
commencement of any study-related assessments or procedures. However, an ECG performed at 
presentation and in accordance to the institution’s standard-of-care, but prior to ICF signature, may 
be used to assess the patient’s eligibility to the study.  
Screening ends when the patient is randomized or is deemed a Screen Failure; if an enrolled patient 
meets at least 1 exclusion criterion, they will be considered a screening failure. Screening and 
Treatment Procedures should be conducted at the same visit; however, all Screening Procedures 
must be completed prior to randomization.  
The following procedures will be performed at Screening: 
1. Obtain written informed consent. 
2. Review inclusion/exclusion criteria.   
• In the event that the reference Screening ECG recording is shorter than one minute (e.g. 
due to the use of a standard-of-care ECG for eligibility assessment), a clinical note from 
qualified site personnel, documenting the monitoring of the heart rate for 1 minute, is 
deemed acceptable to confirm eligibility at Screening. 
3. Record demographics and detailed medical history, including review of concomitant 
medications, and medications taken within 30 days before Screening.  
4. Perform a complete physical examination (excluding breast and genitourinary 
examination) with review of body systems. 
5. Measure height and weight. 
6. Record vital signs (blood pressure, heart rate) after the patient has been in a seated position 
for at least 5 minutes. 
7. Collect urine samples for pregnancy test (applicable only to women of childbearing 
potential). Alternatively, a serum pregnancy test may be performed. 
8. Record any Adverse Events, as per Section 9.2.4. 
8.1.2 Treatment Procedures 
The Treatment Procedures will occur after Screening is completed and the patient’s eligibility has 
been verified.  The following procedures will be performed during the Treatment Period: 
Pre-Dose (at least 10 minutes prior to dosing) 
1. Confirm patient remains eligible for the study. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 36 of 62 
2. By logging in to IWRS, randomize the patient and obtain study drug kit assignment. 
Document the kit number in the patient’s eCRF. 
3. Fit the patient with a Holter monitor, and continuously record ECG from at least 10 minutes 
pre-dose to 6 hours after study drug administration.  
4. Record blood pressure after the patient has been in a seated position for at least 5 minutes:  
1) 10 minutes prior to dosing,  
2) immediately prior to drug administration, to ensure patient eligibility prior to 
dosing with SBP ≥90 mmHg 
5. Perform two ECGs over 10 minutes (from the Holter monitor):  
1) at 10 minutes prior to dosing to confirm the patient is in AF, 
2) immediately prior to drug administration, to confirm that Baseline HR meets 
≥110 bpm threshold 
Patients must exhibit a rapid ventricular rate (≥110 bpm measured during 1 minute on the 
Holter report) prior to drug administration in order to receive the study drug.   
Dosing 
6. Administer Study Drug, and record time of drug administration. Appendix B provides 
detailed instructions for dosing. 
• Study drug must be administered by qualified clinical site staff.  
• Prior to administration, patients should be seated with their head in an upright 
position. Patients will be instructed to hold their breath and avoid inhaling during 
study drug administration.  
• For 10 minutes after drug administration, patients are to remain in a seated position 
with their head upright, breathe normally, and refrain from blowing their nose. 
• Patient should not perform any strenuous physical activity for 1 hour post-dose. 
Post-Dose (up to 1 hour after dosing) 
7. Record blood pressure at 5, 10, 15, 30, and 60 minutes post-dose. 
8. Complete the TSMQ-9 questionnaire at the end of the Treatment Period.   
9. Record any adverse events, as per Section 9.2.4. 
10. Record any concomitant medication taken since study drug administration 
11. In case of systolic blood pressure <90 mmHg or clinical symptoms representing a safety 
risk for the patient, it is the investigator’s prerogative to use any additional treatment within 
60 minutes of study drug administration.  
12. Beyond 60 minutes after study drug administration: 
• Appropriate medical care should be offered, in accordance with the standard of care. 
• The patient may be discharged from the clinic, while still wearing the Holter device 
as per the site staff’s instructions.  
8.1.3  Follow-Up Period 
Following drug administration and post-dose activities, follow-up procedures will be performed. 
If the patient cannot be reached after 3 attempts, they will be considered lost to follow-up.  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 37 of 62 
1. 24 hours post-dose (+/- 6 hours) : Safety follow-up will be performed, either via 
telemedicine or as an in-person visit if deemed necessary by the investigator.  
• Record any Adverse Events, as per Section 9.2.4. 
• Record any concomitant medication taken since study drug administration 
• Return of the Holter device will be arranged (e.g. by courier) 
2. 1 week post-dose : Patients will be contacted by phone 7 days (+/- 1 day) post-dosing for 
safety follow-up.   
• Record any Adverse Events, as per Section 9.2.4. 
• Record any concomitant medication taken since study drug administration 
8.2 
Assessments 
8.2.1 Efficacy 
8.2.1.1 12-Lead ECG Recordings 
A 12-lead ECG will be performed at Screening to assess eligibility (NOTE : an ECG performed 
per standard-of-care on the same day but prior to ICF signature will be accepted for screening 
purposes).  Data from the ECG will be reviewed by qualified site personnel for potential 
concomitant disorders which would exclude the patient from the trial.  
8.2.1.2 Holter ECG Recording 
Continuous ECG recordings will be obtained during the Treatment period, from at least 10 minutes 
pre-dose to 6 hours post-dose via portable monitoring devices (Holter), and will provide the data 
for primary and secondary efficacy analyses.  The files will be uploaded and stored centrally in the 
study database at the end of the study. 
In addition, the Holter device and the associated software will be used by qualified site personnel 
for pre-dose Baseline HR measurements (10 minutes and immediately prior to drug 
administration). Following completion of patient participation, the ECGs recordings will also be 
reviewed by the Medical Monitor (or designee) to determine whether patients met the criteria for 
inclusion in the Efficacy Population. 
8.2.1.3 Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
After study drug administration, patients will be asked to complete the TSQM-9 (Appendix C). 
The TSQM-9 is a 9 question, validated, indication agnostic patient reported outcome.  It includes 
3 items measuring treatment effectiveness, 3 items measuring treatment convenience, and 3 items 
measuring global satisfaction with treatment.  The domain scores range from 0 to 100 with higher 
scores representing higher satisfaction with the treatment.   
8.2.2 Safety 
Safety assessments will include the evaluation of AEs, vital sign measurements, and ECG 
recordings. 
8.2.2.1 Adverse Events 
The definitions and management of and special considerations for AEs are provided in Section 9. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 38 of 62 
8.2.2.2 Clinical Laboratory Safety Assessments 
8.2.2.2.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in 
the schedule of assessments (Appendix A). Samples will be analyzed by the site’s local 
laboratory: 
Pregnancy Test: 
For women of childbearing potential only. A urine or serum test
will be performed at Screening and as required to confirm any
suspected pregnancy 
8.2.2.3 Clinical Examinations 
8.2.2.3.1 Vital Signs 
Vital signs will include blood pressure, heart rate, height and weight. Blood pressure and 
heart rate will be measured after the patient has been in a sitting position for 5 minutes.  
8.2.2.3.2 Physical Examination 
A complete physical examination (excluding breast, genitourinary and rectal examination) 
will be performed at Screening. Systems examined should include General Appearance, 
Eyes, ENT/Mouth, Respiratory, Cardiovascular, Gastrointestinal, Muscular, Skin, 
Neurological, Endocrine (including thyroid), Lymph Nodes, Allergy/Immunological, and 
Psychiatric. 
A symptom-directed physical examination will be performed after drug administration. 
9. ADVERSE EVENTS 
9.1 
Definitions 
9.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the product. An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically significant abnormal laboratory finding), symptom, or disease, temporally associated 
with the product, whether or not related to the product. 
During Screening the Investigator or designee will assess all findings from physical exams, vital 
signs, laboratory assessments, and diagnostic ECGs.  Clinically significant findings will be 
recorded as medical history.  Pre-existing diseases or conditions will not be considered AEs unless 
there is an increase in the frequency or severity, or a change in the quality, of the disease or 
condition. (Worsening of a pre-existing condition is considered an AE.) 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms will be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it will be recorded as a separate AE on the eCRF. In cases requiring 
medical or surgical procedures, the underlying condition, rather than the procedure itself, will be 
recorded as an AE(s). 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 39 of 62 
Clinically significant abnormal assessments that are detected during the study or are present at 
screening and significantly worsen will be reported as AEs or SAEs. The Investigator will exercise 
his or her medical and scientific judgment in deciding whether an abnormal assessment is clinically 
significant. Any abnormal assessments considered clinically significant by the Investigator must 
be recorded on the AE page of the eCRF.  
Events that occur in patients during the Treatment Period while drug is not administered are also 
considered AEs. 
9.1.2 Adverse Drug Reaction 
All noxious and unintended responses to a study drug related to any dose should be considered 
adverse drug reactions (ADRs). 
The phrase “responses to a study drug” means that a causal relationship between a study drug and 
an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. All AEs judged 
by either the reporting investigator or the sponsor as having a reasonable causal relationship to a 
study drug qualify as ADRs. 
All AEs for which the judgment of relationship to the study drug is “possible” or higher will be 
considered ADRs. If a relationship to the study drug is not given, then the AE must be treated as 
if the relationship to the study drug were “possible.”  
9.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For etripamil, the reference safety 
information is included in the Investigator’s Brochure currently in force. The reference safety 
information will be reviewed yearly, and the periodicity of the review will be harmonized with the 
reporting period of the Development Safety Update Report. 
9.1.4 Serious Adverse Events/Drug Reaction 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. 
NOTE: 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. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the study 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE. Further, an overnight stay in the hospital that is only due to 
transportation, organization, or accommodation problems and without medical 
background does not need to be considered a SAE. 
Note: An ablation or cardioversion for treatment of atrial fibrillation will not be 
considered as a SAE. 
• Results in persistent or significant disability/incapacity. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 40 of 62 
• Is a congenital anomaly. 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the study 
drug during pregnancy is an SAE. However, a newly diagnosed pregnancy in a patient who 
has received a study drug is not considered an SAE unless it is suspected that the study 
drug(s) interacted with a contraceptive method and led to the pregnancy.  
• Is an important medical event. 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. The occurrence of 
malignant tumors is also to be considered serious 
9.1.5 Serious Unexpected Suspected Adverse Reaction (SUSAR)  
An adverse reaction that is considered to be both serious and unexpected and of a suspected 
causality. Causality is defined as “reasonable suspected causal relationship to the medicinal 
product. 
9.1.6 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is within 24 hours after the 
administration of the study drug. 
9.1.7 Adverse Events of Special Interest 
Due to the mechanism of action of etripamil, patients could be at a higher risk of certain adverse 
events of special interest. Investigators should be on the alert for these events, or for symptoms 
which indicate an event may be present. Investigators should follow the standard protocol process 
for AE and SAE reporting for these AESI. 
Below is a list of AEs which are of particular interest if they occur within 24 hours of study drug 
administration.   
a) Tachyarrhythmias 
i) 
Supraventricular: occurrence of Atrial Tachycardia or Atrial Flutter lasting 
longer than 30 seconds 
 
