Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia. NODE 301 and RAPID Studies
Phase: PHASE3
Conditions: Paroxysmal Supraventricular Tachycardia
Sponsor: Milestone Pharmaceuticals Inc.

CLINICAL STUDY PROTOCOL 
 
Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, 
Efficacy, and Safety Study of Etripamil Nasal Spray for the 
Termination of Spontaneous Episodes of Paroxysmal 
Supraventricular Tachycardia 
 
The NODE-301 Trial 
 
Investigational Product: Etripamil (MSP-2017) 
Protocol Number: MSP-2017-1138 
 
 
 
Sponsor: 
Milestone Pharmaceuticals Inc. 
1111 Dr. Frederik-Philips Blvd., Suite 420 
Saint-Laurent, QC H4M 2X6, Canada 
Telephone: +1-514-336-0444 
 
Version Number: 5.0 
Original Protocol: 08 November 2017 
Amendment 1: 05 January 2018 
Amendment 2: 20 February 2018 
Amendment 3: 04 October 2018 
Amendment 4: 09 July 2019 
 
 
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 

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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. 

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PROCEDURES IN CASE OF EMERGENCY OR SERIOUS ADVERSE 
EVENT REPORTING 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Study Leader 
Douglas Wight 
dwight@milestonepharma.com/+1-514-336-0444, ext. 226 
Responsible Physician 
Francis Plat 
fplat@milestonepharma.com/+1-514-336-0444, ext. 225 
Medical Monitor 
Silvia Shardonofsky 
sshardonofsky@milestonepharma.com/+1-514-336-0444, 
ext. 235 
Serious Adverse Event Reporting 
Any serious adverse event (SAE) (as defined in Section 8.2) occurring from the time of study drug 
administration at the Test Dose Randomization Visit through the Final Study Visit must be 
reported to Medpace Clinical Safety within 24 hours of awareness of the event. Any SAE 
occurring within a 30-day follow-up period after taking the study drug that the Investigator 
considers related to study drug administration must be reported in the same manner. 
To report an SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Clinical Safety personnel will be 
notified electronically and will retrieve the form. 
To report an SAE if the EDC system is not available: 
• Send an e-mail to Medpace Clinical Safety at medpace-safetynotification@medpace.com or 
call the Medpace SAE Reporting Line (number listed below); 
• Fax/e-mail a completed SAE form to Medpace Clinical Safety (number and e-mail address 
listed below); and 
• When the EDC system becomes available, the SAE information must be entered within 
24 hours of the system becoming available. 
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 via e-mail or fax. 
Medpace Clinical Safety Contact Information 
Medpace Clinical Safety 
SAE Reporting Line (USA/Canada): +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax (USA/Canada): +1-866-336-5320 or +1-513-570-5196 
E-mail: medpace-safetynotification@medpace.com 
 
Medical Monitor 
Silvia Shardonofsky, MD 
Telephone: +1-514-336-0444, ext. 235 
E-mail: sshardonofsky@milestonepharma.com 

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SIGNATURE PAGE 
STUDY TITLE: Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, 
and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of 
Paroxysmal Supraventricular Tachycardia. The NODE-301 Trial 
 
We, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 
Francis Plat, MD 
Chief Medical Officer 
Milestone Pharmaceuticals Inc. 
 
Douglas Wight, MSc 
Vice President, Drug Development 
Milestone Pharmaceuticals Inc. 
 
Guy Rousseau, PhD 
Vice President, Regulatory Affairs 
Milestone Pharmaceuticals Inc. 

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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 Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
 

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SYNOPSIS 
TITLE:  Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety 
Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal 
Supraventricular Tachycardia. The NODE-301 Trial 
SHORT TITLE:  Efficacy and Safety of Etripamil for the Termination of Spontaneous PSVT. 
NODE-301 
PROTOCOL NUMBER:  MSP-2017-1138 
INVESTIGATIONAL PRODUCT:  Etripamil (MSP-2017) 
PHASE:  3 
INDICATION:  Paroxysmal supraventricular tachycardia (PSVT) 
OBJECTIVES: 
The primary objective of this study is to determine whether etripamil nasal spray (NS) 70 mg
self-administered by patients is superior to placebo at terminating episodes of PSVT in an 
outpatient setting. 
The secondary objective of this study is to evaluate the safety of etripamil NS 70 mg when 
self-administered by patients without medical supervision. 
The exploratory objectives of the study are: 
• To evaluate the safety, hemodynamic, and cardiac conduction effects of a test dose of 
etripamil NS 70 mg, and  
• To evaluate the safety and efficacy of etripamil NS 70 mg in various subgroups of interest 
(e.g., concomitant medications). 
POPULATION: 
The population for this study is patients at least 18 years of age who have electrographically 
documented history of PSVT with a history of sustained episodes (i.e., typically lasting 
approximately 20 minutes or longer). 
Inclusion criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Male or female patients at least 18 years of age; 
2. Electrographically documented history of PSVT (e.g., electrocardiogram [ECG] obtained 
during an episode of PSVT, Holter monitoring, loop recorder, etc.). If patient had a prior 
ablation for PSVT, patient must have documented ECG evidence of PSVT post-ablation; 

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3. History of sustained episodes of PSVT (i.e., typically lasting approximately 20 minutes or 
longer); 
4. Females of childbearing potential who are sexually active must agree to use an approved 
highly effective form of contraception from the time of signed informed consent until 30 days 
after the last administration of study drug. Females of childbearing potential should have a 
negative serum pregnancy test result at the Screening Visit and at the Final Study Visit, a 
negative urine pregnancy test at the Test Dose Randomization Visit and must use an approved 
form of contraception between the visits. Approved forms of contraception include hormonal 
intrauterine devices or hormonal contraceptives (oral birth control pills, Depo-Provera®, 
patch, or other injectables) together with supplementary double-barrier methods, such as 
condoms or diaphragms with spermicidal gel or foam; 
The following categories define females who are NOT considered to be of childbearing potential:
• Premenopausal females with 1 of the following: 
 Documented hysterectomy; 
 Documented bilateral salpingectomy; or 
 Documented bilateral oophorectomy; or 
• Postmenopausal females, defined as having amenorrhea for at least 12 months without an 
alternative medical cause; 
5. Male patients, except those who are surgically sterile, must use an approved highly effective 
form of contraception during the 3 days after any study drug administration; and 
6. Signed written informed consent. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from participation in the study:
1. Systolic blood pressure (SBP) <90 mmHg after a 5-minute rest in sitting position at the
Screening Visit or before the test dose. In patients treated with a chronic prophylactic drug 
for PSVT (e.g., beta-blockers, verapamil, and diltiazem), the drug may be stopped for at least 
the equivalent of 5 half-lives and patients may be rescreened once; 
2. History of severe symptoms of hypotension, especially syncope, during episodes of PSVT; 
3. History of atrial arrhythmia that does not involve the atrioventricular (AV) node as part of the 
tachycardia circuit (e.g., atrial fibrillation, atrial flutter, intra-atrial tachycardia); 
4. History of allergic reaction to verapamil; 
5. Current therapy with digoxin or any Class I or III antiarrhythmic drug, except if these drugs 
are stopped at least the equivalent of 5 half-lives before the Test Dose Randomization Visit;
6. Current therapy with amiodarone, or have taken amiodarone within 30 days prior to the Test 
Dose Randomization Visit; 
7. Evidence of ventricular pre-excitation (e.g., delta waves, short PR interval <100 msec,
Wolff-Parkinson-White syndrome) on the ECG performed at the Screening Visit or before 
the test dose administration; 

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8. Evidence of a second- or third-degree AV block on the ECG performed at the Screening Visit
or before the test dose administration; 
9. History or evidence of severe ventricular arrhythmia (e.g., torsades de pointes, ventricular 
fibrillation, or sustained ventricular tachycardia); 
10. Current congestive heart failure defined by the New York Heart Association Class II to IV; 
11. Stroke in the last 6 months; 
12. Evidence of hepatic dysfunction defined as alanine aminotransferase or aspartate 
aminotransferase >3 × the upper limit of normal (ULN) or total bilirubin >2 × ULN at the 
Screening Visit, unless due to Gilbert syndrome; 
13. Evidence of renal dysfunction as determined by an estimated glomerular filtration rate 
assessed at the Screening Visit as follows: 
 <60 mL/min/1.73 m2 for patients <60 years of age; 
 <40 mL/min/1.73 m2 for patients ≥60 and <70 years of age; or 
 <35 mL/min/1.73 m2 for patients ≥70 years of age; 
14. Females who are pregnant or lactating; 
15. Evidence or history of any significant physical or psychiatric condition including drug abuse,
which, in the opinion of the Investigator, could jeopardize the safety of patients or affect their 
participation in the study. Additionally, the Investigator has the ability to exclude a patient if 
for any reason the Investigator judges the patient is not a good candidate for the study or will 
not be able to follow study procedures; or 
16. Participation in any investigational drug or device study or the use of any investigational drug 
or device within 30 days of the Screening Visit. 
Before randomization, all patients will receive a test dose of etripamil NS 70 mg to evaluate 
tolerability and to train patients on the study procedures. A failure of the test dose is considered 
if patients meet any of the following criteria occurring after administration of the etripamil NS 
70 mg test dose: 
1. Any symptoms consistent with clinically severe hypotension such as pre-syncope, medically 
significant lightheadedness, syncope, nausea, or vomiting; 
2. For patients with a pre-test dose SBP above 100 mmHg: 
 Decrease in SBP ≥40 mmHg after test dose; or 
 Post-test dose SBP <80 mmHg; 
3. For patients with a pre-test dose SBP between 90 mmHg and 100 mmHg (inclusive): 
 Post-test dose SBP <75 mmHg; 
4. Third-degree AV block, Mobitz II second-degree AV block, or Wenckebach with bradycardia 
≤40 bpm; 

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5. New, significant sinus bradycardia heart rate (HR) ≤40 bpm or sinus pauses (≥3 seconds), if 
considered by the Investigator to put the patient’s safety at risk if either were to occur while 
not under medical supervision; 
6. Any new significant ventricular arrhythmia (premature ventricular beats and couplets
[>6 premature ventricular contractions per 45 seconds ECG] are considered significant); or 
7. Atrial fibrillation or atrial flutter (event lasting longer than 30 seconds). 
Patients who fail the test dose will proceed in the study as follows: 
• If the Investigator identifies a possible reversible cause of the initial test dose failure 
(e.g., concomitant medication such as beta-blocker), a re-challenge with a new test dose of 
etripamil NS 70 mg within a 14-day window from the initial test dose will be possible after 
elimination of the reversible cause (e.g., withdrawal of concomitant therapy with the 
appropriate washout period). Patients may be randomized if they pass the second test dose,
and the cause of the test dose failure is eliminated for the duration of the study; or 
• If the Investigator cannot identify a reversible cause of the initial test dose failure, or if the 
potential cause cannot be modified (e.g., necessary antihypertensive drug to control blood 
pressure), patients will not be randomized and will complete a Final Study Visit. Patients who 
fail the test dose will be part of the Test Dose Only Population, including all patients who 
received at least 1 test dose of etripamil NS 70 mg. 
During each patient’s Test Dose Randomization Visit, the test dose Cardiac Monitoring 
System (CMS) ECG data will be reviewed by the cardiac monitoring core laboratory, and a report 
will be sent to the site. The operational aspects are described in the manual of operations and 
procedures (MoOP).  
STUDY DESIGN AND DURATION: 
NODE-301 is a multi-centre, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of etripamil NS 70 mg self-administered by patients who experience an 
episode of PSVT in an outpatient setting. Each episode will be documented by an ambulatory 
CMS that will be placed on the chest by the patient or caregiver when symptoms begin and will
record at least 5 hours of continuous ECG. Each CMS will be identified by a unique number. 
The study will comprise of 2 parts, Part 1 and Part 2.  
Part 1 will consist of patients that will be dosed with the double-blind study drug or have 
discontinued the study before the adjudication of the 150th positively adjudicated PSVT episode. 
The data from patients in Part 1 will be cleaned and locked, on a per-patient basis, and will be 
included in pivotal analyses. Pivotal analyses will include safety; and primary, secondary, and 
exploratory efficacy analyses for Part 1 only. Patients in Part 1 will be unblinded after data is 
locked.  
Part 2 will consist of patients that will not be included in Part 1, i.e., Part 2 will consist of patients 
who were not dosed with the double-blind study drug or have not discontinued the study before 
the adjudication of the 150th positively adjudicated PSVT episode. The data from patients in 
Part 2 will be combined with that from Part 1 and will be included in exploratory analyses. 
Exploratory analyses will include safety; and primary, secondary, and exploratory efficacy 

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analyses for Parts 1 and 2 combined. Patients in Part 2 will be unblinded at the end of the study. 
Part 2 will end when one of the following criteria is met: 
• 75% of patients in Part 2 have completed the study (Final Study Visit), or 
• Approximately 9 months after the date of the adjudication of the 150th positively adjudicated 
PSVT episode.  
Based on the results of the pivotal analyses from Part 1, the planned statistical analysis and 
conduct of Part 2 may be amended. However, in no case will the Part 2 dataset be integrated with 
the Part 1 pivotal dataset for primary efficacy or primary safety analyses.  
The study will include a Screening Visit, a Test Dose Randomization Visit, Follow-up Visits, a 
Treatment Period, and a Final Study Visit. 
Screening Visit 
Prospective study patients will be asked to sign the informed consent form before the 
commencement of any study-related assessments or procedures. Once the informed consent is 
signed, patients will be considered enrolled in the study. 
Test Dose Randomization Visit 
The initial Test Dose Randomization Visit must occur within 28 days after the Screening Visit. 
Before randomization, all patients will receive a test dose of etripamil NS 70 mg to evaluate 
tolerability and to train patients on the study procedures. 
Follow-up Visits 
Follow-up Visits will occur approximately monthly from the time of randomization and can be 
conducted by patients returning to the investigative site (preferred) or by the site personnel 
contacting patients by telephone. 
Treatment Period 
All randomized patients will perform a sequence of steps, including study drug
self-administration when patients identify symptoms of an episode of PSVT. A caregiver may 
help the patient with these procedures, and this should be annotated in the electronic case report 
form. 
Final Study Visit 
A Final Study Visit will occur at the study site within 7 days after the final Treatment Period day 
with usage of the study drug, or if for any other reason the patient has completed participation in 
the study. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Investigational Product and Dosage: The formulation of etripamil 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 the NODE-301 study is 70 mg. The 
same formulation will be used for the Test Dose Randomization Visit and for the Treatment 
Period. 
 