ii) 
Ventricular: 
- 
Non-sustained ventricular tachycardia defined as equal or greater than 3 
consecutives wide beats originating in the ventricles at a rate >100 bpm and 
terminating spontaneously 
- 
Sustained ventricular tachycardia defined as wide consecutive beats 
originating in the ventricles at a rate >100 bpm during >30 sec or requiring 
termination due to hemodynamic compromise in <30 sec 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 41 of 62 
b) Bradyarrhythmia 
i) Any Sinus rate equal or less than 40 bpm lasting longer than 30 seconds 
ii) Any pause equal or greater than 3 seconds 
c) Atrio-Ventricular Block 
i) New onset (not present in the ECG performed at the screening visit) of 1st° AV 
Block 
ii) Any occurrence of 2nd or 3rd degree AV Block (including AV dissociation or the 
presence of more than 2 consecutives non-conducted P waves) 
d) Syncope and related events 
i) Syncope defined as a transient, self-limited loss of consciousness with an inability 
to maintain postural tone that is followed by spontaneous recovery. 
ii) Pre-syncope defined as a state consisting of light-headedness, muscular weakness, 
blurred vision, and feeling faint 
iii) Loss of consciousness defined as a partial or complete loss of consciousness with 
interruption of awareness of oneself and one’s surroundings. When the loss of 
consciousness is temporary and there is spontaneous recovery it is referred to as 
syncope. 
iv) Dizziness defined as a false sense of motion or spinning, light-headedness or feeling 
faint, unsteadiness or a loss of balance, a feeling of floating, wooziness or heavy 
headedness. The episode may last seconds or days and may recur. 
v) Drop attack defined as a sudden fall without loss of consciousness 
vi) Hypotension is defined as a SBP <90 mmHg after a 5-minute rest in sitting position; 
when clinically severe hypotension patients experience light-headedness, nausea or 
vomiting. 
vii) Orthostatic hypotension defined as a physical finding defined as a systolic blood 
pressure decrease of at least 20 mmHg or a diastolic blood pressure decrease of at 
least 10 mmHg within three minutes of standing 
9.2 
Management of Adverse Events 
Adverse events will be collected from the time of signing the ICF until 7 days post-dose, or until 
the patient withdraws or discontinues from the study.   
9.2.1 Collection of Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. The patient will be allowed time to 
spontaneously report any issues since the last visit or evaluation. The investigator will then monitor 
and/or ask about or evaluate AEs using nonleading questions, such as: 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 42 of 62 
9.2.2 Evaluation of Adverse Events 
9.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the patient. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 9.1.4. 
9.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in Section 9.1.4. 
9.2.2.3 Outcome at the Time of Last Observation 
The outcome, including Fatal, at the time of last observation will be classified per eCRF 
completion instructions.  Only select fatal as an outcome when the AE results in death. If more 
than 1 AE is possibly related to the patient’s death, the outcome of death should be indicated for 
each such AE. Although “fatal” is usually an event outcome, events such as sudden death or 
unexplained death should be reported as SAEs. 
9.2.2.4 Adverse Event Relationship to the Study Drug 
The assessment of the relationship of an AE to study drug administration is a clinical decision 
based on all available information at the time the event is reported. 
The relationship of an AE to study drug administration is to be assessed according to the following 
definitions: 
• Not related – An event that is definitely not associated with study drug administration and is 
judged clearly due to causes other than study drug. 
• Unlikely related – An event that follows a temporal sequence from study drug administration, 
such that a relationship is not likely and could be reasonably explained by the patient’s 
clinical state or other modes of therapy administered to the patient. 
• Possibly related – An event that follows a reasonable temporal sequence from study drug 
administration, but may be due to another cause and could also be reasonably explained by 
the patient’s clinical state or other modes of therapy administered to the patient. 
• Probably related – An event that follows a reasonable temporal sequence from study drug 
administration that is not easily explained by another cause (e.g., known characteristics of the 
patient’s clinical state or other treatment), and is confirmed by improvement on stopping or 
slowing study drug administration. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 43 of 62 
• Definitely related – An event that is clearly associated with study drug administration. 
An AE/SAE that has been assessed as "possibly related" "probably related" or "definitely related" 
will be classified as "related" for regulatory reporting purposes. An AE/SAE that has been assessed 
as "not related" or "unlikely related" will be classified as "unrelated" for regulatory reporting 
purposes.  
The following factors will also be considered: 
• The temporal sequence from study drug administration; 
o The event should occur after study drug administration. The length of time from 
study drug exposure to event will be evaluated in the clinical context of the 
event. 
• Underlying, concomitant, and/or intercurrent diseases; 
o Each report will be evaluated in the context of the natural history and course of 
the disease being treated and any other disease the patient may have. 
• Concomitant medication; 
o The other medications the patient is taking or the treatment the patient receives 
will be examined to determine whether any might be recognized to cause the 
event in question. 
• Known response pattern for this class of study drug; 
o Clinical and/or preclinical data may indicate whether a particular response is 
likely to be a class effect. 
• Exposure to physical and/or mental stresses; and 
o The exposure to stress might induce adverse changes in the recipient and 
provide a logical and better explanation for the event. 
• The pharmacology and PK of the study drug. 
The known pharmacological properties (e.g., absorption, distribution, metabolism, and excretion) 
of the study drug will be considered. 
9.2.3 Documentation 
All AEs occurring within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 9.2) 
• AE name or term. 
• When the AE first occurred (start date and time). 
• When the AE stopped (stop date and time or an indication of “ongoing”). 
• Severity of the AE. 
• Seriousness (e.g., hospitalization or death). 
• Outcome. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 44 of 62 
• Investigator opinion regarding the AE relationship to the study drug(s). 
9.2.4 Follow-up of Adverse Events 
Any AE / SAE (occurring up to a maximum of 7 days after single dose administration in the study) 
will be followed to a satisfactory resolution, until it becomes stable, or until it can be explained by 
another known cause(s) (i.e., concurrent condition or medication) and clinical judgment indicates 
that further evaluation is not warranted. All findings relevant to the final outcome of an AE must 
be included in the EDC. Patients who do not receive study drug during the study do not need AEs 
followed. 
9.2.5 SAE Reporting 
9.2.5.1 Serious Adverse Events 
Initial Reports 
The Investigator or designee must report all SAEs occurring from the time of signing the ICF until 
7 days post-dose, or until the patient withdraws or discontinues from the study. To report the SAE, 
the investigator or designee must complete the SAE form electronically in the EDC system 
immediately and with undue delay, and under no circumstances later than 24 hours of awareness 
of the event. When the form is completed, MHICC Medical Monitor will be notified electronically 
and will retrieve the SAE form. 
In case the EDC system is not available, the SAE should be reported within the same timeframe 
by completing the SAE paper form and send it by email to ReVeRA-SAFETY@mhicc.org. When 
the EDC system is once again functional, the SAE information must be entered within 24 hours of the 
system becoming available.  
At the time of first notification, the investigator or designee should provide the following 
information, if available: 
• Protocol number 
• Reporter (study site and investigator) 
• Patient’s study number and initials 
• Patient’s date of birth 
• Patient’s gender 
• Date of dosing of study drug(s) 
• Adverse event term 
• Time and date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria(on) that were met 
• Concomitant medication at onset of the event (if any) 
• Relevant past history information 
• Relevant laboratory test findings (if any) 
• Investigator’s opinion of the relationship to the study drug(s). (“Is there a reasonable possibility 
that the study drug caused the SAE? Yes or No?”). 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 45 of 62 
The  MHICC medical monitor will write a narrative report/CIOMS for all Suspected Serious 
Adverse Drug Reactions and will provide it to Milestone for immediate regulatory reporting 
purposes. 
The MHICC medical monitor  will review all SAEs that are recorded in eCRF on a regular basis. 
The investigator is required to comply with applicable regulations (including local laws and 
guidance) regarding the notification of his or her health authorities, IRB/IEC, principal and 
coordinating investigators, study investigators, and institutions. The detailed reporting duties and 
division of responsibilities between Milestone and designated vendors will be provided in a 
separate document (see the Medical Review Plan). Each investigator is obligated to learn about 
the reporting requirements for investigators in his or her country. The study monitor may be able 
to assist with this. 
Follow-up SAE Reports 
The investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes or the patient dies. 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically in the EDC system and submit any supporting documentation (e.g. patient discharge 
summary or autopsy report) via e-mail to ReVeRA-SAFETY@mhicc.org.  If it is not possible to 
access the EDC system, follow the procedures outlined above for the initial reporting of SAEs. 
 
These documents must be thoroughly redacted to ensure that the confidentiality of the patient is 
maintained. 
9.2.5.2 Adverse Drug Reactions 
Milestone will report all ADRs related to the study drug to the proper health authorities; serious 
ADRs will be reported immediately and nonserious ADRs will be reported after completion of the 
study. Suspected serious adverse drug reactions must be reported to Milestone immediately, 
regardless of the time that has elapsed since the end of the period of observation. 
9.2.5.3 Nonserious Adverse Events 
The MHICC medical monitor will review all nonserious AEs that are recorded in the eCRF on a 
regular basis. 
9.3 
Special Considerations 
9.3.1 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the need 
to practice at least 1 form of adequate birth control and on the importance of avoiding pregnancy 
during study participation. Women should be instructed to contact the investigator or study staff 
immediately if pregnancy occurs or is suspected within 30 days of study drug administration.   
Pregnancy testing will be conducted at the Screening Visit on every woman of childbearing 
potential. A woman who is found to be pregnant at the Screening Visit will be excluded from the 
study and considered to be a screening failure. 
Should a woman become pregnant within 30 days of receiving the study drug, the investigator 
must report the pregnancy as per the instructions below :  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 46 of 62 
1) Investigator must report the pregnancy within 24 hours of learning of the pregnancy and 
record the information related to the pregnancy on the study specific “Pregnancy Form” to 
MHICC at ReVeRA-SAFETY@mhicc.org  
2) Pregnancy in itself is not an SAE. The event of Pregnancy meets the SAE criterion only if it 
results in a spontaneous abortion or a congenital anomaly or it is suspected that the study 
drug interacted with the contraceptive method and has led to pregnancy. 
3) If pregnancy is associated with an SAE (e.g., if the mother is hospitalized for haemorrhage), 
a separate “SAE Form” must be filed in addition to “Pregnancy Form”. 
4) Investigator is also responsible for following the pregnancy until delivery or termination.    
MHICC will be requesting follow up query with the Investigator in a “Pregnancy query form” for 
the status of the pregnancy (at least once in each trimester) until the outcome of the pregnancy, 
even if the patient has completed the study or study is closed. Also, the baby should be followed 
until one month post-delivery. 
9.3.2 Overdose 
The maximal dose of etripamil should not be exceeded during the study, as study drug is dispensed 
for single use only.   
Overdose that occurs during the study will be treated and documented as an AE/unexpected 
adverse event/SAE if it fulfills the criteria. If the overdose does not result in an AE, it should be 
reported in written form to the designated individual(s) who receive SAE notification. The 
information contained therein should include study site identification, reporter identification, 
patient identification, study drug, dose, action taken (e.g., administration of antidote [if available] 
or supportive measures or therapy), and any comments. 
10. STATISTICS 
This section describes the statistical methods to be used to analyze efficacy and safety endpoints. 
These methods may be revised and updated due to reasons such as regulatory requirements or need 
for further clarifications.  
 
The final analysis plan will be documented in a formal statistical analysis plan (SAP) that must be 
finalized before database lock. The SAP will include details on how variables will be derived, how 
missing and censoring data will be handled, and how data will be presented as well as the details 
on statistical methods to be used for safety and efficacy analyses.  
 
The SAP will take precedence over the protocol for any description of statistical analyses. The 
final clinical study report will discuss deviations from the SAP, if any. 
10.1 Study Endpoints 
10.1.1 Efficacy Endpoints 
Efficacy variables will be obtained from the Holter recordings measured by a central core 
laboratory. In case of conversion to sinus rhythm, only heart rate measurements prior to sinus 
conversion will be used to derive efficacy variables. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 47 of 62 
The primary efficacy variable will be: 
• The maximum reduction in ventricular rate, measured on Holter monitoring, within 60 
minutes from drug administration.  
o Baseline ventricular rate is defined as the average heart rate over five minutes 
immediately prior to drug administration.  
o Nadir is defined as the lowest moving average heart rate over five minutes recorded 
in the primary evaluation period, i.e., 60 minutes post drug administration. The 
moving averages are 5 minutes’ averages of different subsets of the full data set and 
are calculated by using the "shifting forward" method; that is, excluding the first 
number of the series and including the next value in the subset. 
o Maximum reduction will be calculated as the change between baseline value and 
nadir. 
The secondary efficacy variables will include: 
• Elapsed time from drug administration to nadir 
• Percentage of patients achieving ventricular rate of <100 bpm in the 60 minutes post drug 
administration. 
o Elapsed time from drug administration to ventricular rate < 100 bpm 
o Duration of ventricular rate < 100 bpm in the 60 minutes post drug administration. 
Duration will be set to zero in patients who will not achieve ventricular rate <100 bpm 
and will be calculated as the sum of the time periods during which the patient has a 
heart rate below the target ventricular rate. 
• Percentage of patients with 10% reduction from baseline ventricular rate in the 60 minutes 
post drug administration. 
o Elapsed time from drug administration to 10% reduction from baseline ventricular 
rate 
o Duration of 10% reduction from baseline ventricular rate in the 60 minutes post drug 
administration. Duration will be set to zero in patients who will not achieve 10% 
reduction and will be calculated as the sum of the time periods during which the 
patient has a heart rate below the target ventricular rate. 
• Percentage of patients with 20% reduction from baseline ventricular rate in the 60 minutes 
post drug administration. 
o Elapsed time from drug administration to 20% reduction in ventricular rate 
o Duration of 20% reduction from baseline ventricular rate in the 60 minutes post drug 
administration. Duration will be set to zero in patients who will not achieve 20% 
reduction and will be calculated as the sum of the time periods during which the 
patient has a heart rate below the target ventricular rate.  
• Percentage of patients cardioverting into sinus rhythm (for at least 30 seconds) in the 60 
minutes post drug administration 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 48 of 62 
o Elapsed time from drug administration to cardioversion into sinus rhythm 
• Area under the curve (AUC) of heart rate over the 60 minutes and the 360 minutes post drug 
administration. 
• Patient satisfaction with treatment, as measured by the TSQM-9. 
10.1.2 Safety Endpoints 
Safety variables will include clinical AEs, vital signs, and findings from electrocardiographic 
analysis (ventricular arrhythmia [premature ventricular contractions, non-sustained ventricular 
tachycardia], any AV block). 
10.2 Sample Size Determination 
The primary efficacy variable for this study is the maximal reduction of ventricular rate after study 
drug administration. Accounting for a two-sided test with a type I error rate of α=0.05, 25 patients 
per group will provide 93% power to detect a 20 bpm absolute difference in ventricular rate from 
baseline between active drug and placebo, assuming a standard deviation of 20 bpm.   
10.3 Analysis Populations 
The following 3 analysis populations are planned for this study:  
• Safety Population: All randomized patients who receive the study drug. Patients will be 
analyzed as per actual treatment received in the Safety population. 
• Modified Intent to Treat (mITT) Population: All randomized patients who receive the study 
drug and who have a Holter recording post study drug administration. Patients will be 
analyzed as per treatment assigned by randomization in the mITT population.  
• Efficacy Population: All patients included in the mITT population, excluding patients who 
convert to sinus rhythm or with a lost ECG signal within 60 minutes post study drug 
administration. Patients will be analyzed as per treatment assigned by randomization in the 
Efficacy population.  
10.4 Statistical Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant.  
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of patients, mean, standard 
deviation (SD), median, minimum, Q1, Q3 and maximum. For categorical variables, these 
statistics will typically include the number and percentage of patients in each category. 
In general, parametric analyses are planned. However, according to the distribution of the efficacy 
variables, non-parametric tests could be used or a logarithmic transformation could be applied on 
the variables before proceeding to the planned parametric analyses.  
10.4.1 Efficacy Analyses 
The efficacy analyses will compare placebo-treated patients versus etripamil-treated patients. 
Efficacy endpoint analyses will include summaries, both over time and as comparisons between 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 49 of 62 
placebo and etripamil. Continuous efficacy data will be presented with n, minimum, maximum, 
median, mean, and standard deviation, whereas discrete efficacy data will be summarized with 
frequency counts and percentages.   
10.4.1.1 Primary Efficacy Analysis 
The primary efficacy analysis will be performed on the Efficacy Population, and will compare 
the maximum reduction in ventricular rate in placebo-treated patients versus etripamil-treated 
patients. This comparison will be done using an analysis of covariance (ANCOVA) adjusting for 
the value of ventricular rate at baseline.  
Sensitivity analysis for the primary efficacy endpoint will also be performed in the mITT 
population using an ANCOVA as described above.  
10.4.1.2 Secondary Efficacy Analyses 
The secondary efficacy analyses will be performed on the Efficacy Population and on the mITT 
Population, and will compare : 
• Elapsed time from drug administration to nadir. Group comparison will be done using an 
ANCOVA adjusting for baseline ventricular rate.  
• Percentage of patients achieving ventricular rate of <100 bpm, reaching 10% and 20% 
reduction from baseline ventricular rate. For each of these three endpoints, group comparison 
will be done using a chi-square test or a Fisher exact test if more than 20% of cells have 
expected frequencies <5.  
• Elapsed time from drug administration to ventricular rate <100 bpm, to 10% reduction from 
baseline ventricular rate, and to 20% reduction from baseline ventricular rate. For each of 
these three endpoints, group comparison will be done using the Kaplan-Meier method and a 
Wilcoxon test for censored data. . 
• Duration of 10% and 20% ventricular rate reductions will be analyzed using an ANCOVA 
adjusting for baseline ventricular rate.  
• Mean heart rate over time will be plotted with 95% confidence interval error bars. 
• AUC of heart rate over 60 minutes. AUC will be calculated over the specific Holter recording 
period for each patient and indexed to a period of 60 minutes. Group comparison will be done 
using an ANCOVA adjusting for baseline ventricular rate. 
• Patient satisfaction with treatment, as measured by the TSQM-9. Domaine scores (ranging 
from 0 to 100) will be analyzed using a t-test or a Mann-Whitney-Wilcoxon test, according 
to the distribution of the variable.  
• Parameters analyzed in mITT Population only :  
o Percentage of patients cardioverting into sinus rhythm (for at least 30 seconds).  Group 
comparison will be done using a chi-square test or a Fisher exact test if more than 20% 
of cells have expected frequencies <5.  
o Elapsed time from drug administration to cardioversion into sinus rhythm. Group 
comparison will be done using using the Kaplan-Meier method and a Wilcoxon test for 
censored data.  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 50 of 62 
o AUC of heart rate over 360 minutes. AUC will be calculated over the specific Holter 
recording period for each patient and indexed to a period of 360 minutes. Group 
comparison will be done using an ANCOVA adjusting for baseline ventricular rate. 
10.4.2 Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 10.3).   
Safety and tolerability will be assessed through AEs, vital signs measurements, and ECG 
recordings.  
Safety data will be summarized with descriptive statistics. Continuous safety data will be presented 
with n, minimum, Q1, Q3, maximum, median, mean, and standard deviation, whereas discrete 
safety data will be summarized with frequency counts and percentages. 
10.4.2.1 Adverse Events 
Adverse events will be coded by SOC and preferred term using the Medical Dictionary for 
Regulatory Activities reporting system. 
The number and percentage of patients with AEs will be displayed for each treatment group by 
SOC and preferred term. Additionally, AEs will be tabulated for each treatment group by severity 
and by relationship to the study drug. A listing of and tabulation of SAEs will be provided. 
Treatment Emergent Adverse Events (adverse events occur within 24 hours after study drug 
administration) will be coded by system organ class and analyzed for each treatment group. 
10.4.3 Interim Analyses 
No interim analyses are planned in this study. 
11. INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
Steps to ensure the accuracy and reliability of data include the selection of qualified Investigators 
and appropriate study sites, review of protocol procedures with the Investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
11.1 Ethical Conduct of the Study 
The ICH GCP guidelines serve as an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human patients. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study patients 
are protected consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
11.2 Institutional Review Board/Independent Ethics Committee 
The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of patients. The study will only be conducted at sites where IRB/IEC 
approval has been obtained. The protocol, Investigator’s Brochure, informed consent form, 
advertisements (if applicable), written information given to the patients, safety updates, annual 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 51 of 62 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by the 
Investigator. 
Local regulations and the ICH GCP guidelines require that approval be obtained from an IRB/IEC 
prior to participation of patients in research studies. Prior to study onset, the protocol, any protocol 
amendments, informed consent forms, advertisements to be used for patient recruitment, and any 
other written information regarding this study to be provided to a patient or patient’s legal guardian 
must be approved by the IRB/IEC. 
No drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by Milestone or authorized clinical research organization (CRO). 
11.3 Informed Consent 
The informed consent form and any changes to the informed consent form made during the course 
of the study must be agreed to by Milestone or their designee and the IRB/IEC prior to its use and 
must be in compliance with ICH GCP guidelines, local regulatory requirements, and legal 
requirements.  
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and will document in the 
source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the informed consent form must be maintained by the Investigator and is subject to 
inspection by a representative of Milestone, their representatives, auditors, the IRB/IEC, and/or 
regulatory agencies. A copy of the signed informed consent form will be given to the patient. 
11.4 Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP guidelines, and applicable regulatory 
requirements, and that valid data are entered into the eCRFs. 
To achieve this objective, the CRA’s duties are to aid the Investigator and, at the same time, 
Milestone in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any patient in this study, Milestone or their designee will review with the 
Investigator and site personnel the following: the study protocol, Investigator’s Brochure,  eCRFs 
and procedures for their completion, informed consent process, site and/or patient training 
material, and the procedure for reporting SAEs. 
The Investigator will permit Milestone or their designee to monitor the study as frequently as 
deemed necessary to determine if data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents, and requests for clarification or correction may be made. After the eCRF data are 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the CRA and 
provide any missing information, whenever possible. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 52 of 62 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 Data Collection 
Data for the study will be collected at the site and entered into the EDC for inclusion in the 
database.  Data from the IWRS and from Holter ECG recordings will be transmitted to the sponsor 
or designee and integrated into the database prior to official lock.  All electronic data collection 
systems will be designed for 21 CFR Part 11 compliance, with audit trail capability.  
This study will be conducted in compliance with applicable regional data privacy and data handling 
regulations and laws.  
11.6 Disclosure of Data 
Data generated by this study must be available for inspection by local regulatory authorities, 
Milestone or their designee, applicable foreign health authorities, and the IRB/IEC as appropriate. 
Patients or their legal representatives may request their medical information be given to their 
personal physician or other appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.7 Retention of Records 
To enable evaluations and/or audits from regulatory authorities or Milestone, the Investigator will 
keep records, including the identity of all participating patients (sufficient information to link 
records [e.g., eCRFs and hospital records]), all original signed informed consent forms, copies of 
all eCRFs, SAE forms, source documents, and detailed records of treatment disposition. The 
records will be retained by the Investigator according to specifications in the ICH GCP guidelines, 
local law regulations, or as specified in the clinical study agreement, whichever is longer. The 
Investigator must obtain written permission from Milestone before disposing of any records, even 
if retention requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, Milestone will be 
prospectively notified. The study records must be transferred to an acceptable designee, such as 
another Investigator, another institution, or to Milestone. 
11.8 Data Protection 
The Sponsor complies with applicable laws and regulations, notably the General Data Protection 
Regulation related to Personal Data protection arising from company-sponsored clinical trials 
involving EU data subjects, via a set of policies relating to data protection practice and retention 
of personal information, privacy notices and security measures, all supervised by the Data 
Protection Officer. The Sponsor and its contractors have implemented various methods to assure 
the security and integrity of personal information including, but not limited to: pseudonymization, 
logical access controls, traceability, encryption, operating systems security, data breach 
procedures, backup, business continuity, and disaster recovery. 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 53 of 62 
which would make the subject identifiable will not be transferred. The subject will be informed 
that his/her personal study-related data will be used by the Sponsor in accordance with local data 
protection law(s). The level of disclosure will be explained to the subject. The subject will 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. 
The Sponsor policy requires all notified breaches to be investigated, categorized, and remediation 
activities implemented. When the rights and freedoms of the data subject are affected then data 
breaches are notified to the relevant authorities and, when there is a high risk, to the data subject. 
11.9 Audits and Inspections 
Authorized representatives of Milestone, a regulatory authority, or an IRB/IEC may visit the site 
to perform audits or inspections, including source data verification. The purpose of a Milestone 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted and data were recorded, analyzed, 
and accurately reported according to the protocol, GCP guidelines of the ICH, and any applicable 
regulatory requirements. The Investigator should contact Milestone immediately if contacted by a 
regulatory agency about an inspection. 
11.10 Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with Milestone before any study 
data are submitted for publication. Milestone reserves the right to deny publication rights until 
mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication is achieved. 
11.11 Financial Disclosure 
Investigators are required to provide financial disclosure information to Milestone to permit 
Milestone to fulfill its obligations under 21 CFR §54 and other appropriate international 
regulations. In addition, Investigators must commit to promptly updating this information if any 
relevant changes occur during the study and for a period of 1 year after the completion of the study. 
The ReVeRA-201 Trial is sponsored and funded fully by Milestone Pharmaceuticals Inc.   
12. STUDY ADMINISTRATIVE INFORMATION 
12.1 Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by CRO or the 
Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC, unless immediate implementation of the change is necessary for patient safety.  