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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.  
Mode of Administration: All 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 into child-resistant boxes. Instructions for its use are 
provided in the MoOP and will be provided in the study drug box. 
DURATION OF TREATMENT: 
This is an event-driven study; approximately 150 randomized patients presenting with a 
positively adjudicated episode of PSVT and treated with the study drug are required to control 
the type I error rate at the desired alpha = 0.01 and to get an adequate power. Since the time from 
enrollment to when patients experience their first positively adjudicated episode of PSVT treated 
with study drug is unknown, the study is projected to randomize up to 500 patients. The final 
number of randomized patients and of adjudicated episodes of PSVT will depend on the 
frequency and timing of episodes of PSVT during the study. Enrollment into the study will stop 
on the date of the adjudication of the 150th positively adjudicated PSVT episode. 
EFFICACY VARIABLES:  
The primary efficacy endpoint is defined as an adjudicated termination of a positively adjudicated 
episode of PSVT (AV nodal reentrant tachycardia [AVNRT] or AV reentrant tachycardia
[AVRT] determination if possible) and conversion to sinus rhythm (SR) for at least 30 seconds.
The primary efficacy endpoint will be evaluated using the time to conversion of an episode of 
PSVT to SR after study drug administration as the primary efficacy variable. 
The secondary efficacy endpoints will include: 
• Relief of specific symptoms (i.e., heart palpitations, rapid pulse feeling, chest pain, anxiety, 
shortness of breath, dizziness, and fainting) potentially associated with an episode of PSVT;
and 
• Rating of Treatment Satisfaction Questionnaire for Medication (TSQM). 
The exploratory efficacy endpoints will include: 
• The number of positively adjudicated episodes of PSVT terminated by a vagal 
maneuver (VM),  
• The percentage of patients requiring additional medical intervention to terminate an episode 
of PSVT, and 
• The repeat of key efficacy endpoints in various subgroups of interest (e.g., concomitant 
medications). 

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SAFETY VARIABLES: 
Safety variables will include clinical adverse events (AEs), vital signs (blood pressure and HR), 
laboratory testing (hematology, chemistry, and urinalysis), arrhythmias, and conduction disorders 
detected on surface ECG or CMS recordings.  
During the etripamil test dose period, vital signs, SBP, diastolic blood pressure, HR 
measurements, arrhythmia, conduction disorders on the ECGs, and clinical AEs will be recorded. 
These data will be reported in the Overall Safety Population. These variables will be reported in 
the pre-identified relevant subgroups of patients (e.g., those receiving concomitant beta-blockers, 
calcium channel blockers, or other drugs known to reduce blood pressure or alter AV conduction)
for pre-defined subgroup analyses.  
During the Treatment Period, safety variables will be recorded. 
STATISTICAL ANALYSES: 
Analysis populations 
The Efficacy Population includes all randomized patients who use the study drug to treat a 
positively adjudicated episode of PSVT. This population does not include patients who take the
study drug for a negatively adjudicated episode of PSVT (i.e., symptoms not associated with an 
episode of PSVT). The subjects will be included in the treatment arm (placebo or double-blind 
study drug) in which they were randomized. 
The modified Intent to Treat (mITT) Population includes all randomized patients who take the 
randomized study drug, not during a test dose visit. The subjects will be included in the treatment 
arm (placebo or double-blind study drug) in which they were randomized. 
The Test Dose Only Population includes all patients who receive the test dose of etripamil NS
70 mg, but do not receive randomized drug (Overall Safety Population, minus the Safety 
Population). The Test Dose Only Population will also include pre-identified relevant subgroups 
of patients (e.g., those receiving concomitant beta-blockers, calcium channel blockers, or other 
drugs known to reduce blood pressure or alter AV conduction) for pre-defined subgroup analyses.
The Safety Population includes all randomized patients who take the study drug, not during a 
test dose visit. The subjects will be included in the treatment arm (placebo or double-blind study 
drug) according to actual received treatment. 
The Overall Safety Population includes the Safety Population and the Test Dose Only Population.
Efficacy analyses 
The efficacy analyses will be performed on the Efficacy Population. Additional sensitivity 
efficacy analyses and exploratory efficacy analyses will be performed on the mITT Population. 
The data from patients in Part 1 will be included in pivotal analyses. Pivotal analyses will include 
safety; and primary, secondary, and exploratory efficacy analyses for Part 1 only.  
The data from patients in Part 2 will be combined with that from Part 1 and will be included in 
exploratory analyses. Exploratory analyses will include safety; and primary, secondary, and 
exploratory efficacy analyses for Parts 1 and 2 combined. 

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The primary efficacy variable is the time to conversion of an episode of PSVT to SR after study 
drug administration. 
Only episodes of true PSVT that occur by the date of the adjudication of the 150th episode of true 
PSVT will be included in the primary efficacy analysis. 
For the primary efficacy endpoint analyses, the proportional hazards assumption will be tested 
first by examining plots of complementary log-log (event times) versus log (time). If the 
proportional hazard assumption remains valid the statistical analysis for the time to conversion 
will be performed using the log-rank test. If the proportional hazard assumption raises concerns, 
the statistical analysis for time to conversion will be performed using the Peto-Peto test. Patients 
who did not convert after 5 hours following study drug administration or who converted following 
medical assistance will be censored at 5 hours or at the time of medical assistance (whichever is 
earliest). The hazard ratio and 95% confidence interval (CI) will be calculated using the Cox 
proportional hazards model. If non-proportional hazards are observed, a stratified Cox regression 
model or an extended Cox regression model will be used, as appropriate. 
In addition to the primary analysis of the primary endpoint, Kaplan-Meier estimates of time to 
conversion will be calculated and reported as a Kaplan-Meier plot. Conversion rates at 3, 5, 10, 
15, 20, 30, 60, and 90 minutes after study drug administration will be reported for the etripamil 
group and the placebo group. The odds ratio (OR), and the CI for the OR, will be calculated. The 
Kaplan-Meier estimate of the time at which 25%, 50%, and 75% of episodes of PSVT conversions 
occur will be calculated. 
A sensitivity analysis for the primary efficacy endpoint will be performed on the mITT 
Population. In this analysis, the time to PSVT episode conversion will include “misidentification 
of PSVT by the patient.” All of these patients will be censored at the conversion of the non-reentry 
supraventricular tachycardia to SR or at 5 hours if conversion is not observed or if there were no 
tachycardia observed at all. 
For the secondary efficacy endpoint analyses, relief of specific symptoms associated with the 
termination of an episode of PSVT by the study drug will be analyzed by comparing the numeric 
scoring scale scores in the 2 treatment groups, and treatment satisfaction will be analyzed by 
comparing the rating of TSQM in the 2 treatment groups. 
Exploratory efficacy endpoint analyses will include descriptive statistics of the number of patients 
requiring additional medical intervention to terminate an episode of PSVT and descriptive 
statistics of the number of positively adjudicated episodes of PSVT converted by performing a 
VM. 
The primary, secondary, and subgroup analyses (e.g., concomitant medications) for efficacy may 
be repeated in all patients (Parts 1 and 2).  
Safety analyses 
Safety data will be summarized with descriptive statistics. Continuous safety data will be 
presented with n, minimum, maximum, median, mean, and standard deviation, whereas discrete 
safety data will be summarized with frequency counts and percentages. 
Safety summaries will be presented for patients in Part 1 of the study. Additional safety analyses 
will be conducted for all patients (Parts 1 and 2). 

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SAMPLE SIZE DETERMINATION: 
It is assumed that 30% of the episodes of PSVT will be converted to SR in the placebo group and 
70% in the etripamil group at 10 minutes. Based on these numbers and assuming exponential
survival curves, a hazard ratio of 3.38 is estimated. This represents a difference in median times 
to conversion of 13.6 minutes (median time to conversion of 5.8 minutes and 19.4 minutes in the 
etripamil and placebo group, respectively). These assumptions are based on results obtained in 
the NODE-1 study (MSP-2017-1109). 
Assuming a type I error rate of alpha = 0.01 and a 2:1 ratio in the number of positively adjudicated 
episodes of PSVT etripamil:placebo, a minimum of 46 positive conversion events would be 
required in order to attain 90% power on the primary variable of time to conversion (using a 
2-sided log-rank test). 
However, since patients will be randomized before they have a qualifying episode of PSVT, it is 
unlikely that the 2:1 etripamil:placebo PSVT episodes ratio will match the 2:1 randomization 
ratio. In such a case, it is preferable to target a higher sample size to cover for the worst-case 
scenarios in terms of unbalance. 
A total of 150 positively adjudicated PSVT episodes will ensure at least 90% power for extreme 
cases of unbalance in the etripamil:placebo PSVT episodes ratio.  
Only episodes of true PSVT that occur by the date of the adjudication of the 150th episode of true 
PSVT will be included in the primary efficacy analysis. 
It is anticipated that as many as 500 patients may need to be randomized in order to accrue a 
sufficient number of patients in the Efficacy Population within 18 months. 
MONITORING COMMITTEES: 
Steering Committee 
The Steering Committee will be responsible for the scientific oversight of the study. The Steering 
Committee Chair will review the original protocol and potential amendments. 
Data and Safety Monitoring Committee 
The Data and Safety Monitoring Committee (DSMC) will review the accumulating safety data 
on a regular basis to detect any safety issue that could be related to the study drug or the protocol 
procedures involved in the patient’s management of an episode of PSVT. The committee will be 
entitled to request a review of unblinded safety data. 
Adjudication Committee 
The Adjudication Committee will comprise at least 5 members, all cardiac electrophysiologists,
who are independent from the Sponsor and from Sponsor-related operational activities and the 
DSMC. The Adjudication Committee will review all data, i.e., the entire 5-hour CMS recording,
sent to them by the core laboratory for each study episode. 
The EPs will adjudicate the following:  
1. The presence of PSVT (AVNRT or AVRT determination if possible);  

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Note: Sinus tachycardia, atrial tachycardia, atrial fibrillation, and atrial flutter will not be 
included in the Efficacy Population. 
2. Termination of PSVT due to VM if PSVT was present; and  
3. Termination of PSVT to SR for at least 30 seconds after study drug administration if PSVT 
was present.  
Any bias will be limited by the adjudicators being fully blinded to the patient identifiers and study 
treatment. 
The Adjudication Committee will also adjudicate the time between study drug administration and 
PSVT termination or time to censoring if termination is not observed or is due to a medical 
intervention (e.g., use of intravenous adenosine in a medical care facility). 
The conclusion of the Adjudication Committee will be used in the primary and secondary 
analyses. 
The Adjudication Committee will review the secondary ECG safety endpoints (i.e., arrhythmia 
and conduction disorders). 
SITES: 
This study will be conducted at up to 75 sites. 
SPONSOR: 
Milestone Pharmaceuticals Inc. 
1111 Dr. Frederik-Philips Blvd., Suite 420 
Saint-Laurent, QC H4M 2X6, Canada 
Telephone: +1-514-336-0444 