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 54 of 62 
12.2 Protocol Authors 
This study protocol was written and finalized by Milestone Pharmaceuticals employees, with 
external scientific advice provided by the Montreal Heart Institute.   
13. FINAL CLINICAL STUDY REPORT 
Milestone will retain ownership of the data generated from the study. 
The final clinical study report will be written within 1 year of completion of the clinical part of the 
study. This report will include a summary of the study results based on a statistical evaluation and 
clinical assessment of the protocol-defined endpoints. 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 55 of 62 
14. REFERENCES
 
 
1.    Henrard V et al. Cardiac Remodeling With Rhythm Versus Rate Control Strategies For Atrial 
Fibrillation In Patients With Heart Failure: Insights From The AF-CHF Echocardiographic Sub-Study. 
International Journal of Cardiology 165 (2013) 430–436 
 
2.  Olshansky B et al. The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) 
Study – Approaches to Control Rate in Atrial Fibrillation. Journal of the American College of 
Cardiology 2004;43:1201–8 
 
3. 
Cain ME, Curtis AB, Rhythm Control In Atrial Fibrillation--One Setback After Another New England 
Journal of Medicine 2008; 358:2725-2727 
 
4.  Camm AJ et al. Rate Control In The Medical Management Of Atrial Fibrillation. Heart 2007;93:35–3 
 
5.  Fromm C et al. Diltiazem vs. Metoprolol In The management Of Atrial Fibrillation Or Flutter With 
Rapid Ventricular Rate In The Emergency Department. The Journal of Emergency Medicine, Vol. 49, 
No. 2, pp. 175–182, 2015 
 
6.   January CT et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial 
Fibrillation. Journal of the American College of Cardiology (2014) 
 
7. 
Andrade, JG et al., The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society 
Comprehensive Guidelines for the Management of Atrial Fibrillation. Canadian Journal of Cardiology 
2020 Dec; 36(12): 1847-1948. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 56 of 62 
APPENDICES 
A. Schedule of Assessments 
B. Etripamil Administration Instructions 
C. Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
D. Regulations and Good Clinical Practice Guidelines 
 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 57 of 62 
A. SCHEDULE OF ASSESSMENTS  
 
SCREENING a 
TREATMENT PROCEDURES b 
FOLLOW-UP c 
Pre-Dose 
(Baseline) 
Dosing 
Post-Dose 
~24 hrs 
post-dose 
~7 days 
post-dose 
Informed Consent 
X 
 
 
 
 
 
Eligibility Evaluation 
X 
X 
 
 
 
 
Demographic / Medical 
History 
X 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
X 
Physical Examination 
X 
 
 
X d   
 
 
Pregnancy test 
X 
 
 
 
 
 
Vital Signs e 
X 
X 
X 
X 
 
 
Height and Weight 
X 
 
 
 
 
 
ECG f 
X 
 
 
 
 
 
Randomization g 
 
X 
 
 
 
 
Holter ECG Monitoring h 
 
------------------- X ------------------- 
Return 
 
Drug administration 
 
 
X 
 
 
 
TSMQ 
 
 
 
X 
 
 
Adverse Events i 
X j 
------------------- X ------------------- 
X 
X 
 
 
a   Screening and Treatment procedures should be performed on the same day. 
b   Baseline / Pre-dose procedures must be performed at least 10 minutes prior to dosing.  
c   Safety follow-up will be performed approximately 24 hours post-dose; if performed via telemedicine, return of 
the Holter device must be arranged accordingly. An in-person visit may be performed if deemed necessary by the 
investigator. Patients will also be contacted by phone 7 days (+/- 1 day) post-dose for safety follow-up.  If the 
patient cannot be reached after 3 attempts, they will be considered lost to follow-up. 
d   Post-dose physical examination can be symptom-directed. 
e    Screening vital signs include blood pressure, heart rate, weight, and height. Blood pressure must be monitored 
and recorded at 10 minutes pre-dose and immediately prior to dosing, to ensure patient eligibility prior to dosing 
with SBP >90 mmHg. Blood pressure must be recorded at 5, 10, 15, 30, and 60 minutes post-dose. 
f   Ventricular rate used to evaluate patient eligibility should be documented from the screening ECG. A standard-of-
care ECG performed on the same day but prior to ICF signature may be used for eligibility assessment.  
g   Randomization procedure and study drug preparation must be completed prior to other pre-dose procedures. 
h   Following confirmation of eligibility and randomization, patient will be fitted with a Holter monitor for 
continuous ECG recording throughout the treatment period (from 10 minutes pre-dose to 6 hours post-dose). 
Baseline ECG must be assessed 10 minutes prior to and immediately before drug administration; patients must 
exhibit a rapid ventricular rate (≥110 bpm measured during 1 minute) prior to drug administration in order to be 
treated. Holter device will be returned by the following day.  
i   Adverse events considered potentially related to treatment should be followed until resolution. 
j   Worsening of a pre-existing condition discovered during the screening period is considered an AE. 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 58 of 62 
B. STUDY DRUG ADMINISTRATION INSTRUCTIONS 
 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 59 of 62 
C. TREATMENT SATISFACTION QUESTIONNIARE FOR MEDICATION (TSQM-9) 
TSQM-9 
Abbreviated Treatment Satisfaction Questionnaire for Medication 
 
Instructions:  Please take some time to think about your level of satisfaction or 
dissatisfaction with the medication you are taking in this clinical trial.  We are 
interested in your evaluation of the effectiveness and convenience of the 
medication since you last used it.  For each question, please place a single check 
mark next to the response that most closely corresponds to your own experiences. 
 
1. How satisfied or dissatisfied are you with the ability of the medication to treat your condition?  
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
2. How satisfied or dissatisfied are you with the way the medication relieves your symptoms?  
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
3. How satisfied or dissatisfied are you with the amount of time it takes the medication to start 
working?  
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 60 of 62 
 
4. How easy or difficult is it to use the medication in its current form?  
 □1   Extremely Difficult 
□2   Very Difficult 
□3   Difficult 
□4   Somewhat Easy 
□5   Easy 
□6   Very Easy 
□7   Extremely Easy 
 
5. How easy or difficult is it to plan when you will use the medication each time?  
 □1   Extremely Difficult 
□2   Very Difficult 
□3   Difficult 
□4   Somewhat Easy 
□5   Easy 
□6   Very Easy 
□7   Extremely Easy 
 
6. How convenient or inconvenient is it to take the medication as instructed?  
 □1   Extremely Inconvenient 
□2   Very Inconvenient 
□3   Inconvenient 
□4   Somewhat Convenient 
□5   Convenient 
□6   Very Convenient 
□7   Extremely Convenient 
 
 
7. Overall, how confident are you that taking this medication is a good thing for you?  
 □1   Not at All Confident 
□2   A Little Confident 
□3   Somewhat Confident 
□4   Very Confident 
□5   Extremely Confident 
 
 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 61 of 62 
8. How certain are you that the good things about your medication outweigh the bad things?  
 □1   Not at All Certain 
□2   A Little Certain 
□3   Somewhat Certain 
□4   Very Certain 
□5   Extremely Certain 
 
9. Taking all things into account, how satisfied or dissatisfied are you with this medication?  
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 
 


Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
The ReVeRA-201 Trial 
 
MSP-2017-5001 
 
 
Version : FINAL 6.0, 06 JULY 2022 
 
Page 62 of 62 
D. REGULATIONS AND GOOD CLINICAL PRACTICE GUIDELINES 
1. Regulations 
Refer to the following applicable regulations: 
CANADA : Under the Canadian Food and Drugs Act (R.S.C., 1985, c. F-27), 
• Food and Drug Regulations C.R.C c.870, Part C - Drugs, Division 5: Drugs for 
Clinical Trials Involving Human Subjects 
https://laws-lois.justice.gc.ca/eng/regulations/C.R.C.,_c._870/page-134.html#h-
577812 
• Medical Devices Regulations SOR/98-282 
https://laws-lois.justice.gc.ca/eng/Regulations/SOR-98-282/index.html 
NETHERLANDS 
• Dutch Medical Research Involving Human Subjects Act (WMO) 
https://wetten.overheid.nl/BWBR0009408/2022-03-15 
• EU Clinical Trial Regulation (CTR) 
https://eur-lex.europa.eu/legal-
content/EN/TXT/HTML/?uri=CELEX%3A32014R0536&from=NL 
• EU Medical Device Regulation (MDR) 
https://eur-lex.europa.eu/legal-
content/EN/TXT/HTML/?uri=CELEX%3A32017R0745&from=NL 
2. Good Clinical Practice Guidelines 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Harmonised Guideline: Integrated Addendum to ICH E6(R1): 
Guideline for Good Clinical Practice E6(R2) 
https://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html 
 
 
 

SAP_001.pdf: 
 
BS-T1-001-05 
Confidential 
Page 1 of 24 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Protocol number: MSP-2017-5001 
 
 
 Multi-Centre, Placebo-Controlled, Phase 2 Study of Etripamil Nasal Spray (NS) for the 
Reduction of Ventricular Rate in Patients with Atrial Fibrillation (AF) 
 
 
The ReVeRA-201 Trial 
 
 
 
 
 
 
 
 
Date of Final Statistical Analysis Plan:  
09-NOV-2022 
Amendment 1 
06-DEC-2022 
Amendment 2 
27-JUL-2023 
 
 
Prepared by: 
Annik Fortier, M.Sc. 
Senior Biostatistician  
Montreal Health Innovations Coordinating Center (MHICC) 
5000 Bélanger Street 
Montréal, QC  H1T 1C8 
Phone: 514-461-1300 ext. 2143 / Fax: 514-461-1301 
 
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 2 of 24 
 
 
 
Signature Approval Page 
 
 
By signing below, I indicate that I have reviewed the Statistical Analysis Plan in its entirety and approve its 
contents. 
 
 
Signature: 
 
 
Date: 
 
 
Denis Roy, M.D., F.R.C.P., F.H.R.S.  
Principal Investigator  
Montreal Heart Institute 
 
 
(DD-MMM-YYYY) 
Signature 
 
 
Date: 
 
 
David Bharucha, M.D. 
Chief Medical Officer 
Milestone Pharmaceuticals Inc. 
 
 
(DD-MMM-YYYY) 
Signature: 
 
 
Date: 
 
 
Jeff Nelson   
Chief Operating Officer 
Milestone Pharmaceuticals Inc. 
 
 
(DD-MMM-YYYY) 
Signature: 
 
 
Date: 
 
 
Marie-Claude Guertin, Ph.D. 
Principal Biostatistician, Biometrics 
MHICC  
 
 
(DD-MMM-YYYY) 
 
 
 
 
 
Denis Roy (Jul 27, 2023 15:25 EDT)
Denis Roy
David Bharucha (Jul 27, 2023 16:45 EDT)
David Bharucha
Jeff Nelson (Jul 27, 2023 20:07 EDT)
Jeff Nelson
Marie-Claude Guertin (Jul 28, 2023 08:44 EDT)
Marie-Claude Guertin


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 3 of 24 
  
Revision History 
 
Version 
Date 
(DD-MMM-YYYY) 
Author 
Summary of Changes 
Final 
09-NOV-2022 
Annik Fortier 
Initial version 
Amendment 1 
06-DEC-2022 
Annik Fortier 
Section 3.2 
Correction of a typo in the definition of the 
efficacy population  
 
Section 7 
Removal of TLF 14.2.8.1 on time to 
cardioversion to sinus rhythm in the efficacy 
population (not applicable since subjects with 
cardioversion to sinus rhythm are excluded 
from the efficacy population) 
 
Section 7 
Minor corrections/clarifications to titles and 
numbering of TFL 
Amendment 2 
27-JUL-2023 
Annik Fortier 
Signature approval page 
Removal of Francis Plat as signatory 
 
List of abbreviations 
Addition of IA – Interim Analysis 
 
Section 4 
Clarification concerning HR values of 0 during 
Holter ECG monitoring 
 
Section 4.1 
Clarification to the moving average calculation 
 
Section 6.2.1 
Update to state that two interim analyses 
have been conducted 
 
Section 6.5.2.1 
Clarification to the definition of TEAE 
 
Section 7 
Minor corrections/clarifications to titles of TFL 
 
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 4 of 24 
 
TABLE OF CONTENTS  
 
1 
Introduction ......................................................................................................................................... 5 
2 
Study Description ................................................................................................................................. 5 
2.1 
Study Design ................................................................................................................................ 5 
2.2 
Study Objectives .......................................................................................................................... 6 
3 
Datasets Analyzed ................................................................................................................................ 6 
3.1 
Modified Intent-To-Treat (mITT) Population ............................................................................... 6 
3.2 
Efficacy Population ...................................................................................................................... 7 
3.3 
Safety Population ........................................................................................................................ 7 
4 
Efficacy Endpoints ................................................................................................................................ 7 
4.1 
Primary Efficacy Endpoint............................................................................................................ 7 
4.2 
Secondary Efficacy Endpoints ...................................................................................................... 8 
5 
Safety Parameters ................................................................................................................................ 9 
5.1 
Adverse Events ............................................................................................................................ 9 
5.2 
Serious Adverse Events................................................................................................................ 9 
5.3 
Adverse Events of Special Interest .............................................................................................. 9 
5.4 
Other Safety Parameters ........................................................................................................... 10 
6 
Statistical Methodology ..................................................................................................................... 11 
6.1 
Determination of Sample Size ................................................................................................... 11 
6.2 
Statistical Considerations .......................................................................................................... 11 
6.2.1 
Interim analysis ..................................................................................................................... 11 
6.3 
Study Subjects ........................................................................................................................... 12 
6.3.1 
Subject Disposition ................................................................................................................ 12 
6.3.2 
Protocol Deviations ............................................................................................................... 12 
6.3.3 
Datasets Analyzed ................................................................................................................. 13 
6.3.4 
Demographic and Baseline Characteristics ........................................................................... 13 
6.4 
Efficacy Analysis ......................................................................................................................... 13 
6.4.1 
Primary Analysis .................................................................................................................... 13 
6.4.2 
Secondary Analysis ................................................................................................................ 13 
6.4.3 
Sensitivity Analysis ................................................................................................................ 14 
6.5 
Safety Analysis ........................................................................................................................... 15 
6.5.1 
Prior and Concomitant Medications ..................................................................................... 15 
6.5.2 
Adverse Events and Serious Adverse Events ......................................................................... 15 
6.5.2.1 
Adverse Events ............................................................................................................. 15 
6.5.2.2 
Serious Adverse Events ................................................................................................ 15 
6.5.2.3 
Adverse Events of Special Interest ............................................................................... 15 
6.5.3 
Procedures ............................................................................................................................ 16 
6.5.4 
Other Safety Parameters ....................................................................................................... 16 
7 
Summary Tables, Figures and Listings ................................................................................................ 17 
8 
Appendix 1   Treatment Satisfaction Questionnaire for Medication (TSQM-9) ................................. 22 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 5 of 24 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AF 
Atrial Fibrillation 
ANCOVA 
Analysis of Covariance 
ASB 
Annotated Study Book 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
BPM 
Beat Per Minute 
CMS 
Cardiac Monitoring System 
DTS 
Data Transfer Specifications 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
HR 
Heart Rate 
IA 
Interim Analysis 
ICF 
Informed Consent Form 
INR 
International Normalized Ratio  
ITT 
Intent To Treat 
IWRS 
Interactive Web Randomization System 
MHICC 
Montreal Health Innovations Coordinating Center 
NS 
Nasal Spray 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
VKA 
Vitamin K Antagonists 
 
1 
INTRODUCTION 
 
This statistical analysis plan (SAP) presents the statistical methodology that will be used for the final 
analysis of Milestone Pharmaceuticals Inc. protocol MSP-2017-5001.  This plan also provides a 
description of the tables, figures and listings that will be included in the final statistical report. It is based 
on the protocol Version 6.0 dated 06JUL2022 and on the Annotated Study Book (ASB) version 2.0. In 
case of differences in terms of descriptions or explanations between the SAP and the clinical protocol, 
the SAP will supersede the protocol. Any deviation from this SAP would be reported in the statistical 
report. 
 
2 
STUDY DESCRIPTION 
 
2.1 
Study Design 
 
This is a multi-center, randomized, double-blind, placebo-controlled study to evaluate the effects of 
etripamil NS in patients with AF. This study includes Screening, the Treatment Period and Follow-up 
procedures. Each subject will receive Placebo or 70 mg etripamil NS; treatment will be randomized in a 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 6 of 24 
1:1 ratio, to yield approximately 50 evaluable patients with AF (i.e. qualified for Efficacy Population, see 
section 3.2 for definition) in 2 groups of approximately 25.  Screening and treatment procedures will be 
done at the same visit. Informed consent shall be obtained prior to any study procedures.  
 
Screening Procedures 
Patients with AF will be selected by the Investigator. The screening procedures will include a review of 
inclusion/exclusion criteria and recording of any concomitant medications. 
 
Treatment Procedures 
After screening procedures are complete, eligible patients will be randomized to receive etripamil NS or 
placebo. Heart rate (HR) will be measured via Holter electrocardiogram (ECG) 10 minutes prior to and 
immediately before drug administration; patients must exhibit a rapid ventricular rate (≥110 beat per 
minute (bpm) measured during 1 minute) prior to drug administration in order to be dosed.  
Blinded study drug will be administered during Holter ECG monitoring, which will be conducted for at least 
10 minutes prior to and for 6 hours after administration. Investigators will record adverse events and 
concomitant medications.  
Study drug will be administered by clinical site staff. Patient must be seated for drug administration and 
should not perform any physical activity within 1-hour post-dose. Patient can be discharged 1 hour after 
drug administration. 
 
Follow-up Procedures 
Patients will undergo a safety follow-up assessment and return the Holter device approximately 24 hours 
post-dose. The use of telemedicine is encouraged. Patients will also be contacted by phone 7 days post-
dosing for safety follow-up.  
 
Following completion of patient participation, the Holter ECG recordings will be blindly reviewed by the 
Medical Monitor (or designee) to determine whether patients met the criteria for inclusion in the Efficacy 
Population (see section 3.2 for definition). This information will be recorded in the Interactive Web 
Randomization System (IWRS), which will allow to determine when enrollment can be completed (i.e. 
when 50 evaluable patients are confirmed by the Medical Monitor). 
 
2.2 
Study Objectives 
 
The primary objective of this study is to demonstrate the superiority of etripamil NS over placebo in 
reducing ventricular rate in patients with AF.  
 
The secondary objective is to evaluate the safety and efficacy of etripamil NS in patients with AF.  
 
3 
DATASETS ANALYZED 
 
Subjects who were not eligible for randomization but who have been erroneously randomized into the 
study will be excluded from all datasets analyzed if they did not receive study product.  
 
3.1 
Modified Intent-To-Treat (mITT) Population 
 
The mITT population will consist of all randomized subjects who receive the study drug (electronic case 
report form (eCRF) Form “Randomization and Drug Administration” [Date and Time of Randomization = 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 7 of 24 
Not missing] and [Medication administered to the subject = Yes]) and who have a Holter recording post 
study drug administration (eCRF Form “Holter ECG Monitoring” [ECG data electronically transmitted = 
Yes]). In the mITT population, subjects allocated to a treatment group by randomization will be followed 
up, assessed and analyzed as members of that group irrespective of their compliance to the planned 
course of treatment. 
 
3.2 
Efficacy Population 
 
The efficacy population is all subjects included in the mITT population, excluding patients who were not 
in AF at time of dosing, who convert to sinus rhythm or with a significant lost ECG signal within 60 
minutes post study drug administration. The efficacy population qualification status will be taken from 
the IWRS database. In the Efficacy population, patients will be analyzed as per treatment assigned by 
randomization. 
 
3.3 
Safety Population 
 
The safety population refers to all randomized patients who receive the study drug (eCRF Form 
“Randomization and Drug Administration” [Date and Time of Randomization = Not missing] and 
[Medication administered to the subject = Yes]).  Subjects in the Safety population will be analyzed as 
per actual treatment received. 
 
4 
EFFICACY ENDPOINTS 
 
Efficacy variables will be obtained from the Holter recordings measured by a central core laboratory. The 
procedure and requirements for the delivery of CMS data (Holter ECG) from Global Instrumentation’s 
M12A application to the Montreal Health Innovations Coordinating Center (MHICC), following review by 
the Milestone Pharmaceuticals Medical Reviewer, are specified in the Data Transfer Specifications (DTS) 
version 1.0 dated 08JUN2022. In case of conversion to sinus rhythm, only heart rate measurements prior 
to sinus conversion will be used to derive efficacy variables.  If values of HR equal to 0 are recorded during 
Holter ECG monitoring, these values will be set to missing (unless the patient is dead) prior to variables 
derivation. 
 