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TABLE OF CONTENTS 
Procedures in Case of Emergency or Serious Adverse Event Reporting ....................................... 3 
Signature Page ................................................................................................................................ 4 
Investigator Agreement ................................................................................................................... 5 
Synopsis .......................................................................................................................................... 6 
Table of Contents .......................................................................................................................... 16 
List of Tables ................................................................................................................................ 20 
List of Figures ............................................................................................................................... 21 
List of Abbreviations and Definition of Terms............................................................................. 22 
1  Introduction and Background Information ............................................................................. 24 
1.1 
Phase 1 Study ................................................................................................................ 24 
1.2 
Phase 2 Study ................................................................................................................ 24 
1.3 
Rationale ........................................................................................................................ 28 
2  Study Objectives ..................................................................................................................... 30 
2.1 
Primary Objective ......................................................................................................... 30 
2.2 
Secondary Objective ..................................................................................................... 30 
2.3 
Exploratory Objectives .................................................................................................. 30 
3  Study Description.................................................................................................................... 31 
3.1 
Summary of Study Design ............................................................................................ 31 
3.2 
Study Visits ................................................................................................................... 32 
3.2.1  Screening Visit .................................................................................................. 32 
3.2.2  Test Dose Randomization Visit ......................................................................... 32 
3.2.3  Follow-up Visits ................................................................................................ 33 
3.2.4  Treatment Period ............................................................................................... 34 
3.2.5  Final Study Visit ................................................................................................ 35 
4  Selection and Withdrawal of Patients ..................................................................................... 36 
4.1 
Inclusion Criteria ........................................................................................................... 36 
4.2 
Exclusion Criteria .......................................................................................................... 36 
4.3 
Withdrawal Criteria ....................................................................................................... 39 
5  Study Treatments .................................................................................................................... 40 
5.1 
Treatment Groups .......................................................................................................... 40 

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5.2 
Rationale for Dosing ..................................................................................................... 40 
5.3 
Randomization and Blinding ......................................................................................... 40 
5.4 
Unblinding ..................................................................................................................... 41 
5.5 
Drug Supplies ................................................................................................................ 41 
5.5.1  Formulation and Packaging ............................................................................... 41 
5.5.2  Study Drug Administration ............................................................................... 42 
5.5.3  Treatment Compliance ...................................................................................... 42 
5.5.4  Storage and Accountability ............................................................................... 42 
5.5.5  Study Drug Handling and Disposal ................................................................... 43 
5.6 
Prior and Concomitant Medications and/or Devices ..................................................... 43 
5.6.1  Excluded Medications and/or Devices .............................................................. 43 
5.6.2  Documentation of Prior and Concomitant Medication Use .............................. 43 
6  Site Study Procedures ............................................................................................................. 44 
6.1 
Screening Visit .............................................................................................................. 44 
6.2 
Test Dose Randomization Visit ..................................................................................... 44 
6.3 
Follow-up Visits ............................................................................................................ 46 
6.4 
Treatment Period ........................................................................................................... 47 
6.5 
Final Study Visit ............................................................................................................ 47 
7  Efficacy Assessments .............................................................................................................. 49 
7.1 
Primary Efficacy Endpoint ............................................................................................ 49 
7.2 
Secondary Efficacy Endpoints ...................................................................................... 49 
7.3 
Exploratory Efficacy Endpoints .................................................................................... 49 
7.4 
Adjudication Process ..................................................................................................... 49 
8  Safety Assessments ................................................................................................................. 51 
8.1 
Adverse Events .............................................................................................................. 51 
8.1.1  Adverse (Drug) Reaction .................................................................................. 52 
8.1.2  Unexpected Adverse Drug Reaction ................................................................. 52 
8.1.3  Assessment of Adverse Events by the Investigator .......................................... 52 
8.1.3.1  Assessment of severity ........................................................................ 52 
8.1.3.2  Causality assessment ........................................................................... 52 
8.2 
Serious Adverse Event .................................................................................................. 53 
8.3 
Serious Adverse Event Reporting – Procedures for Investigators ................................ 54 

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8.4 
Pregnancy Reporting ..................................................................................................... 55 
8.5 
Expedited Reporting ...................................................................................................... 55 
8.6 
Medical Device Complaints .......................................................................................... 56 
8.7 
Clinical Laboratory Evaluations .................................................................................... 56 
8.8 
Vital Signs ..................................................................................................................... 56 
8.9 
Electrocardiograms ........................................................................................................ 56 
8.10  Physical Examinations .................................................................................................. 56 
9  Statistics .................................................................................................................................. 57 
9.1 
Analysis Populations ..................................................................................................... 57 
9.2 
Statistical Methods ........................................................................................................ 57 
9.2.1  Patient Disposition and Demographic/Baseline Characteristics ....................... 57 
9.2.2  Study Drug Administration and Concomitant Medications .............................. 57 
9.2.3  Analysis of Efficacy .......................................................................................... 58 
9.2.3.1  Primary efficacy analysis .................................................................... 58 
9.2.3.2  Secondary efficacy analysis ................................................................ 58 
9.2.3.3  Exploratory efficacy analyses ............................................................. 59 
9.2.4  Analysis of Safety ............................................................................................. 59 
9.2.5  Sample Size Determination ............................................................................... 59 
10  Data Management and Record Keeping ................................................................................. 60 
10.1  Data Management ......................................................................................................... 60 
10.1.1  Data Handling ................................................................................................... 60 
10.1.2  Computer Systems ............................................................................................. 60 
10.1.3  Data Entry ......................................................................................................... 60 
10.1.4  Medical Information Coding ............................................................................. 60 
10.1.5  Data Validation ................................................................................................. 60 
10.2  Record Keeping ............................................................................................................. 60 
11  Investigator Requirements and Quality Control ..................................................................... 62 
11.1  Ethical Conduct of the Study ........................................................................................ 62 
11.2  Institutional Review Board/Independent Ethics Committee ......................................... 62 
11.3  Informed Consent .......................................................................................................... 62 
11.4  Study Monitoring Requirements ................................................................................... 62 
11.5  Disclosure of Data ......................................................................................................... 63 

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11.6  Retention of Records ..................................................................................................... 63 
11.7  Monitoring Committees ................................................................................................ 64 
11.7.1  Steering Committees ......................................................................................... 64 
11.7.2  Data and Safety Monitoring Committee ........................................................... 64 
11.7.3  Adjudication Committee ................................................................................... 64 
11.8  Audits and Inspections .................................................................................................. 65 
11.9  Publication Policy ......................................................................................................... 65 
11.10 Financial Disclosure ...................................................................................................... 65 
12  Study Administrative Information .......................................................................................... 66 
12.1  Protocol Amendments ................................................................................................... 66 
12.2  Address List ................................................................................................................... 66 
12.2.1  Sponsor .............................................................................................................. 66 
12.2.2  Contract Research Organization ........................................................................ 66 
12.2.3  ECG Core Laboratory for Test Dose CMS Data and CMS Monitoring ........... 66 
12.2.4  ECG Core Laboratory for Primary Endpoint Adjudication .............................. 66 
12.2.5  Study Drug Distribution and Accountability .................................................... 66 
12.2.6  Medpace Clinical Safety ................................................................................... 67 
12.2.7  Biological Specimens ........................................................................................ 67 
13  References ............................................................................................................................... 68 
Appendix A:  Schedule of Procedures .......................................................................................... 69 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 71 

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LIST OF TABLES 
Table 1. 
Summary of Induced, Sustained Paroxysmal Supraventricular Tachycardia to Sinus 
Rhythm Conversion Within 15 Minutes After Study Drug Administration ............... 25 
Table 2. 
Schedule of Procedures ............................................................................................... 69 
 
 

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LIST OF FIGURES 
Figure 1.  Kaplan-Meier Plot of Conversion 15 Minutes After Study Drug Administration...... 26 
Figure 2.  Mean (±Standard Error) Systolic Blood Pressure (mmHg) Over Time ..................... 27 
Figure 3.  Dose Response Maximal Efficacy Model ................................................................... 28 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
AV 
Atrioventricular 
AVNRT 
Atrioventricular nodal reentrant tachycardia 
AVRT 
Atrioventricular reentrant tachycardia 
BDS 
Aptar Pharma Nasal Spray Bidose System 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMS 
Cardiac Monitoring System 
CRA 
Clinical Research Associate 
CSR 
Clinical study report 
DBP 
Diastolic blood pressure 
DSMC 
Data and Safety Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylene-diamine-tetra-acetic acid 
Emax 
Maximal efficacy 
EP 
Electrophysiologist 
EPL 
Electrophysiology laboratory 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HR 
Heart rate 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IN 
Intranasal(ly) 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
Intravenous(ly) 
MFD 
Maximum feasible dose 
MoOP 
Manual of operations and procedures 
NS 
Nasal spray 
OR 
Odds ratio 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PSVT 
Paroxysmal supraventricular tachycardia 
SAE 
Serious adverse event 

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Abbreviation 
Definition 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure  
SR 
Sinus rhythm 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
VM 
Vagal maneuver 
WHODD 
World Health Organization Drug Dictionary 
 

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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Etripamil (also referred to as MSP-2017 in study documents), an L-type calcium channel 
antagonist and short-acting verapamil analog, is being developed by Milestone Pharmaceuticals 
Inc. (hereinafter Milestone) for the treatment of paroxysmal supraventricular tachycardia (PSVT), 
hereinafter used in reference to both the disorder and its associated tachyarrhythmia. A relatively 
common disorder, PSVT is characterized by episodes of tachyarrhythmia typically with a heart 
rate (HR) over 100 bpm and a QRS duration of <120 msec.1 Etripamil is directed towards the 
2 most 
common 
subtypes 
of 
PSVT, 
atrioventricular 
(AV) 
nodal 
reentrant 
tachycardia (AVNRT) and AV reentrant tachycardia (AVRT), together accounting for 
approximately 90% of PSVT cases.1 In both conditions, a pharmaceutical agent capable of 
transiently prolonging AV conduction time can result in arrhythmia termination and restoration of 
normal sinus rhythm (SR). 
Historically, intravenous (IV) verapamil has been used as an effective agent for treatment of acute 
episodes of PSVT.2 However, it has been replaced in recent years by IV adenosine, which is 
equally effective in terminating acute episodes of PSVT.3 Adenosine has the advantage of having 
a very short half-life, as it is rapidly metabolized during the time required to terminate an episode 
of PSVT.4 However, the short half-life of adenosine renders it ineffective when given via routes 
of administration other than IV. As both of these medications require the establishment of 
IV access, they are not appropriate for a patient self-administration paradigm in an outpatient 
setting. 
1.1 
Phase 1 Study 
A Phase 1 study 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 (i.e., 2 sprays of 
100 µL of solution of 35 mg of etripamil in each nostril). 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. The 4 doses selected to be studied in a Phase 2 study were 35, 70, 105, 
and 140 mg. 
1.2 
Phase 2 Study 
NODE-1, 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 

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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 nasal spray (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 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 
AVNRT.  
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 
20 received placebo. The percentage of patients in whom PSVT converted to 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 

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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. 
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.  

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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 (see 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 
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 (±Standard Error) Systolic Blood Pressure (mmHg) Over Time 
 
Note: Asterisks (*) indicate statistically significant as p<0.05 versus baseline. 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. 
PSVT = paroxysmal supraventricular tachycardia. 
Source: Clinical Study Report MSP-2017-1109 
The Cochran-Armitage test for trend showed the presence of an association between conversion 
rate and the etripamil treatment groups (p<0.0001). The maximal efficacy (Emax) asymptotic model 
best fits the dose response relationship showing a plateau starting at or before 70 mg (see Figure 3). 
 

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Figure 3. Dose Response Maximal Efficacy Model 
 
D50 = dose (mg) related to 50% of the maximal effect; E0 = fitted efficacy at time 0 (placebo effects); Emax = maximal efficiency; 
R2 = coefficient of determination. 
Source: Clinical Study Report MSP-2017-1109 
The observed balance between efficacy and safety in the etripamil NS 70 mg group makes this 
dose a good candidate for future studies. 
1.3 
Rationale 
The primary objective of this study is to determine whether etripamil NS 70 mg is superior to 
placebo at terminating acute episodes of PSVT in an outpatient setting. Therefore, a double-blind, 
placebo-controlled, parallel design study is the most appropriate to reach the objective. 
Etripamil addresses an unmet medical need since there are currently no short-acting products 
available for patient self-administered treatment of acute episodes of PSVT. The only currently 
available acute pharmacological therapy is IV treatment with adenosine or verapamil in a hospital 
environment, which is expensive and greatly inconveniences the patient. A self-administered 
product for acute PSVT would give patients the option to safely terminate acute episodes of PSVT 
without the need for a hospital visit. An episodic treatment option would also allow selected 
patients to discontinue chronic prophylactic therapy with Class I, II (e.g., beta-blockers), III, and/or 
IV (e.g., calcium channel blockers) antiarrhythmic agents, thus avoiding the side effects and 

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quality of life implications associated with these medications. Furthermore, patients weighing the 
risks of bridging therapy and an invasive catheter ablation procedure to address their PSVT would 
have the opportunity to consider episodic management with etripamil as a viable alternative 
treatment option.  
The goal of this double-blind Phase 3 NODE-301 study is to demonstrate the safety and 
effectiveness of etripamil NS 70 mg in the treatment of spontaneous episodes of PSVT when 
self-administered by patients in an outpatient setting. 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to determine whether etripamil NS 70 mg self-administered 
by patients is superior to placebo at terminating episodes of PSVT in an outpatient setting. 
2.2 
Secondary Objective 
The secondary objective of this study is to evaluate the safety of etripamil NS 70 mg when 
self-administered by patients without medical supervision. 
2.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To evaluate the safety, hemodynamic, and cardiac conduction effects of a test dose of etripamil 
NS 70 mg, and 
• To evaluate the safety and efficacy of etripamil NS 70 mg in various subgroups of interest 
(e.g., concomitant medications). 

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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
NODE-301 is a multi-centre, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of etripamil NS 70 mg self-administered by patients who experience an episode 
of PSVT in an outpatient setting. Each episode will be documented by an ambulatory Cardiac 
Monitoring System (CMS) that will be placed on the chest by the patient or caregiver when 
symptoms begin and will record at least 5 hours of continuous electrocardiogram (ECG). Each 
CMS will be identified by a unique number. This study will be conducted at up to 75 sites. 
This is an event-driven study; approximately 150 randomized patients presenting with a positively 
adjudicated episode of PSVT and treated with the study drug are required to control the type I error 
rate at the desired alpha = 0.01 and to get an adequate power. Since the time from enrollment to 
when patients experience their first positively adjudicated episode of PSVT treated with study drug 
is unknown, the study is projected to randomize up to 500 patients. The final number of 
randomized patients and of adjudicated episodes of PSVT will depend on the frequency and timing 
of episodes of PSVT during the study. Enrollment into the study will stop on the date of the 
adjudication of the 150th positively adjudicated PSVT episode. See the sample size determination 
section (Section 9.2.5) for additional details. 
The study will comprise of 2 parts, Part 1 and Part 2.  
Part 1 will consist of patients that will be dosed with the double-blind study drug or have 
discontinued the study before the adjudication of the 150th positively adjudicated PSVT episode. 
The data from patients in Part 1 will be cleaned and locked, on a per-patient basis, and will be 
included in pivotal analyses. Pivotal analyses will include safety; and primary, secondary, and 
exploratory efficacy analyses for Part 1 only. Patients in Part 1 will be unblinded after data is 
locked.  
Part 2 will consist of patients that will not be included in Part 1, i.e., Part 2 will consist of patients 
who were not dosed with the double-blind study drug or have not discontinued the study before 
the adjudication of the 150th positively adjudicated PSVT episode. The data from patients in Part 2 
will be combined with that from Part 1 and will be included in exploratory analyses. Exploratory 
analyses will include safety; and primary, secondary, and exploratory efficacy analyses for 
Parts 1 and 2 combined. Patients in Part 2 will be unblinded at the end of the study. Part 2 will end 
when one of the following criteria is met: 
• 75% of patients in Part 2 have completed the study (Final Study Visit), or 
• Approximately 9 months after the date of the adjudication of the 150th positively adjudicated 
PSVT episode.  
Based on the results of the pivotal analyses from Part 1, the planned statistical analysis and conduct 
of Part 2 may be amended. However, in no case will the Part 2 dataset be integrated with the Part 1 
pivotal dataset for primary efficacy or primary safety analyses.  
The study will include the following: 
• A Screening Visit, 
• A Test Dose Randomization Visit, 

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• Follow-up Visits, 
• A Treatment Period, and 
• A Final Study Visit. 
3.2 
Study Visits 
3.2.1 
Screening Visit 
During the Screening Visit, the Investigator will review the patient’s medical history and complete 
assessments to confirm eligibility, including confirmation of PSVT.  
Investigators will be provided with a manual of operations and procedures (MoOP) that will define 
acceptable source documents required to confirm the PSVT diagnosis. 
The Investigators will enroll patients who have a history of sustained episodes of 
PSVT (i.e., typically lasting approximately 20 minutes or longer). 
Females of childbearing potential and male patients, except those who are surgically sterile, who 
are sexually active must agree to use an approved highly effective form of contraception. 
Prospective study patients will be asked to sign the informed consent form before the 
commencement of any study-related assessments or procedures. Once the informed consent is 
signed, patients will be considered enrolled in the study. 
If an enrolled patient meets at least 1 exclusion criterion, the patient will be considered a screening 
failure. Re-screening may be allowed after consultation with the Investigator and Medical Monitor. 
3.2.2 
Test Dose Randomization Visit 
The initial Test Dose Randomization Visit must occur within 28 days after the Screening Visit. 
Before randomization, all patients will receive a test dose of etripamil NS 70 mg to evaluate 
tolerability and to train patients on the study procedures. The test dose administration will take 
place at the study site under medical supervision while the patient is in SR. Any post-dose AEs 
will be recorded. The test dose procedures are detailed in the MoOP. The test dose failure criteria 
are listed in the protocol exclusion criteria (Section 4.2).  
• Patients who pass the test dose will be randomized in a 2:1 ratio to etripamil or placebo using 
an Interactive Response Technology (IRT) system. If the CMS ECG test dose report is delayed 
for any unforeseen reason, patients will be allowed to leave and return to the site another day 
for randomization. 
• Patients who fail the test dose will proceed in the study as follows:  
o If the Investigator identifies a possible reversible cause of the initial test dose failure 
(e.g., concomitant medication such as beta-blocker), a re-challenge with a new test dose 
of etripamil NS 70 mg within a 14-day window from the initial test dose will be possible 
after elimination of the reversible cause (e.g., withdrawal of concomitant therapy with the 
appropriate washout period). Patients may be randomized if they pass the second test dose, 
and the cause of the test dose failure is eliminated for the duration of the study; or 

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o If the Investigator cannot identify a reversible cause of the initial test dose failure, or if 
the potential cause cannot be modified (e.g., necessary antihypertensive drug to control 
blood pressure), patients will not be randomized and will complete a Final Study Visit. 
Patients who fail the test dose will be part of the Test Dose Only Population, including all 
patients who received at least 1 test dose of etripamil NS 70 mg. 
The interpretation of the CMS ECG will be provided by the cardiac monitoring core laboratory to 
the site in a report based on the mobile system’s proprietary arrhythmia detection algorithms and 
automatic ECG collection. During each patient’s Test Dose Randomization Visit, the cardiac 
monitoring core laboratory will generate a summary test dose report within approximately 
1 to 2 hours of the receipt of the ECG data. This report will be used by the site to determine if the 
patient passes or fails the test dose and if the eligibility criteria to be randomized in the study have 
been met. The operational aspects of the use of the CMS during the test dose are described in the 
MoOP. 
Randomized patients will be trained on how to report AEs to the sites during the study for 
evaluation and on specific procedures to be followed when they experience an episode of PSVT, 
including how to identify and report PSVT symptoms, contact the Telephone Coach (if possible), 
set up and use the CMS, perform a vagal maneuver (VM), and self-administer study drug. A 
caregiver may help the patient with these procedures. Each randomized patient will receive a study 
kit, which includes the blinded study drug (placebo or etripamil NS), a CMS, a study identification 
card, patient’s study instructions, and other study-related material. Randomized patients will also 
be provided with a patient diary to be completed after experiencing a PSVT episode. The patient 
diary collects information about symptoms of the patient’s PSVT episode and includes a Treatment 
Satisfaction Questionnaire for Medication (TSQM). Standardized training will be described in the 
MoOP. 
3.2.3 
Follow-up Visits 
Follow-up Visits will occur approximately monthly from the time of randomization and can be 
conducted by patients returning to the investigative site (preferred) or by the site personnel 
contacting patients by telephone. During this visit, inclusion/exclusion criteria will be reviewed to 
ensure patients are eligible to continue in the study, and patients will be re-trained on the 
procedures they will need to follow when they experience the symptoms of an episode of PSVT. 
Routine monthly Follow-up Visits are highly recommended but are not mandatory. A missing 
Follow-up Visit will not be considered a deviation of the protocol, and patients will not be excluded 
from the study for missing their monthly Follow-up Visits. 
A Follow-up Visit will also occur if patients experience an episode of PSVT for which they apply 
the CMS, and the episode is subsequently terminated by a VM. In this case, it is mandatory for 
patients to be on-site for the Follow-up Visit so that site personnel can ensure that all data has been 
downloaded from the CMS device. Patients will retain their CMS and remain in the study for 
subsequent episodes of PSVT. 

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3.2.4 
Treatment Period 
All randomized patients will perform a sequence of steps, including study drug self-administration 
when patients identify symptoms of an episode of PSVT. A caregiver may help the patient with 
these procedures, and this should be annotated in the electronic case report form (eCRF). The steps 
of the procedures are the following: 
1. Contact the Telephone Coach (if possible) who will guide the patient through the study 
procedures. If the patient is unable to reach the Telephone Coach, he/she may proceed with the 
procedures using the printed and electronic guides provided; 
2. Apply the CMS to record cardiac activity; 
3. Perform a VM. If the VM is successful in relieving symptoms, the patient will not 
self-administer study drug but will keep the CMS device on for 5 hours. The episode of PSVT 
and the results of the VM will be adjudicated, and the patient will remain in the study for a 
subsequent episode of PSVT; 
4. Administer study drug if the symptoms do not resolve after completion of the VM. The patient 
will push the CMS event marker button to record the time of dosing immediately prior to 
self-administering the study drug IN as instructed. The CMS should not be removed, and the 
recording should continue for at least 5 hours after study drug administration; 
5. Report and rate symptoms of PSVT as well as overall treatment satisfaction, in a patient diary 
and TSQM; 
6. If the symptoms of PSVT have not resolved within 20 minutes after study drug administration, 
patients may seek appropriate medical care and follow these steps: 
 When the patient reaches a medical care facility to seek treatment for the episode of 
PSVT, the patient must give the study identification card included in the study kit to 
the on-site medical personnel. The study identification card contains a brief description 
of the study, the Investigator and Medical Monitor contact information, and a short 
questionnaire to be filled out by the on-site physician to document the diagnosis of the 
episode, the treatment administered, and the outcome; 
 The CMS should not be removed, and recording should continue for at least 5 hours 
after study drug administration; 
 If unblinding is judged necessary by the on-site treating physician, a 24/7 assistance 
telephone number will be provided on the study identification card so that the situation 
can be discussed with the Medical Monitor. It is recommended to contact the study 
Medical Monitor before any unblinding occurs; and 
7. Schedule a Final Study Visit within 7 days of study drug administration. 
The interpretation of the CMS ECG will be provided by the cardiac monitoring core laboratory to 
the site in a report based on the mobile system’s proprietary arrhythmia detection algorithms and 
automatic ECG collection. The cardiac monitoring core laboratory will generate a summary report 
within 48 hours of the receipt of ECG data. The operational aspects are described in the MoOP. 
These reports will be sent to the site and the Medical Monitor.  

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In all cases, the presence of an episode of PSVT and termination will be evaluated by an 
independent Adjudication Committee. The Adjudication Committee’s evaluations will be done 
using the complete CMS ECG recorded during the patient’s PSVT episode. 
3.2.5 
Final Study Visit 
A Final Study Visit will occur at the study site within 7 days after the final Treatment Period day 
with usage of the study drug, or if for any other reason the patient has completed participation in 
the study. 
This visit will occur under the following circumstances: 
• The patient fails the test dose, 
• The patient self-administers study drug (or with the help of a caregiver) for an episode of PSVT 
whether or not the episode is subsequently adjudicated as a true episode of PSVT, 
• The patient has started treatment with a prohibited medication before experiencing an episode 
of PSVT, 
• The patient withdraws consent from the study for any reason, 
• The Sponsor decides to terminate the study for any reason, or 
• The patient is deemed to have completed participation in the study for any other reason. 