4.1 
Primary Efficacy Endpoint 
 
The primary efficacy variable will be the maximum reduction in ventricular rate, measured on Holter 
monitoring, within 60 minutes from drug administration.  
 
o Baseline ventricular rate is defined as the average heart rate over five minutes immediately 
prior to drug administration.  
o Nadir is defined as the lowest moving average heart rate over five minutes recorded in the 
primary evaluation period, i.e., 60 minutes post drug administration. The moving averages are 5 
minutes’ averages of different subsets of the full data set and are calculated by using the 
"shifting forward" method; that is, excluding the first number of the series and including the 
next value in the subset.  As a general rule, HR measurements outside the primary evaluation 
period of 60 minutes will be used to calculate the moving averages of the last minutes of this 
observational period (for example, the 5-minute moving average calculated at minute 58 will 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 8 of 24 
use HR measurements at minutes 58, 59, 60, 61 and 62).  For patients with conversion to sinus 
rhythm, HR measurements starting from the time of conversion will be set to missing and 
moving average of the last minutes just before the conversion will be calculated on the available 
non missing values (for example, if sinus conversion occurs at minute 40, the 5-minute moving 
average at minute 36 will use HR measurements at minutes 36, 37, 38 and 39; the 5-minute 
moving average at minute 37 will use HR measurements at minutes 37, 38 and 39, etc.).  Moving 
averages calculated on 2, 3 and 10 minutes will be considered for sensitivity analyses on the 
primary efficacy endpoint (see section 6.4.3 for details) and will be calculated using the same 
rule.  Nadir defined as the lowest value recorded in the primary evaluation period will also be 
considered for sensitivity analyses on the primary efficacy endpoint. 
o Maximum reduction will be calculated as the change between baseline value and nadir.  
 
 
4.2 
Secondary Efficacy Endpoints 
 
The secondary efficacy variables will include: 
 
• 
Elapsed time from drug administration to nadir  
• 
Percentage of patients achieving ventricular rate of <100 bpm in the 60 minutes post drug 
administration.  
o Elapsed time from drug administration to ventricular rate < 100 bpm  
o Duration of ventricular rate < 100 bpm in the 60 minutes post drug administration.   
Duration will be set to zero in patients who will not achieve ventricular rate <100 bpm 
and will be calculated as the sum of the time periods during which the patient has a 
heart rate below the target ventricular rate.  
• 
Percentage of patients with 10% reduction from baseline ventricular rate in the 60 minutes post 
drug administration.  
o Elapsed time from drug administration to 10% reduction from baseline ventricular rate  
o Duration of 10% reduction from baseline ventricular rate in the 60 minutes post drug 
administration.  
Duration will be set to zero in patients who will not achieve 10% reduction and will be 
calculated as the sum of the time periods during which the patient has a heart rate 
below the target ventricular rate. 
• 
Percentage of patients with 20% reduction from baseline ventricular rate in the 60 minutes post 
drug administration.  
o Elapsed time from drug administration to 20% reduction in ventricular rate  
o Duration of 20% reduction from baseline ventricular rate in the 60 minutes post drug 
administration.  
Duration will be set to zero in patients who will not achieve 20% reduction and will be 
calculated as the sum of the time periods during which the patient has a heart rate 
below the target ventricular rate. 
• 
Percentage of patients cardioverting into sinus rhythm (for at least 30 seconds) in the 60 
minutes post drug administration  
o Elapsed time from drug administration to cardioversion into sinus rhythm  


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 9 of 24 
• 
Area under the curve (AUC) of heart rate over the 60 minutes and the 360 minutes post drug 
administration.  
• 
Patient satisfaction with treatment, as measured by the Treatment Satisfaction Questionnaire 
for Medication (TSQM-9) (see the appendices for the detailed questionnaire and the calculation 
of the domain scores).  
 
5 
SAFETY PARAMETERS 
 
Safety will be assessed through adverse events (AEs) and serious adverse events (SAEs) (eCRF Form 
“Adverse Events”), physical examination (eCRF Form “Physical Examination”), vital signs measurements 
(eCRF Form “Vital Signs”), concomitant medications, procedures (eCRF Form “Concomitant Medication” 
and “Procedures”) and ECG findings (eCRF Form “Cardiac Monitoring System Data Review”). 
 
5.1 
Adverse Events 
 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product that does not necessarily have a causal relationship with the 
product. An AE can therefore be any unfavorable and unintended sign (including a new, clinically 
significant abnormal laboratory finding), symptom, or disease, temporally associated with the product, 
whether or not related to the product.  
 
During Screening the Investigator or designee will assess all findings from physical exams, vital signs, 
laboratory assessments, and diagnostic ECGs. Clinically significant findings will be recorded as medical 
history. Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition.  Worsening of a pre-existing 
condition is considered an AE. 
 
Events that occur in patients during the Treatment Period while drug is not administered are also 
considered AEs. 
 
An AE is defined as treatment emergent if the first onset or worsening is within 24 hours after the 
administration of the study drug.  
 
5.2 
Serious Adverse Events 
 
A SAE is any untoward medical occurrence that at any dose: 
• 
Result in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly 
• 
Is an important medical event 
 
5.3 
Adverse Events of Special Interest 
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 10 of 24 
Due to the mechanism of action of etripamil, patients could be at a higher risk of certain adverse events 
of special interest (AESI). Investigators should be on the alert for these events, or for symptoms which 
indicate an event may be present. Investigators should follow the standard protocol process for AE and 
SAE reporting for these AESI. Below is a list of AEs which are of particular interest if they occur within 24 
hours of study drug administration.  
 
a) Tachyarrhythmias  
i) Supraventricular: occurrence of Atrial Tachycardia or Atrial Flutter lasting longer than 30 
seconds  
ii) Ventricular:  
- Non-sustained ventricular tachycardia defined as equal or greater than 3 consecutives 
wide beats originating in the ventricles at a rate >100 bpm and terminating spontaneously  
- Sustained ventricular tachycardia defined as wide consecutive beats originating in the 
ventricles at a rate >100 bpm during >30 sec or requiring termination due to 
hemodynamic compromise in < 30 sec 
b) Bradyarrhythmia  
i) Any Sinus rate equal or less than 40 bpm lasting longer than 30 seconds  
ii) Any pause equal or greater than 3 seconds  
c) Atrio-Ventricular Block  
i) New onset (not present in the ECG performed at the screening visit) of 1st° AV Block  
ii) Any occurrence of 2nd or 3rd degree AV Block (including AV dissociation or the presence of 
more than 2 consecutives non-conducted P waves)  
d) Syncope and related events  
i) Syncope defined as a transient, self-limited loss of consciousness with an inability to maintain 
postural tone that is followed by spontaneous recovery.  
ii) Pre-syncope defined as a state consisting of light-headedness, muscular weakness, blurred 
vision, and feeling faint  
iii) Loss of consciousness defined as a partial or complete loss of consciousness with interruption 
of awareness of oneself and one’s surroundings. When the loss of consciousness is temporary and 
there is spontaneous recovery, it is referred to as syncope.  
iv) Dizziness defined as a false sense of motion or spinning, light-headedness or feeling faint, 
unsteadiness or a loss of balance, a feeling of floating, wooziness or heavy headedness. The 
episode may last seconds or days and may recur.  
v) Drop attack defined as a sudden fall without loss of consciousness  
vi) Hypotension is defined as a SBP 
 
5.4 
Other Safety Parameters 
 
Screening vital signs include blood pressure (BP), heart rate, weight, and height. Blood pressure must be 
monitored and recorded at 10 minutes pre-dose and immediately prior to dosing, to ensure subject 
eligibility prior to dosing with Systolic BP > 90 mmHg, and must be recorded at 5, 10, 15, 30, and 60 
minutes post-dose. 
 
A complete physical examination (excluding breast, genitourinary and rectal examination) will be 
performed at screening on the following body systems: General Appearance, Eyes, ENT/Mouth, 
Respiratory, Cardiovascular, Gastrointestinal, Muscular, Skin, Neurological, Endocrine (including 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 11 of 24 
thyroid), Lymph Nodes, Allergy/Immunological, and Psychiatric.  A symptom-directed physical 
examination will be performed after drug administration. 
 
All concomitant medications and treatments used (including over-the-counter medications and herbal 
supplements) ongoing or started 30 days before the time of signing the ICF will be recorded in the source 
document and on the appropriate eCRF.  Procedures (other than the study-related assessments and 
procedures) performed from the time of signing the ICF until 7 days post-dose, or until the patient 
discontinues the study, will be recorded. 
 
Findings from electrocardiographic analysis include occurrence of tachyarrhythmias, atrioventricular 
blocks and bradyarrhythmias. 
 
6 
STATISTICAL METHODOLOGY 
 
6.1 
Determination of Sample Size 
 
The primary efficacy variable for this study is the maximal reduction of ventricular rate after study drug 
administration. Accounting for a two-sided test with a type I error rate of α=0.05, 25 patients per group 
will provide 93% power to detect a 20 bpm absolute difference in ventricular rate from baseline between 
active drug and placebo, assuming a standard deviation of 20 bpm. 
 
6.2 
Statistical Considerations 
 
Statistical analyses will be performed using SAS Version 9.4 or higher. Unless otherwise specified, all 
statistical tests will be two-sided and performed at a significance level of 0.05.  No adjustment for multiple 
testing will be done. 
 
Data summaries will be presented using descriptive statistics: N, mean, standard deviation, median, 
Q1, Q3, minimum and maximum are presented for continuous variables while count and proportion are 
presented for categorical variables. 
 
Prior to all parametric analyses, basic assumptions will be checked and if they are violated, non parametric 
analyses will be performed or a logarithmic transformation will be applied on the variables before 
proceeding to the planned parametric analyses. If outliers are identified, analysis with and without the 
outliers may be presented. 
 
No missing data will be imputed. 
 
6.2.1 
Interim analysis 
 
As requested by the sponsor, two interim analyses (IAs) of the data were done while the study is 
ongoing (on the first 15 and 36 subjects randomized and dosed). The rationale for performing these IAs 
has remained, as was stated in prior study documentation, to inform the planning of next studies and 
the program. These interim looks included the following analyses, conducted on all the subjects included 
in the snapshot of database at the time of interim and fulfilling the criteria of the efficacy population 
(unless otherwise specified): 
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 12 of 24 
1) Analysis of the primary endpoint, as described in in section 6.4.1 (See shell of Table 14.2.1.1 for 
layout of the output)  
 
2) Analysis of the following secondary endpoints, as described in section 6.4.2  
a. Elapsed time from drug administration to nadir (Table 14.2.2.1) 
b. Elapsed time from drug administration to ventricular rate < 100 bpm (Table 14.2.4.1) 
c. Duration of ventricular rate < 100 bpm (Table 14.2.5.1) 
 
3) Plots of the mean change from baseline in ventricular rate vs. time (in minutes, from baseline to 
60 minutes / 360 minutes) for each treatment group. Specifically, the change from baseline 
(baseline ventricular rate defined as the average heart rate over five minutes immediately prior 
to drug administration) was calculated for each minute post drug administration and the mean ± 
standard deviation (or ± standard error of the mean) at each minute post drug administration 
were plotted.  A listing of these values was also provided. These plots were generated with and 
without some subjects with outlier values. 
 