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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Male or female patients at least 18 years of age; 
2. Electrographically documented history of PSVT (e.g., ECG obtained during an episode of 
PSVT, Holter monitoring, loop recorder, etc.). If patient had a prior ablation for PSVT, patient 
must have documented ECG evidence of PSVT post-ablation; 
3. History of sustained episodes of PSVT (i.e., typically lasting approximately 20 minutes or 
longer); 
4. Females of childbearing potential who are sexually active must agree to use an approved highly 
effective form of contraception from the time of signed informed consent until 30 days after 
the last administration of study drug. Females of childbearing potential should have a negative 
serum pregnancy test result at the Screening Visit and at the Final Study Visit, a negative urine 
pregnancy test at the Test Dose Randomization Visit and must use an approved form of 
contraception between the visits. Approved forms of contraception include hormonal 
intrauterine devices or hormonal contraceptives (oral birth control pills, Depo-Provera®, patch, 
or other injectables) together with supplementary double-barrier methods, such as condoms or 
diaphragms with spermicidal gel or foam; 
The following categories define females who are NOT considered to be of childbearing potential: 
• Premenopausal females with 1 of the following: 
 Documented hysterectomy; 
 Documented bilateral salpingectomy; or 
 Documented bilateral oophorectomy; or 
• Postmenopausal females, defined as having amenorrhea for at least 12 months without an 
alternative medical cause; 
5. Male patients, except those who are surgically sterile, must use an approved highly effective 
form of contraception during the 3 days after any study drug administration; and 
6. Signed written informed consent. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Systolic blood pressure <90 mmHg after a 5-minute rest in sitting position at the Screening 
Visit or before the test dose. In patients treated with a chronic prophylactic drug for 
PSVT (e.g., beta-blockers, verapamil, and diltiazem), the drug may be stopped for at least the 
equivalent of 5 half-lives and patients may be rescreened once; 
2. History of severe symptoms of hypotension, especially syncope, during episodes of PSVT; 
3. History of atrial arrhythmia that does not involve the AV node as part of the tachycardia 
circuit (e.g., atrial fibrillation, atrial flutter, intra-atrial tachycardia); 

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4. History of allergic reaction to verapamil; 
5. Current therapy with digoxin or any Class I or III antiarrhythmic drug, except if these drugs 
are stopped at least the equivalent of 5 half-lives before the Test Dose Randomization Visit; 
6. Current therapy with amiodarone, or have taken amiodarone within 30 days prior to the Test 
Dose Randomization Visit; 
7. Evidence of ventricular pre-excitation (e.g., delta waves, short PR interval <100 msec, 
Wolff-Parkinson-White syndrome) on the ECG performed at the Screening Visit or before the 
test dose administration; 
8. Evidence of a second- or third-degree AV block on the ECG performed at the Screening Visit 
or before the test dose administration; 
9. History or evidence of severe ventricular arrhythmia (e.g., torsades de pointes, ventricular 
fibrillation, or sustained ventricular tachycardia); 
10. Current congestive heart failure defined by the New York Heart Association Class II to IV;  
11. Stroke in the last 6 months; 
12. Evidence of hepatic dysfunction defined as alanine aminotransferase or aspartate 
aminotransferase >3 × the upper limit of normal (ULN) or total bilirubin >2 × ULN at the 
Screening Visit, unless due to Gilbert syndrome; 
13. Evidence of renal dysfunction as determined by an estimated glomerular filtration rate assessed 
at the Screening Visit as follows: 
 <60 mL/min/1.73 m2 for patients <60 years of age; 
 <40 mL/min/1.73 m2 for patients ≥60 and <70 years of age; or 
 <35 mL/min/1.73 m2 for patients ≥70 years of age; 
14. Females who are pregnant or lactating; 
15. Evidence or history of any significant physical or psychiatric condition including drug abuse, 
which, in the opinion of the Investigator, could jeopardize the safety of patients or affect their 
participation in the study. Additionally, the Investigator has the ability to exclude a patient if 
for any reason the Investigator judges the patient is not a good candidate for the study or will 
not be able to follow study procedures; or 
16. Participation in any investigational drug or device study or the use of any investigational drug 
or device within 30 days of the Screening Visit. 

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Before randomization, all patients will receive a test dose of etripamil NS 70 mg to evaluate 
tolerability and to train patients on the study procedures. A failure of the test dose is considered if 
patients meet any of the following criteria occurring after administration of the etripamil NS 70 mg 
test dose: 
1. Any symptoms consistent with clinically severe hypotension such as pre-syncope, medically 
significant lightheadedness, syncope, nausea, or vomiting; 
2. For patients with a pre-test dose SBP above 100 mmHg: 
 Decrease in SBP ≥40 mmHg after test dose; or 
 Post-test dose SBP <80 mmHg; 
3. For patients with a pre-test dose SBP between 90 mmHg and 100 mmHg (inclusive): 
 Post-test dose SBP <75 mmHg; 
4. Third-degree AV block, Mobitz II second-degree AV block, or Wenckebach with 
bradycardia ≤40 bpm; 
5. New, significant sinus bradycardia HR ≤40 bpm or sinus pauses (≥3 seconds), if considered 
by the Investigator to put the patient’s safety at risk if either were to occur while not under 
medical supervision; 
6. Any 
new 
significant 
ventricular 
arrhythmia 
(premature 
ventricular 
beats 
and 
couplets [>6 premature ventricular contractions per 45 seconds ECG] are considered 
significant); or 
7. Atrial fibrillation or atrial flutter (event lasting longer than 30 seconds). 
Patients who fail the test dose will proceed in the study as follows: 
• If the Investigator identifies a possible reversible cause of the initial test dose failure 
(e.g., concomitant medication such as beta-blocker), a re-challenge with a new test dose of 
etripamil NS 70 mg within a 14-day window from the initial test dose will be possible after 
elimination of the reversible cause (e.g., withdrawal of concomitant therapy with the 
appropriate washout period). Patients may be randomized if they pass the second test dose, and 
the cause of the test dose failure is eliminated for the duration of the study; or 
• If the Investigator cannot identify a reversible cause of the initial test dose failure, or if the 
potential cause cannot be modified (e.g., necessary antihypertensive drug to control blood 
pressure), patients will not be randomized and will complete a Final Study Visit. Patients who 
fail the test dose will be part of the Test Dose Only Population, including all patients who 
received at least 1 test dose of etripamil NS 70 mg (see Section 9.1). 
During each patient’s Test Dose Randomization Visit, the test dose CMS ECG data will be 
reviewed by the cardiac monitoring core laboratory, and a report will be sent to the site. The 
operational aspects are described in the MoOP. 

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4.3 
Withdrawal Criteria 
Patient participation in this clinical study may be discontinued for any of the following reasons: 
• The patient withdraws consent or requests discontinuation from the study for any reason; 
• Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol; 
• Any medical condition which indicates to the Investigator that continued participation is not 
in the best interest of the patient; 
• Requirement of prohibited concomitant medication; 
• Patient failure to comply with protocol requirements or study-related procedures; or  
• Termination of the study by Milestone or a regulatory authority. 
If a patient withdraws consent after the test dose and before an episode of PSVT, he/she will be 
required to undergo the Final Study Visit procedures and will still be considered evaluable in the 
Test Dose Only Population and Safety Population (see Section 9.1). 

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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Before randomization, all patients will receive a test dose of etripamil NS 70 mg to evaluate 
tolerability and to train patients on the study procedures. The test dose administration will take 
place at the study site under medical supervision while the patient is in SR. Patients who pass the 
test dose will be randomized in a 2:1 ratio to etripamil NS 70 mg or placebo using IRT. 
5.2 
Rationale for Dosing 
The choice of the dose level of etripamil NS was made according to the data obtained in Phase 1 
and Phase 2 studies. 
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 1.1). 
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 1.2). 
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. Mean SBP did not drop following administration of etripamil 35 and 
70 mg. 
Etripamil 35 mg had an overall success rate of 65% at 15 minutes compared to 35% with the 
placebo. The treatment effect of 30% compared to the high efficacy rates of existing therapies 
renders the 35 mg dose inadequate as a development candidate.  
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 
SBP in contrast to the 2 higher doses. 
For these reasons, etripamil NS 70 mg has been selected as the only dose for NODE-301. 
5.3 
Randomization and Blinding 
At the Screening Visit, a unique patient identification number will be established for each patient 
at the investigational site. This patient identification number will be used for patient identification 
throughout the study and in all study-related documentation. This will be a 6 digit hyphenated 
number of the following format: XXX-YYY, where XXX is the unique site identification number 
and YYY is a sequential unique number assigned to the patient at that site. Each patient number 
will be assigned only once and will not be reassigned to another patient if a patient fails during the 

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Screening Visit. The IRT will not allow repeat of numbers. This unique identifier is used in all 
study documentation for that patient from first to last contact.  
The Investigator or designee must electronically contact the IRT to acquire a treatment assignment 
for each patient.  
This study will be conducted in a double-blind manner and all Sponsor, investigative site, 
Adjudication Committee, and Clinical Research Organization personnel involved in the study will 
be blinded to the treatment assignment with the following exceptions: 
• Sponsor Clinical Study Supplies Coordinator and personnel directly involved in 
manufacturing/packaging of the study drug, 
• The Data and Safety Monitoring Committee (DSMC) (if unblinded safety data is requested), 
and 
• IRT services personnel. 
5.4 
Unblinding 
In the event of an emergency, it will be possible to determine to which treatment the patient has 
been allocated by calling a 24/7 assistance telephone number provided on the patient’s study 
identification card. The Medical Monitor should be consulted prior to unblinding whenever 
possible. Any unblinding performed by the Investigator or medical personnel must be recorded in 
the source documents. 
5.5 
Drug Supplies 
Milestone will provide sufficient quantities of etripamil and placebo NS for the study. The lot 
numbers of supplied study drug will be recorded in the final clinical study report (CSR). 
5.5.1 
Formulation and Packaging 
The formulation of etripamil is for IN administration and 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 the NODE-301 study is 70 mg. The same formulation will be 
used for the Test Dose Randomization Visit and for the Treatment Period. 
The formulation of placebo will consist of water, sodium acetate, disodium EDTA, and sulfuric 
acid to reproduce the same pH as the etripamil formulation. 
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 Harmonisation (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 
language for investigative material. Proof labels, detailing actual label text, will be available in the 
study files. 
Study drug will be packaged according to current GMP and ICH GCP guidelines. The study drug 
distributor will package the study drug. Double-blind study drug will be uniquely identified with 
a randomly generated kit identifier. The kit identifier for each patient will be recorded in the 
electronic data capture (EDC) system for the study. 

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Bellwyck Pharma Services is the study drug distributor and will facilitate the delivery and resupply 
of study drug to the investigational site. The Investigator or designee must contact the IRT when 
any unscheduled replacements of study drug are required. 
5.5.2 
Study Drug Administration 
All 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 [BDS]). The devices will be prefilled and 
packaged into child-resistant boxes. Instructions for its use are provided in the MoOP and will be 
provided in the study drug box. 
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 (a 
caregiver may help the patient with this procedure). 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. Patients will receive study drug (randomized in a 2:1 ratio to 
etripamil:placebo) as determined by their treatment group assignment. 
If the BDS does not deploy, it will be considered a missed dose. 
5.5.3 
Treatment Compliance 
The patient will administer the test dose of study drug at the clinical site with the guidance of study 
personnel. The date, dosing initiation time, and dose completion time will be recorded. For the 
double-blind portion of the study, study drug will be self-administered or administered with the 
help of a caregiver. Patients will be required to return the used BDS, the CMS, and the study 
identification card to the site at their Final Study Visit. The patient will be questioned about the 
drug administration, including any issues related to the use of the device such as failure in 
deployment of the BDS, to confirm drug compliance and accountability. 
5.5.4 
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. 
During the study, the patient will be instructed to keep and return used BDS devices to the site for 
final drug accountability. Patients will be instructed to maintain the study drug in an ambient 
temperature environment at all times. At the conclusion of the study, patients will return unused 
study drug to the site for final drug accountability during their Final Study Visit. 
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. 

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5.5.5 
Study Drug Handling and Disposal 
The final accountability of study drug will be performed by the Clinical Research Associate (CRA) 
at the sites. Sites will not be allowed to destroy study drug. All study drug kits will be returned to 
Milestone’s designee at study closeout after CRA accountability is completed. If no study drug 
remains, this will be indicated in the drug accountability log. 
5.6 
Prior and Concomitant Medications and/or Devices 
5.6.1 
Excluded Medications and/or Devices 
Current participation in any investigational drug or device study or the use of any investigational 
drug or device within 30 days of the Screening Visit is prohibited. 
The use of digoxin or any Class I or III antiarrhythmic drug with less than the equivalent of 
5 half-lives of this drug prior to the Test Dose Randomization Visit is prohibited. The use of 
amiodarone within 30 days prior to the Test Dose Randomization Visit is prohibited. 
Drugs for chronic prophylactic treatment of episodes of PSVT (e.g., beta-blockers, verapamil, and 
diltiazem) cannot be started after randomization. 
If the treatment with antihypertensive drugs (monotherapy or combinations) is modified after the 
randomization, a new test dose may be conducted, after consultation with the Medical Monitor. 
The use of any drugs of abuse which, in the opinion of the Investigator, would impact the validity 
of the study results is prohibited. 
5.6.2 
Documentation of Prior and Concomitant Medication Use 
The use of any concomitant medications or devices will be recorded in the eCRF by the 
Investigator and documented in the final CSR. 