4) Number and proportion of subjects experiencing a treatment-emergent serious adverse events, 
as described in section 6.5.2.2 (Tables 14.3.1.4, 14.3.1.5 and 14.3.1.6; these tables were 
produced on subjects fulfilling the criteria of the safety population) 
 
The ReVeRa-201 trial is a double-blind study but the analyses for these interim looks required that the 
blind be broken. At the time of the interim, the study biostatistician received the randomization list from 
the IWRS provider, generated the above analyses based on the true randomization list, and sent the 
results to the sponsor, who shared them with selected principal investigators, at its discretion. These 
individuals are no longer blinded. The purpose of these interim looks is not to disseminate the results at 
large, but rather to help plan future studies. Importantly, the study is not to be stopped or altered based 
on the results of these interim looks. In other words, the final and definitive analysis will remain the one 
that will be conducted when all 50 evaluable subjects have been randomized and followed until study 
completion.  
 
6.3 
Study Subjects 
 
6.3.1 
Subject Disposition  
 
Number of subject screened, reason of screen failure, number of enrolled subjects (signing informed 
consent), number of subjects randomized and reasons why some enrolled subjects were not randomized 
will be provided.  Number of subjects who receive the medication, the route of administration or the 
reason if not administered will also be provided.  In addition, number of subjects completing the study 
and reasons for discontinuation will be summarized by treatment group. 
 
Information on subject disposition will be listed.  
 
6.3.2 
Protocol Deviations  
 
Protocol deviations collected on the eCRF Form “Protocol Deviation” will be listed.  
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 13 of 24 
6.3.3 
Datasets Analyzed 
 
The number of subjects in each dataset will be summarized overall and by treatment group. Reason for 
being excluded from a given dataset will be provided as well. 
 
6.3.4 
Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics (including atrial fibrillation history and confirmation of AF 
diagnosis, medical history, vital signs, use of vitamin K antagonists (VKA) and INR result, drug 
administration) will be compiled for all patients of the mITT population. 
 
Physical examination and details about Holter ECG monitoring (performed/transmitted/devices returned) 
will be listed.  
 
6.4 
Efficacy Analysis 
 
Unless it is specified otherwise, all efficacy analyses will be performed using the Efficacy population. 
 
6.4.1 
Primary Analysis 
 
The maximum reduction in ventricular rate will be compared between treatment groups using an analysis 
of covariance (ANCOVA) adjusting for value of ventricular rate at baseline.  Specifically, the null and 
alternative hypotheses to be tested are:   
 
H0: placebo = etripamil vs. 
HA: placebo ≠  etripamil 
 
where placebo is the maximum reduction in the placebo group and  etripamil is the maximum reduction in 
the etripamil group. Estimates of treatment effect will be presented with 95% CI and p-values.  
 
6.4.2 
Secondary Analysis 
 
The secondary efficacy analyses will be performed on the Efficacy Population, unless otherwise specified. 
 
Group comparison for the following secondary endpoints will be done using the same approach as the 
primary analysis. 
 
• 
Elapsed time from drug administration to nadir  
• 
Duration of ventricular rate < 100 bpm in the 60 minutes post drug administration.    
• 
Duration of 10% reduction from baseline ventricular rate in the 60 minutes post drug 
administration. 
• 
Duration of 20% reduction from baseline ventricular rate in the 60 minutes post drug 
administration. 
• 
Area under the curve (AUC) of heart rate over the 60 minutes.  AUC will be calculated using the 
trapezoidal rule over the specific Holter recording period for each patient and indexed to a 
period of 60 minutes.   


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 14 of 24 
• 
AUC of heart rate over 360 minutes post drug administration. AUC will be calculated using the 
trapezoidal rule over the specific Holter recording period for each patient and indexed to a 
period of 360 minutes.   
 
 
For the following four endpoints, group comparison will be done using a chi-square test or a Fisher exact 
test if more than 20% of cells have expected frequencies < 5.  
 
• 
Percentage of patients achieving ventricular rate of <100 bpm in the 60 minutes post drug 
administration.  
• 
Percentage of patients with 10% reduction from baseline ventricular rate in the 60 minutes post 
drug administration.  
• 
Percentage of patients with 20% reduction from baseline ventricular rate in the 60 minutes post 
drug administration. 
• 
Percentage of patients cardioverting into sinus rhythm (for at least 30 seconds) in the 60 
minutes post drug administration (mITT population only) 
 
Kaplan-Meier method and a Wilcoxon test for censored data will be used to compare the two groups for 
the following endpoints. 
 
• 
Elapsed time from drug administration to ventricular rate < 100 bpm  
• 
Elapsed time from drug administration to 10% reduction from baseline ventricular rate  
• 
Elapsed time from drug administration to 20% reduction from baseline ventricular rate  
• 
Elapsed time from drug administration to cardioversion into sinus rhythm (mITT population 
only) 
 
Mean heart rate over time will be plotted with 95% confidence interval error bars.  
 
Patient satisfaction with treatment, as measured by the Treatment Satisfaction Questionnaire for 
Medication (TSQM-9), domain scores (the scores of effectiveness, convenience, and global satisfaction 
domain, ranging from 0 to 100) and the TSQM-9 Question 2 (symptoms), will be analyzed using a t-test 
or a Mann-Whitney-Wilcoxon test, according to the distribution of the variable (see the appendices for 
the detailed questionnaire and the calculation of the domain scores).   
 
6.4.3 
Sensitivity Analysis 
 
To support the results of the primary endpoint, the primary analysis will also be performed on the mITT 
population using the same ANCOVA model described in section 6.4.1.  The secondary analyses described 
in section 6.4.2 will also be repeated on the mITT population. 
 
As additional sensitivity analyses, the maximum reduction in ventricular rate (primary endpoint) will be 
calculated with a nadir based on moving averages calculated on 2, 3 and 10 minutes respectively, and also 
based on the lowest value of the primary evaluation period. These maximum reductions will then be 
analyzed on the Efficacy population using the same ANCOVA model described in section 6.4.1. 
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 15 of 24 
6.5 
Safety Analysis 
 
The safety analyses described in this section will be conducted on the safety population.  No formal 
statistical testing is planned for the safety parameters. 
 
6.5.1 
Prior and Concomitant Medications 
 
Concomitant medications will be coded with respect to therapeutic class and preferred term using the 
WHO drug dictionary (March 2018).  Frequency of use of concomitant medications will be presented for 
the patients of the analysis population by both therapeutic class and preferred term.   
 
Listing of concomitant medications will also be provided. 
 
6.5.2 
Adverse Events and Serious Adverse Events 
 
6.5.2.1 
Adverse Events 
 
AEs will be coded by system organ class (SOC) and preferred term according to the MedDRA dictionary 
(version 23.1).   
 
A treatment-emergent AE (TEAE) will be defined as an AE with onset date within 24 hours after study drug 
administration.  In case of a missing AE onset time, the AE will be considered treatment emergent if 
onset date is equal to study drug administration date. 
 
Number and proportion of subjects experiencing a TEAE will be presented by SOC and preferred term and, 
in addition, by severity [Mild, Moderate, Severe] and relationship to study medication [Not Related, 
Related].  For subjects experiencing repeated episodes, only the most severe episode and the episode 
with the strongest relationship will be reported. 
 
In addition, number and proportion of patients with at least one TEAE, one TEAE related (definitely, 
probably or possibly) to study drug and one severe AE will be presented. 
 
A listing of all AEs will be provided.   
 
6.5.2.2 
Serious Adverse Events 
 
All SAEs will be listed but only treatment-emergent SAEs will be summarized as it will be done for AEs and 
TEAEs.   
 
6.5.2.3 
Adverse Events of Special Interest 
 
A listing of all AESIs will be provided.   
 
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 16 of 24 
6.5.3 
Procedures 
 
Procedures will be coded by system organ class (SOC) and preferred term according to the MedDRA 
dictionary (version 23.1).   
 
A listing of all procedures will be provided.   
 
6.5.4 
Other Safety Parameters 
 
Vital signs [BP and HR] at each timepoint (10 minutes pre-dose and immediately prior to dosing for BP and 
HR; 5, 10, 15, 30, and 60 minutes post-dose for BP only) will be summarized by treatment arm. 
 
As mentioned in section 6.3.4, physical examination results (at baseline and symptom directed after drug 
administration) will be listed. 
 
Occurrence of tachyarrhythmias, atrioventricular blocks and bradyarrhythmias (findings from 
electrocardiographic analysis) will be summarized by treatment arm. 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 17 of 24 
7 
SUMMARY TABLES, FIGURES AND LISTINGS 
 
14.1 Demographic Data 
Table 14.1.1 
Subject disposition and summary of drug administration 
Figure 14.1.1 
Subject Disposition (flow chart) 
Table 14.1.2 
Datasets analyzed 
Table 14.1.3 
Summary of demographics, mITT population 
Table 14.1.4 
Summary of AF history and confirmation of AF diagnosis (as reported by the 
site), mITT population 
Table 14.1.5 
Summary of vital signs at baseline, mITT population 
Table 14.1.6 
Summary of medical history by preferred term, system organ class and 
medical condition, mITT population 
 
14.2 Efficacy analysis 
 
Table 14.2.1.1 
Summary of and statistical analysis for maximum reduction in ventricular 
rate, Efficacy population 
Table 14.2.1.2 
Summary of and statistical analysis for maximum reduction in ventricular 
rate, Sensitivity analysis on the mITT population 
Table 14.2.1.3 
Summary of and statistical analysis for maximum reduction in ventricular 
rate (nadir as lowest HR), Efficacy population 
Table 14.2.1.4 
Summary of and statistical analysis for maximum reduction in ventricular 
rate (nadir as lowest moving average calculated on 2 minutes), Efficacy 
population 
Table 14.2.1.5 
Summary of and statistical analysis for maximum reduction in ventricular 
rate (nadir as lowest moving average calculated on 3 minutes), Efficacy 
population 
Table 14.2.1.6 
Summary of and statistical analysis for maximum reduction in ventricular 
rate (nadir as lowest moving average calculated on 10 minutes), Efficacy 
population 
 