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6 
SITE STUDY PROCEDURES 
6.1 
Screening Visit 
The following procedures will be performed at the Screening Visit. See also Table 2 (Schedule of 
Procedures): 
• Obtain informed consent. The patient is considered enrolled in the study when informed 
consent is obtained; 
• Record demographics and medical/surgical history; 
• Evaluate and record concomitant medications; 
• Perform physical examination (including height and weight); 
• Obtain and record vital signs (blood pressure and HR); 
• Collect urine sample for central laboratory urinalysis; 
• Collect blood sample for safety laboratory testing (hematology, chemistry, and serum 
pregnancy test for females of childbearing potential) by the central laboratory; 
• Perform 12-lead ECG; and 
• Confirm eligibility based on inclusion/exclusion criteria (including confirmation of PSVT 
diagnosis per the MoOP). 
6.2 
Test Dose Randomization Visit 
The Test Dose Randomization Visit must occur within 28 days after the Screening Visit. The 
following procedures will occur at the Test Dose Randomization Visit: 
• Confirm eligibility (additional eligibility criteria apply to pass the test dose at the Test Dose 
Randomization Visit only); 
• Record the CMS identifier number in the EDC system for the test dose; 
• Train the patient on: 
o Symptom identification, assessment, and reporting; 
o Contacting the Telephone Coach (if possible) who will guide the patient through the study 
procedures. For the Test Dose Randomization Visit only, the Telephone Coach should be 
contacted once the 10 minutes of baseline recording with the CMS is complete. If the 
patient is unable to reach the Telephone Coach, he/she may proceed with the procedures 
using the printed and electronic guides provided; 
o Set up and use of the CMS; 
o Performance of VMs; 
o Recording of time of administration of study drug; 
o Administration of etripamil NS (as described in the MoOP); 

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o Use of patient diary; and 
o Reporting of AEs to the sites during the study for evaluation; 
• Record concomitant medications; 
• Record any post-dose AEs; 
• Collect urine sample for pregnancy test for females of childbearing potential;  
• All patients will receive a test dose of etripamil NS 70 mg before randomization. Patients 
should be placed in a comfortable sitting position for a minimum of 5 minutes before starting 
the test dose administration procedure. The procedure must not be carried out in the standing 
or fully supine position: 
o Apply the CMS to record cardiac activity at least 10 minutes pre-test dose. The CMS 
recording should continue for at least 30 minutes post-test dose. A caregiver may assist 
with this procedure; 
o Perform a 12-lead ECG recording for 10 seconds within approximately 30 minutes 
pre-test dose and 30 minutes post-test dose. The paper speed for these recordings should 
be 25 mm/sec. A continuous on-screen ECG monitoring (at least 2-leads) is required from 
the beginning until the end of the test dose; 
o Vital signs (SBP, diastolic blood pressure [DBP], and HR) will be obtained within 
10 minutes pre-test dose and every 5 minutes (±1 minute) for 30 minutes post-test dose; 
o Additional vital signs and ECGs should also be performed in the event of patient 
symptoms, and the time and nature of those symptoms as well as potential medical 
interventions should be reported in the EDC; in this case, ECG and vital sign monitoring 
should continue until symptoms disappear; 
o Perform a VM; 
o Push the CMS event marker button;  
o Administer etripamil NS 70 mg; 
o In case of AE, bradycardia, hypotension, arrhythmia or AV block, the patient will stay 
under medical surveillance until the symptoms and anomalies disappear; and 
• Send (transmit) the CMS ECG to the cardiac monitoring core laboratory. 
Patients who pass the test dose will be randomized using the IRT to obtain the study kit assignment. 
Each randomized patient will receive a study kit, which includes the blinded study drug (placebo 
or etripamil NS), a CMS (the CMS identifier number will be recorded in the EDC system for the 
test dose), a study identification card, patient’s study instructions, and other study-related material. 
Randomized patients will also be provided with a patient diary to be completed after experiencing 
a PSVT episode. The patient diary collects information about symptoms of the patient’s PSVT 
episode and includes a TSQM. If the CMS ECG test dose report is delayed for any unforeseen 
reason, patients will be allowed to leave and return to the site another day for randomization. 

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Patients who fail the test dose will proceed in the study as follows: 
• If the Investigator identifies a possible reversible cause of the initial test dose 
failure (e.g., concomitant medication such as beta-blocker), a re-challenge with a new test dose 
of etripamil NS 70 mg within a 14-day window from the initial test dose will be possible after 
elimination of the reversible cause (e.g., withdrawal of concomitant therapy with the 
appropriate washout period). Patients may be randomized if they pass the second test dose, and 
the cause of the test dose failure is eliminated for the duration of the study; or 
• If the Investigator cannot identify a reversible cause of the initial test dose failure, or if the 
potential cause cannot be modified (e.g., necessary antihypertensive drug to control blood 
pressure), patients will not be randomized and will complete a Final Study Visit. Patients who 
fail the test dose will be part of the Test Dose Only Population, including all patients who 
received at least 1 test dose of etripamil NS 70 mg (see Section 9.1). 
6.3 
Follow-up Visits 
Follow-up Visits will occur approximately monthly from the time of randomization and can be 
conducted by patients returning to the investigative site (preferred) or by the site personnel 
contacting patients by telephone. A missing Follow-up Visit will not be considered a deviation of 
the protocol, and patients will not be excluded from the study for missing their monthly Follow-up 
Visits. 
The following procedures will occur at this visit: 
• Ensure the patient continues to be eligible for the study; 
• Re-train the patient on (re-training procedures are described in the MoOP): 
o Symptom identification, assessment, and reporting; 
o Contacting the Telephone Coach (if possible) who will guide the patient through the study 
procedures. If the patient is unable to reach the Telephone Coach, he/she may proceed 
with the procedures using the printed and electronic guides provided; 
o Set up and use of the CMS; 
o Performance of VMs; 
o Recording of time of administration of study drug; 
o Use of patient diary; 
o Reporting of AEs to the sites during the study for evaluation; and 
o Administration of study drug (etripamil or placebo) with BDS (as described in the MoOP); 
• Record concomitant medications. If the patient has started any medication that could interact 
unfavorably with etripamil (e.g., blood pressure, AV conduction), the Investigator may 
conduct an additional test dose. The Medical Monitor may be consulted when deciding if an 
additional test dose is required. If an additional test dose is required, the same procedures as 
described in the Test Dose Randomization Visit will be followed; and 
• Record any AEs. 

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An on-site Follow-up Visit must occur if patients experience an episode of PSVT for which they 
apply the CMS, and the episode is subsequently terminated by a VM. In this case, it is mandatory 
for patients to be on-site for the Follow-up Visit so that site personnel can ensure that all data has 
been downloaded from the CMS device. Patients will retain their CMS and remain in the study for 
subsequent episodes of PSVT. 
6.4 
Treatment Period 
All randomized patients will be instructed to perform the steps described in Section 3.2.4 after they 
have identified the symptoms they consider to be consistent with an episode of PSVT. A caregiver 
may help the patient with these procedures, and this should be annotated in the eCRF. 
In all cases, the presence of an episode of PSVT and termination will be evaluated by an 
independent Adjudication Committee. The Adjudication Committee’s evaluation will be done 
using the complete CMS ECG recorded during the patient’s PSVT episode. 
6.5 
Final Study Visit 
A Final Study Visit will occur at the study site within 7 days after the final Treatment Period day 
with usage of the study drug, or if for any other reason the patient has completed participation in 
the study. 
This visit will occur under the following circumstances: 
• The patient fails the test dose; 
• The patient self-administers study drug (or with the help of a caregiver) for an episode of PSVT 
whether or not the episode is subsequently adjudicated as a true episode of PSVT; 
• The patient has started treatment with a prohibited medication before experiencing an episode 
of PSVT; 
• The patient withdraws consent from the study for any reason; 
• The Sponsor decides to terminate the study for any reason; or 
• The patient is deemed to have completed participation in the study for any other reason. 
For patients who failed the test dose, the following procedures will be performed: 
• Identify the reason for failure (predefined list is provided in the MoOP); 
• Evaluate the patient’s medical status before discharge; 
• Review the cardiac core laboratory CMS test dose report; and 
• Close the case with IRT. 
For all other patients, the following assessments will be conducted during this visit: 
• Identify reason for study completion; 
• Evaluate the patient’s medical status; 
• Review the patient’s diary entries of scoring scales; 
• Record any post-dose AEs; 

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• Collect/return the study kit, including: 
o Used or unused study drug; 
o Study identification card; and 
o Used or unused CMS; 
• Evaluate any medical intervention during the Treatment Period; 
• Perform physical examination; 
• Obtain and record vital signs (blood pressure and HR); 
• Record concomitant medications; 
• Ensure that all data from the patient’s CMS has been downloaded and sent to the cardiac 
monitoring core laboratory; 
• Perform a 12-lead ECG; 
• Collect urine sample for central laboratory urinalysis; 
• Collect blood sample for safety laboratory testing (hematology, chemistry, and serum 
pregnancy test for females of childbearing potential) by the central laboratory; 
• Assess eligibility for the open-label extension study; and 
• Close the case with IRT. 

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7 
EFFICACY ASSESSMENTS 
Efficacy assessments will be based on the data derived from CMS recordings. The Adjudication 
Committee will evaluate the complete ECG data recorded from patients to determine if a true 
PSVT episode occurred. If the event is related to a confirmed episode of PSVT, the primary 
endpoint conversion to SR after study drug administration will be adjudicated and the primary 
variable, the time to conversion, will be adjudicated for the primary efficacy analysis. 
The patient will report and rate symptoms of the episode of PSVT and its evolution as well as 
overall treatment satisfaction in the patient diary and TSQM. 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as an adjudicated termination of a positively adjudicated 
episode of PSVT (AVNRT or AVRT determination if possible) and conversion to SR for at least 
30 seconds.  
The primary efficacy endpoint will be evaluated using the time to conversion of an episode of 
PSVT to SR after study drug administration as the primary efficacy variable. 
7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will include: 
• Relief of specific symptoms (i.e., heart palpitations, rapid pulse feeling, chest pain, anxiety, 
shortness of breath, dizziness, and fainting) potentially associated with an episode of PSVT; 
and 
• Rating of TSQM. 
7.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints will include: 
• The number of positively adjudicated episodes of PSVT terminated by a VM,  
• The percentage of patients requiring additional medical intervention to terminate an episode of 
PSVT, and 
• The repeat of key efficacy endpoints in various subgroups of interest (e.g., concomitant 
medications). 
7.4 
Adjudication Process 
Each event from each patient who assesses symptoms as being caused by PSVT will be 
documented with an ambulatory CMS recording.  
The cardiac monitoring core laboratory will provide the entire 5-hour ECG captured by the CMS 
to the Adjudication Committee.  
The 
Adjudication 
Committee 
will 
comprise 
at 
least 
5 
members, 
all 
cardiac 
electrophysiologists (EPs), who are independent from the Sponsor and from Sponsor-related 
operational activities and the DSMC. The Adjudication Committee will review all data, i.e., the 
entire 5-hour CMS recording, sent to them by the core laboratory for each study episode.  

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The EPs will adjudicate the following:  
1. The presence of PSVT (AVNRT or AVRT determination if possible);  
Note: Sinus tachycardia, atrial tachycardia, atrial fibrillation, and atrial flutter will not be 
included in the Efficacy Population. 
2. Termination of PSVT due to VM if PSVT was present; and  
3. Termination of PSVT to SR for at least 30 seconds after study drug administration if PSVT 
was present.  
Any bias will be limited by the adjudicators being fully blinded to the patient identifiers and study 
treatment. 
The Adjudication Committee will also adjudicate the time between study drug administration and 
PSVT termination or time to censoring if termination is not observed or is due to a medical 
intervention (e.g., use of IV adenosine in a medical care facility). The Adjudication Committee 
will review the full disclosure of the 5-hour CMS recording and will report arrhythmias and AV 
blocks in the eCRF. 
Further details are provided in the NODE-301 study Adjudication Committee Charter. 

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8 
SAFETY ASSESSMENTS 
Safety variables will include clinical AEs, vital signs (blood pressure and HR), laboratory 
testing (hematology, chemistry, and urinalysis), arrhythmias, and conduction disorders detected 
on surface ECG or CMS recordings.  
During the etripamil test dose period, vital signs, SBP, DBP, HR measurements, arrhythmia, 
conduction disorders on the ECGs, and clinical AEs will be recorded. These data will be reported 
in the Overall Safety Population. These variables will be reported in the pre-identified relevant 
subgroups of patients (e.g., those receiving concomitant beta-blockers, calcium channel blockers, 
or other drugs known to reduce blood pressure or alter AV conduction) for pre-defined subgroup 
analyses. 
During the Treatment Period, safety variables will be recorded. 
8.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. An AE can therefore be any unfavorable and/or unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of study drug, whether or not related to the study drug. All AEs, including observed or 
volunteered problems, complaints, or symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored from the time 
of test dose administration (i.e., Test Dose Randomization Visit) until study participation is 
complete (i.e., after the Final Study Visit). Patients will be instructed to report any AE they 
experience to the Investigator. Investigators will assess for AEs at each visit and record event(s) 
on the appropriate AE eCRF.  
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). 
Any medical condition that is present when a patient is screened or present at baseline that does 
not deteriorate will not be reported as an AE. However, medical conditions or signs or symptoms 
present at baseline that change in severity or seriousness at any time during the study will be 
reported as an AE(s). 
Clinically significant abnormal assessments that are detected during the study or are present at 
baseline 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. Clinically significant abnormal assessments occurring 
during the study will be followed until repeat tests return to normal, stabilize, or are no longer 
clinically significant. 
The Investigator will rate the severity (intensity) of each AE as mild, moderate, or severe, and will 
also categorize each AE as to its potential relationship to study drug using the categories of not 
related, unlikely related, possibly related, probably related, or definitely related (see Section 8.1.3). 

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8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an AE is at least a reasonable possibility (i.e., the 
relationship cannot be ruled out). 
8.1.2 
Unexpected 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. 
8.1.3 
Assessment of Adverse Events by the Investigator 
8.1.3.1 
Assessment of severity 
Mild – An event that is usually transient in nature and generally does not interfere with normal 
activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating, causing an inability to work or perform normal activities. 
8.1.3.2 
Causality assessment 
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. 
• Definitely related – An event that is clearly associated with study drug administration.  
An SAE that has been assessed as "possibly related" "probably related" or "definitely related" will 
be classified as "related" for regulatory reporting purposes. An SAE that has been assessed as "not 
related" or "unlikely related" will be classified as "unrelated" for regulatory reporting purposes.  

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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. 
o The known pharmacological properties (e.g., absorption, distribution, metabolism, and 
excretion) of the study drug will be considered. 
In the event of death, a single cause of death will be recorded as an AE. Death is an outcome and 
is not considered an AE. An exception is sudden death, when the cause is unknown. 
8.2 
Serious Adverse Event 
An AE or suspected adverse reaction is considered serious if, in the view of either the Investigator 
or the Sponsor, it results in any of the following outcomes: 
• Death, 
• A life-threatening AE, 
o NOTE: An AE or suspected adverse reaction is considered “life-threatening” if, in the view 
of either the Investigator or Milestone, its occurrence places the patient at immediate risk 
of death. It does not include an event that, had it occurred in a more severe form, might 
have caused death. 
• An event that requires hospitalization or prolongation of existing hospitalizations, 
o Any hospital admission will be considered an inpatient hospitalization, regardless of 
duration. An Ablation for treatment of PSVT will not be considered as an SAE. An 
emergency room visit without hospital admission will not be recorded as an SAE under 
this criterion, nor will hospitalization for a procedure scheduled prior to study drug 
administration. However, unexpected complications and/or prolongation of hospitalization 
that occur during elective surgery will be recorded as AEs and assessed for seriousness; 

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o Admission to the hospital for social or situational reason (e.g., no place to stay or live too 
far away to come for hospital visits) will not be considered inpatient hospitalizations. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, 
• A congenital anomaly/birth defect, or 
• An important medical event. 
o Important medical events that may not result in death, a life-threatening situation, or 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent any of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the 
development of drug dependency. 
8.3 
Serious Adverse Event Reporting – Procedures for Investigators 
Initial Reports 
Any SAE (as defined in Section 8.2) occurring from the time of study drug administration at the 
Test Dose Randomization Visit through the Final Study Visit must be reported to Medpace Clinical 
Safety within 24 hours of awareness of the event. Any SAE occurring within a 30-day follow-up 
period after taking the study drug that the Investigator considers related to study drug 
administration must be reported in the same manner.  
To report the SAE, complete the SAE form electronically in the EDC system for the study. When 
the form is completed, Medpace Clinical Safety personnel will be notified electronically and will 
retrieve the form. 
To report an SAE if the EDC system is not available: 
• Send an e-mail to Medpace Clinical Safety at medpace-safetynotification@medpace.com or 
call the Medpace SAE Reporting Line (number listed below), 
• Fax/e-mail a completed SAE form to Medpace Clinical Safety (number and e-mail address 
listed below), and 
• When the EDC system becomes available, the SAE information must be entered within 
24 hours of the system becoming available. 
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 via e-mail or fax. 
Medpace Clinical Safety Contact Information  
Medpace Clinical Safety 
SAE Reporting Line (USA/Canada): +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax (USA/Canada): +1-866-336-5320 or +1-513-570-5196 
E-mail: medpace-safetynotification@medpace.com 

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Medical Monitor 
Silvia Shardonofsky, MD 
Telephone: +1-514-336-0444, ext. 235 
E-mail: sshardonofsky@milestonepharma.com 
The Investigator is required to submit SAE reports to the Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) in accordance with local requirements. All Investigators involved in 
clinical studies using the same study drug will receive any safety alert notifications for onward 
submission to their local IRB/IEC as required. All reports sent to Investigators will be blinded. 
Follow-up Reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (e.g., persistent impairment), 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 reports) via e-mail or fax. If it is not possible to access the EDC system, 
follow the procedures outlined above for the initial reporting of SAEs. 
8.4 
Pregnancy Reporting 
Patients are requested to report to the Investigator any pregnancies of themselves or their partner(s) 
(informed consent is required for partner[s] prior to collecting any information) that occur within 
30 days of study drug administration. The Investigator should report the pregnancy to Medpace 
Clinical Safety (see Section 8.3) within 24 hours of notification. If a patient becomes pregnant 
during the study, the patient should be withdrawn from the study and Final Study Visit procedures 
should be performed.  
After the pregnancy is reported, Medpace Clinical Safety personnel will forward the exposure in 
utero form to the Investigator for completion. The Investigator should monitor the patient/partner 
until completion of the pregnancy. If the pregnancy ends for any reason before the anticipated date, 
the Investigator should notify Medpace Clinical Safety. At the completion of the pregnancy, the 
Investigator will document the outcome of the pregnancy. If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator should follow 
reporting procedures for an SAE. 
8.5 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the United States Food and Drug 
Administration (FDA), Health Canada, and applicable competent authorities in all the Member 
States concerned, and in any case no later than 7 days after knowledge by the Sponsor of such a 
case, and that relevant follow-up information will subsequently be communicated within an 
additional 8 days. 

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All other suspected unexpected serious adverse reactions will be reported to the FDA, Health 
Canada, and applicable competent authorities concerned as soon as possible but within a maximum 
of 15 days of first knowledge by the Sponsor. 
The Sponsor will also inform all Investigators as required. 
8.6 
Medical Device Complaints 
Medical device complaints will be reported according to the requirements of local law and 
legislation. 
In the United States, medical device complaints or product problems with the spray device may be 
voluntarily reported by the Investigator to the FDA through MedWatch, the FDA Safety 
Information and Adverse Event Reporting Program. 
8.7 
Clinical Laboratory Evaluations 
Standard clinical laboratory profiles for hematology, serum chemistry, and urinalysis will be 
evaluated at the Screening Visit and at the Final Study Visit. Serum pregnancy tests will be 
performed on female patients of childbearing potential at the Screening Visit and at the Final Study 
Visit, and a urine pregnancy test will be performed at the Test Dose Randomization Visit. 
See Appendix B for a list of clinical laboratory analytes. 
8.8 
Vital Signs 
Vital signs (i.e., SBP, DBP, and HR) will be obtained at the Screening Visit, at the Test Dose 
Randomization Visit, and at the Final Study Visit. At the Test Dose Randomization Visit, vital 
signs will be obtained after at least a 5-minute rest in a seated position and within 10 minutes 
before test dose administration. Following etripamil administration, vital signs will be obtained 
every 5 minutes (±1 minute) for 30 minutes. Vital signs will be obtained if the patient reports any 
symptom potentially related to drop in blood pressure. 
8.9 
Electrocardiograms 
A 12-lead ECG will be performed at the Screening Visit, at the Test Dose Randomization Visit, 
and at the Final Study Visit.  
During the Test Dose Randomization Visit, patients should be sitting comfortably for a minimum 
of 5 minutes before starting the procedure. The test dose procedure must not be carried out in the 
standing or fully supine position. The MoOP will provide the details for interpreting ECGs and 
on-screen continuous monitoring. 
8.10 
Physical Examinations 
A physical examination will be performed at the Screening Visit and at the Final Study Visit. Body 
height and weight will be measured at the Screening Visit. 

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9 
STATISTICS 
A separate Statistical Analysis Plan (SAP) will be prepared to provide a full description of the 
analyses to be performed for this study. 
9.1 
Analysis Populations 
The Efficacy Population includes all randomized patients who use the study drug to treat a 
positively adjudicated episode of PSVT. This population does not include patients who take the 
study drug for a negatively adjudicated episode of PSVT (i.e., symptoms not associated with an 
episode of PSVT). The subjects will be included in the treatment arm (placebo or double-blind 
study drug) in which they were randomized. 
The modified Intent-to-Treat (mITT) Population includes all randomized patients who take the 
randomized study drug, not during a test dose visit. The subjects will be included in the treatment 
arm (placebo or double-blind study drug) in which they were randomized. 
The Test Dose Only Population includes all patients who receive the test dose of etripamil NS 
70 mg, but do not receive randomized drug (Overall Safety Population, minus the Safety 
Population). The Test Dose Only Population will also include pre-identified relevant subgroups of 
patients (e.g., those receiving concomitant beta-blockers, calcium channel blockers, or other drugs 
known to reduce blood pressure or alter AV conduction) for pre-defined subgroup analyses. 
The Safety Population includes all randomized patients who take the study drug, not during a test 
dose visit. The subjects will be included in the treatment arm (placebo or double-blind study 
drug) according to actual received treatment. 
The Overall Safety Population includes the Safety Population and the Test Dose Only Population. 
9.2 
Statistical Methods 
9.2.1 
Patient Disposition and Demographic/Baseline Characteristics 
The numbers and percentages of patients will be provided for patient disposition and for each study 
population. For randomized patients who discontinue from the study, the primary reason for 
discontinuation will be listed and summarized by treatment group. 
Summary statistics will be provided by treatment group for demographic characteristics (e.g., age, 
gender, race, and ethnicity) and for baseline disease variables. 
9.2.2 
Study Drug Administration and Concomitant Medications 
Log entries detailing the IN administration of the test dose and the administration of the study 
drug (etripamil or placebo) to randomized patients will be listed. 
Verbatim terms for concomitant medications will be coded using the latest version of the World 
Health Organization Drug Dictionary (WHODD). The numbers and percentages of patients in each 
treatment group taking concomitant medications will be summarized by anatomical therapeutic 
chemical classification and preferred term. 

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9.2.3 
Analysis of Efficacy 
The efficacy analyses will be performed on the Efficacy Population. Additional sensitivity efficacy 
analyses and exploratory efficacy analyses will be performed on the mITT Population.  
The data from patients in Part 1 will be included in pivotal analyses. Pivotal analyses will include 
safety; and primary, secondary, and exploratory efficacy analyses for Part 1 only.  
The data from patients in Part 2 will be combined with that from Part 1 and will be included in 
exploratory analyses. Exploratory analyses will include safety; and primary, secondary, and 
exploratory efficacy analyses for Parts 1 and 2 combined. 
9.2.3.1 
Primary efficacy analysis 
The primary efficacy variable is the time to conversion of an episode of PSVT to SR after study 
drug administration. 
Only episodes of true PSVT that occur by the date of the adjudication of the 150th episode of true 
PSVT will be included in the primary efficacy analysis. 
For the primary efficacy endpoint analyses, the proportional hazards assumption will be tested first 
by examining plots of complementary log-log (event times) versus log (time). If the proportional 
hazard assumption remains valid the statistical analysis for the time to conversion will be 
performed using the log-rank test. If the proportional hazard assumption raises concerns, the 
statistical analysis for time to conversion will be performed using the Peto-Peto test. Patients who 
did not convert after 5 hours following study drug administration or who converted following 
medical assistance will be censored at 5 hours or at the time of medical assistance (whichever is 
earliest). The hazard ratio and 95% confidence interval (CI) will be calculated using the Cox 
proportional hazards model. If non-proportional hazards are observed, a stratified Cox regression 
model or an extended Cox regression model will be used, as appropriate. 
In addition to the primary analysis of the primary endpoint, Kaplan-Meier estimates of time to 
conversion will be calculated and reported as a Kaplan-Meier plot. Conversion rates at 3, 5, 10, 
15, 20, 30, 60, and 90 minutes after study drug administration will be reported for the etripamil 
group and the placebo group. The odds ratio (OR), and the CI for the OR, will be calculated. The 
Kaplan-Meier estimate of the time at which 25%, 50%, and 75% of episodes of PSVT conversions 
occur will be calculated. 
A sensitivity analysis for the primary efficacy endpoint will be performed on the mITT Population. 
In this analysis, the time to PSVT episode conversion will include “misidentification of PSVT by 
the patient.” All of these patients will be censored at the conversion of the non-reentry 
supraventricular tachycardia to SR or at 5 hours if conversion is not observed or if there were no 
tachycardia observed at all. 
9.2.3.2 
Secondary efficacy analysis 
For the secondary efficacy endpoint analyses, relief of specific symptoms associated with the 
termination of an episode of PSVT by the study drug will be analyzed by comparing the numeric 
scoring scale scores in the 2 treatment groups, and treatment satisfaction will be analyzed by 
comparing the rating of TSQM in the 2 treatment groups. 

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9.2.3.3 
Exploratory efficacy analyses 
Exploratory efficacy endpoint analyses will include descriptive statistics of the number of patients 
requiring additional medical intervention to terminate an episode of PSVT and descriptive 
statistics of the number of positively adjudicated episodes of PSVT converted by performing a 
VM. 
The primary, secondary, and subgroup analyses (e.g., concomitant medications) for efficacy may 
be repeated in all patients (Parts 1 and 2).  
All statistical analyses will be described in detail in the SAP. 
9.2.4 
Analysis of Safety 
Safety data will be summarized with descriptive statistics. Continuous safety data will be presented 
with n, minimum, maximum, median, mean, and standard deviation, whereas discrete safety data 
will be summarized with frequency counts and percentages. 
Safety summaries will be presented for patients in Part 1 of the study. Additional safety analyses 
will be conducted for all patients (Parts 1 and 2).   
9.2.5 
Sample Size Determination 
It is assumed that 30% of the episodes of PSVT will be converted to SR in the placebo group and 
70% in the etripamil group at 10 minutes. Based on these numbers and assuming exponential 
survival curves, a hazard ratio of 3.38 is estimated. This represents a difference in median times to 
conversion of 13.6 minutes (median time to conversion of 5.8 minutes and 19.4 minutes in the 
etripamil and placebo group, respectively). These assumptions are based on results obtained in the 
NODE-1 study (MSP-2017-1109). 
Assuming a type I error rate of alpha = 0.01 and a 2:1 ratio in the number of positively adjudicated 
episodes of PSVT etripamil:placebo, a minimum of 46 positive conversion events would be 
required in order to attain 90% power on the primary variable of time to conversion (using a 
2-sided log-rank test). 
However, since patients will be randomized before they have a qualifying episode of PSVT, it is 
unlikely that the 2:1 etripamil:placebo PSVT episodes ratio will match the 2:1 randomization ratio. 
In such a case, it is preferable to target a higher sample size to cover for the worst-case scenarios 
in terms of unbalance. 
A total of 150 positively adjudicated PSVT episodes will ensure at least 90% power for extreme 
cases of unbalance in the etripamil:placebo PSVT episodes ratio.  
Only episodes of true PSVT that occur by the date of the adjudication of the 150th episode of true 
PSVT will be included in the primary efficacy analysis. 
It is anticipated that as many as 500 patients may need to be randomized in order to accrue a 
sufficient number of patients in the Efficacy Population within 18 months. 

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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by CRAs during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data have 
been accounted for and electronically signed by the Investigator. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (CFR) §11 and other appropriate international regulations. All passwords will be 
strictly confidential.  
10.1.4 
Medical Information Coding 
For medical information, the latest versions of the following thesauri will be used: 
• The Medical Dictionary for Regulatory Activities for medical history and AEs, and 
• The WHODD for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs should be reviewed and electronically signed by the Investigator who signed the 
protocol. 
10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, CMS ECG summary reports, 
inventory of study kits and test doses, regulatory documents, and other Milestone correspondence 
pertaining to the study must be kept in the appropriate study files at the site. Source data are defined 
as all information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the evaluation and reconstruction 
of the clinical study. Source data are contained in source documents (i.e., original records or 
certified copies). These records will be retained in a secure file for the period set forth in the clinical 

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study agreement or as required by the local law. Prior to transfer or destruction of these records, 
Milestone must be notified in writing and be given the opportunity to further store such records. 

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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
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 
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. 
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. 

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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, MoOP, 
eCRFs and procedures for their completion, informed consent process, 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. 
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 
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. 
11.6 
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. 

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11.7 
Monitoring Committees 
11.7.1 
Steering Committees 
The Steering Committee will be responsible for the scientific oversight of the study. The Steering 
Committee Chair will review the original protocol and potential amendments. 
Further details are provided in the NODE-301 study Steering Committee Charter. 
11.7.2 
Data and Safety Monitoring Committee 
The DSMC will review the accumulating safety data on a regular basis to detect any safety issue 
that could be related to the study drug or the protocol procedures involved in the patient’s 
management of an episode of PSVT. The committee will be entitled to request a review of 
unblinded safety data. 
Further details are provided in the NODE-301 study DSMC Charter. 
11.7.3 
Adjudication Committee 
The Adjudication Committee will comprise at least 5 members, all cardiac EPs, who are 
independent from the Sponsor and from Sponsor-related operational activities and the DSMC. The 
Adjudication Committee will review all data, i.e., the entire 5-hour CMS recording, sent to them 
by the core laboratory for each study episode. 
The EPs will adjudicate the following:  
1. The presence of PSVT (AVNRT or AVRT determination if possible);  
Note: Sinus tachycardia, atrial tachycardia, atrial fibrillation, and atrial flutter will not be 
included in the Efficacy Population. 
2. Termination of PSVT due to VM if PSVT was present; and  
3. Termination of PSVT to SR for at least 30 seconds after study drug administration if PSVT 
was present.  
Any bias will be limited by the adjudicators being fully blinded to the patient identifiers and study 
treatment. 
The Adjudication Committee will also adjudicate the time between study drug administration and 
PSVT termination or time to censoring if termination is not observed or is due to a medical 
intervention (e.g., use of IV adenosine in a medical care facility). 
The conclusion of the Adjudication Committee will be used in the primary and secondary analyses. 
The Adjudication Committee will review the secondary ECG safety endpoints (i.e., arrhythmia 
and conduction disorders). 
The adjudication process is described in Section 7.4. 
Further details are provided in the NODE-301 study Adjudication Committee Charter. 

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11.8 
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. 
11.9 
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. 
11.10 
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. 

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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace 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. In this 
case, the situation must be documented and reported to the IRB/IEC within 5 working days. 
12.2 
Address List 
12.2.1 
Sponsor 
Milestone Pharmaceuticals Inc. 
1111 Dr. Frederik-Philips Blvd., Suite 420 
Saint-Laurent, QC H4M 2X6, Canada 
Telephone: +1-514-336-0444 
12.2.2 
Contract Research Organization 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227, USA 
Telephone: +1-800-730-5779 
12.2.3 
ECG Core Laboratory for Test Dose CMS Data and CMS Monitoring 
Preventice Solutions, Inc. 
1717 N Sam Houston Parkway West, Suite 100 
Houston, TX 77038, USA 
Telephone: +1-888-747-1442 
12.2.4 
ECG Core Laboratory for Primary Endpoint Adjudication 
Cardiovascular Research Foundation 
1700 Broadway, 9th Floor 
New York, NY 10019, USA 
Telephone: +1-646-434-4595 
12.2.5 
Study Drug Distribution and Accountability 
Bellwyck Pharma Services 
8946 Global Way 
West Chester, OH 45069, USA 
Telephone: +1-513-874-1200 
Fax: +1-513-874-1201 

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12.2.6 
Medpace Clinical Safety 
Medpace Clinical Safety 
5375 Medpace Way 
Cincinnati, OH 45227, USA 
SAE Reporting Line (USA/Canada): +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax (USA/Canada): +1-866-336-5320 or +1-513-570-5196 
E-mail: medpace-safetynotification@medpace.com 
12.2.7 
Biological Specimens 
Medpace Reference Laboratories LLC 
5365 Medpace Way 
Cincinnati, OH 45227, USA 
Telephone: +1-800-749-1737 
Fax: +1-800-705-2177 

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13 
REFERENCES 
1. 
Issa ZF, Miller JM, Zipes DP. Clinical arrhythmology and electrophysiology: a 
companion to Braunwalds’s Heart Disease. 2nd ed. Philadelphia, PA: Elsevier Saunders; 
2010. 
2. 
Krikler DM, Spurrell RA. Verapamil in the treatment of paroxysmal supraventricular 
tachycardia. Postgrad Med J. 1974;50(585):447-453. 
3. 
Ferguson JD, DiMarco JP. Contemporary management of paroxysmal supraventricular 
tachycardia. Circulation. 2003;107(8):1096-1099. 
4. 
DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L. Adenosine: 
electrophysiologic effects and therapeutic use for terminating paroxysmal 
supraventricular tachycardia. Circulation. 1983;68(6):1254-1263. 
 

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APPENDIX A:  SCHEDULE OF PROCEDURES 
Table 2. 
Schedule of Procedures 
Assessment 
Screening 
Visit 
Test Dose 
Randomization 
Visit1 
Follow-up 
Visit2 
Treatment 
Period3 
Final Study 
Visit4 
Informed consent 
X 
 
 
 
 
Eligibility 
X5 
X6 
X7 
 
 
Contact the Telephone Coach8 
 
X 
 
X 
 
Demographics/medical history 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
X 
Physical examination 
X9 
 
 
 
X 
Vital signs (blood pressure and 
heart rate) 
X 
X10 
 
 
X 
Hematology, chemistry, and 
urinalysis 
X 
 
 
 
X11 
Pregnancy test12 
X 
X 
 
 
X 
12-lead ECG13 
X 
X 
 
 
X14 
Test dose administration15 
 
X 
 
 
 
Patient training on PSVT 
episode assessments16 
 
X 
X 
 
 
Randomization (via IRT) 
 
X 
 
 
 
AEs 
 
X 
X 
X 
X 
Dispense study kit17 
 
X 
 
 
 
Ensure all CMS data was 
downloaded and send to cardiac 
monitoring core laboratory 
 
X 
X 
 
X 
Review the CMS report18 
 
X 
 
 
X 
Identify PSVT episode 
 
 
 
X 
 
Apply and start CMS 
 
X 
 
X19 
 
Perform VM 
 
X 
 
X 
 
Administer study drug and 
record time of dosing 
 
 
 
X20 
 
Complete patient diary and 
numeric scoring scale 
 
 
 
X 
 
Evaluate medical intervention 
during the Treatment Period 
 
 
 
 
X 
Collect study kit (used and 
unused) 
 
 
 
 
X 
Identify reason(s) for study 
completion or withdrawal 
 
 
 
 
X 
Close case with IRT 
 
 
 
 
X 
Assess eligibility for open-label 
extension study 
 
 
 
 
X 
Note: Prospective study patients will be asked to sign the informed consent form before the commencement of any 
study-related assessments or procedures. Once the informed consent is signed, patients will be considered enrolled in the 
study. 
1. 
The Test Dose Randomization Visit must occur within 28 days after the Screening Visit. The CMS identifier number will 
be recorded in the EDC system for the test dose. A re-challenge with a new test dose of etripamil NS 70 mg within a 
14-day window from the initial test dose will be possible after elimination of the reversible cause (e.g., withdrawal of 
concomitant therapy with the appropriate washout period). 
2. 
Follow-up Visits to occur approximately monthly via site visit (preferred) or telephone (site visit required for patients 
who have an episode of PSVT terminated by VM). 

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3. 
Treatment Period occurs from randomization until patient has an episode of PSVT treated with study drug. 
4. 
Final Study Visit to occur within 7 days after the final Treatment Period day for patients who fail the test dose or have an 
episode of PSVT treated with study drug. For patients who failed the test dose, the reason for failure will be 
identified (predefined list is in the MoOP), the patient’s medical status will be evaluated before discharge, the CMS ECG 
summary report will be reviewed, and the case will be closed with IRT. For all other patients, the reason for study 
completion will be identified, the patient’s medical status will be evaluated, the patient diary entries of scoring scales will 
be reviewed, and the case will be closed with IRT. 
5. 
Confirmation of eligibility at Screening includes confirmation of PSVT diagnosis. Acceptable source documents to 
confirm the PSVT diagnosis are provided in the MoOP