Table 14.2.2.1 
Summary of and statistical analysis for elapsed time from drug 
administration to nadir, Efficacy population 
Table 14.2.2.2 
Summary of and statistical analysis for elapsed time from drug 
administration to nadir, mITT population 
Table 14.2.3.1 
Summary of and statistical analysis for percentage of patients achieving 
ventricular rate of <100 bpm in the 60 minutes post drug administration, 
Efficacy population 
Table 14.2.3.2 
Summary of and statistical analysis for percentage of patients achieving 
ventricular rate of <100 bpm in the 60 minutes post drug administration, 
mITT population 
Table 14.2.4.1 
Summary of and statistical analysis for elapsed time from drug 
administration to ventricular rate < 100 bpm, Efficacy population 
Figure 14.2.4.1 
Kaplan-Meier curves of time from drug administration to ventricular rate < 
100 bpm, Efficacy population 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 18 of 24 
Listing 14.2.4.1 
Kaplan-Meier estimates of time from drug administration to ventricular 
rate < 100 bpm, Efficacy population 
Table 14.2.4.2 
Summary of and statistical analysis for elapsed time from drug 
administration to ventricular rate < 100 bpm, mITT population 
Figure 14.2.4.2 
Kaplan-Meier curves of time from drug administration to ventricular rate < 
100 bpm, mITT population 
Listing 14.2.4.2 
Kaplan-Meier estimates of time from drug administration to ventricular 
rate < 100 bpm, mITT population 
Table 14.2.5.1 
Summary of and statistical analysis for duration of ventricular rate < 100 
bpm in the 60 minutes post drug administration, Efficacy population 
Table 14.2.5.2 
Summary of and statistical analysis for duration of ventricular rate < 100 
bpm in the 60 minutes post drug administration, mITT population 
Table 14.2.6.1 
Summary of and statistical analysis for percentage of patients with 10% 
reduction from baseline ventricular rate in the 60 minutes post drug 
administration, Efficacy population 
Table 14.2.6.2 
Summary of and statistical analysis for percentage of patients with 10% 
reduction from baseline ventricular rate in the 60 minutes post drug 
administration, mITT population 
Table 14.2.7.1 
Summary of and statistical analysis for elapsed time from drug 
administration to 10% reduction from baseline ventricular rate, Efficacy 
population 
Figure 14.2.7.1 
Kaplan-Meier curves of time from drug administration to 10% reduction 
from baseline ventricular rate, Efficacy population 
Listing 14.2.7.1 
Kaplan-Meier estimates of time from drug administration to 10% 
reduction from baseline ventricular rate, Efficacy population 
Table 14.2.7.2 
Summary of and statistical analysis for elapsed time from drug 
administration to 10% reduction from baseline ventricular rate, mITT 
population 
Figure 14.2.7.2 
Kaplan-Meier curves of time from drug administration to 10% reduction 
from baseline ventricular rate, mITT population 
Listing 14.2.7.2 
Kaplan-Meier estimates of time from drug administration to 10% 
reduction from baseline ventricular rate, mITT population 
Table 14.2.8.1 
Summary of and statistical analysis for duration of 10% reduction from 
baseline ventricular rate in the 60 minutes post drug administration, 
Efficacy population 
Table 14.2.8.2 
Summary of and statistical analysis for duration of 10% reduction from 
baseline ventricular rate in the 60 minutes post drug administration, mITT 
population 
Table 14.2.9.1 
Summary of and statistical analysis for percentage of patients with 20% 
reduction from baseline ventricular rate in the 60 minutes post drug 
administration, Efficacy population 
Table 14.2.9.2 
Summary of and statistical analysis for percentage of patients with 20% 
reduction from baseline ventricular rate in the 60 minutes post drug 
administration, mITT population 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 19 of 24 
Table 14.2.10.1 
Summary of and statistical analysis for elapsed time from drug 
administration to 20% reduction from baseline ventricular rate, Efficacy 
population 
Figure 14.2.10.1 
Kaplan-Meier curves of time from drug administration to 20% reduction 
from baseline ventricular rate, Efficacy population 
Listing 14.2.10.1 
Kaplan-Meier estimates of time from drug administration to 20% 
reduction from baseline ventricular rate, Efficacy population 
Table 14.2.10.2 
Summary of and statistical analysis for elapsed time from drug 
administration to 20% reduction from baseline ventricular rate, mITT 
population 
Figure 14.2.10.2 
Kaplan-Meier curves of time from drug administration to 20% reduction 
from baseline ventricular rate, mITT population 
Listing 14.2.10.2 
Kaplan-Meier estimates of time from drug administration to 20% 
reduction from baseline ventricular rate, mITT population 
Table 14.2.11.1 
Summary of and statistical analysis for duration of 20% reduction from 
baseline ventricular rate in the 60 minutes post drug administration, 
Efficacy population 
Table 14.2.11.2 
Summary of and statistical analysis for duration of 20% reduction from 
baseline ventricular rate in the 60 minutes post drug administration, mITT 
population 
Table 14.2.12 
Summary of and statistical analysis for percentage of patients cardioverting 
into sinus rhythm (for at least 30 seconds) in the 60 minutes post drug 
administration, mITT population 
Table 14.2.13.1 
Summary of and statistical analysis for area under the curve (AUC) of 
heart rate over the 60 minutes, Efficacy population 
Table 14.2.13.2 
Summary of and statistical analysis for area under the curve (AUC) of 
heart rate over the 60 minutes, mITT population 
Table 14.2.14.1 
Summary of and statistical analysis for patient satisfaction with treatment, 
as measured by the TSQM-9 domain scores - Effectiveness, Efficacy 
population 
Table 14.2.14.2 
Summary of and statistical analysis for patient satisfaction with treatment, 
as measured by the TSQM-9 domain scores - Effectiveness, mITT population 
Table 14.2.15.1 
Summary of and statistical analysis for patient satisfaction with treatment, 
as measured by the TSQM-9 domain scores - Convenience, Efficacy 
population 
Table 14.2.15.2 
Summary of and statistical analysis for patient satisfaction with treatment, 
as measured by the TSQM-9 domain scores - Convenience, mITT population 
Table 14.2.16.1 
Summary of and statistical analysis for patient satisfaction with treatment, 
as measured by the TSQM-9 domain scores - Global Satisfaction, Efficacy 
population 
Table 14.2.16.2 
Summary of and statistical analysis for patient satisfaction with treatment, 
as measured by the TSQM-9 domain scores - Global Satisfaction, mITT 
population 
Table 14.2.17.1 
Summary of and statistical analysis for patient satisfaction with treatment, 
as measured by the TSQM-9 Question 2 (symptoms), Efficacy population 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 20 of 24 
Table 14.2.17.2 
Summary of and statistical analysis for patient satisfaction with treatment, 
as measured by the TSQM-9 Question 2 (symptoms), mITT population 
Table 14.2.18 
Summary of and statistical analysis for elapsed time from drug 
administration to cardioversion into sinus rhythm, mITT population 
Figure 14.2.18 
Kaplan-Meier curves of time from drug administration to cardioversion 
into sinus rhythm, mITT population 
Listing 14.2.18 
Kaplan-Meier estimates of time from drug administration to cardioversion 
into sinus rhythm, mITT population 
Table 14.2.19.1 
Summary of and statistical analysis for area under the curve (AUC) of 
heart rate over the 360 minutes, Efficacy population 
Table 14.2.19.2 
Summary of and statistical analysis for area under the curve (AUC) of heart 
rate over the 360 minutes, mITT population 
Figure 14.2.20.1 
Mean heart rate over time, Efficacy population 
Figure 14.2.20.2 
Mean heart rate over time, mITT population 
Listing 14.2.21 
Maximum reduction in ventricular rate value and TSQM-9 scores and 
Question 2 (symptoms) 
 
14.3 Safety Data 
Table 14.3.1.1 
Overall summary of treatment-emergent adverse events (TEAE), safety 
population 
Table 14.3.1.2 
Summary of treatment-emergent adverse events (TEAE) by preferred term, 
system organ class and severity, safety population 
Table 14.3.1.3 
Summary of treatment-emergent adverse events (TEAE) by preferred term, 
system organ class and relationship to study drug, safety population 
Table 14.3.1.4 
Overall summary of treatment-emergent serious adverse events (TESAE), 
safety population 
Table 14.3.1.5 
Summary of treatment-emergent serious adverse events (TESAE) by preferred 
term, system organ class and severity, safety population 
Table 14.3.1.6 
Summary of treatment-emergent serious adverse events (TESAE) by preferred 
term, system organ class and relationship to study drug, safety population 
Listing 14.3.2 
Serious adverse events and deaths 
Table 14.3.5.1 
Summary of vital signs, safety population 
Table 14.3.5.2 
Summary of ECG findings from cardiac monitoring system (Holter), safety 
population 
Listing 14.3.5.2 
ECG monitoring 
Listing 14.3.5.3 
Physical Examination 
Listing 14.3.5.4 
Procedures 
Table 14.3.5.5 
Summary of concomitant medications, safety population 
Listing 14.3.5.5 
Concomitant medications 
 
Listings 
Listing 16.1.7 
Randomization codes 
Listing 16.2.1 
Subject disposition and discontinuation from the study 
Listing 16.2.2 
Protocol deviations 
Listing 16.2.3 
Datasets analyzed and reasons for exclusion 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 21 of 24 
Listing 16.2.4 
Demographics 
Listing 16.2.5 
Drug administration  
Listing 16.2.6.1 
Efficacy data – Part I 
Listing 16.2.6.2 
Efficacy data – Part II 
Listing 16.2.7.1 
Adverse events 
Listing 16.2.7.2 
Adverse events of special interest 
 
 
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 22 of 24 
 
8 
APPENDIX 1   TREATMENT SATISFACTION QUESTIONNAIRE FOR MEDICATION (TSQM-9) 
The TSQM-9 is a validated and widely-used patient reported outcome (PRO) assessment instrument 
designed as a general measure of treatment satisfaction with medication across medication types and 
patients’ conditions. The TSQM-9 was chosen for use in ReVeRA-201 as it was considered to be 
appropriate for evaluating patient assessments associated with the acute, episodic use of a drug such as 
etripamil for the treatment of PSVT episodes, in contrast to other PROs such as the Short Form 36, 
which is used as a measure of health-related quality of life and is commonly associated with chronic use 
medications. Two minor modifications to the TSQM-9 (with approval by IQVIA, the owner of the 
questionnaire) were implemented by Milestone for use in ReVeRA-201. The term “prevent” was 
removed from the initial question in the questionnaire, as etripamil is not a preventative therapy, and 
the instructions were modified to reflect the single use of the medication.  
Treatment satisfaction will be analyzed by comparing the score of TSQM for effectiveness, convenience, 
and global satisfaction domain in the 2 treatment groups.  
TSQM scale scores range from 0 to 100 and no computed score should be lower or higher than these 
limits. Of note, a score can be computed for a domain only if no more than one item is missing from that 
domain. The calculations specific to each domain are presented in detail below: 
 
Effectiveness:  
([(Question 1 + Question 2 + Question 3) − 3] divided by 18) × 100 
If one item is missing: ([(Sum(the two completed items) – 2] divided by 12) * 100 
 
Convenience:  
([(Question 4 + Question 5 + Question 6) − 3] divided by 18) × 100 
If one item is missing: ([(Sum(the two completed items) – 2] divided by 12) * 100 
 
Global satisfaction:  
([(Question 7 + Question 8 + Question 9) − 3] divided by 14) × 100 
If either Item 7 or 8 is missing ([(Sum(the two completed items)) – 2] divided by 10) * 100 
If Item 9 is missing ([(Sum(Item7 and Item8)) – 2] divided by 8) * 100 
 
 
 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 23 of 24 
Treatment Satisfaction Questionnaire for Medication 
 
1. How satisfied or dissatisfied are you with the ability of the medication to treat your condition? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
2. How satisfied or dissatisfied are you with the way the medication relieves your symptoms? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
3. How satisfied or dissatisfied are you with the amount of time it take the medication to start 
working? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
4. How easy or difficult is it to use the medication in its current form? 
1. Extremely Difficult 
2. Very Difficult 
3. Difficult 
4. Somewhat Easy 
5. Easy 
6. Very Easy 
7. Extremely Easy 
5. How easy or difficult is it to plan when you will use the medication each time? 
1. Extremely Difficult 
2. Very Difficult 
3. Difficult 
4. Somewhat Easy 
5. Easy 
6. Very Easy 
7. Extremely Easy 
6. How convenient or inconvenient is it to take the medication as instructed? 
1. Extremely Inconvenient 
2. Very Inconvenient 


 
SAP: 27-JUL-2023 / Amendment 2 
Protocol Number: MSP-2017-5001 
 
BS-T1-001-05 
Confidential 
Page 24 of 24 
3. Inconvenient 
4. Somewhat Convenient 
5. Convenient 
6. Very Convenient 
7. Extremely Convenient 
7. Overall, how confident are you that taking this medication is a good thing for you? 
1. Not at All Confident 
2. A Little Confident 
3. Somewhat Confident 
4. Very Confident 
5. Extremely Confident 
8. How certain are you that the good things about your medication outweigh the bad things? 
1. Not at All Certain 
2. A Little Certain 
3. Somewhat Certain 
4. Very Certain 
5. Extremely Certain 
9. Taking all things into account, how satisfied or dissatisfied are you with this medication? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied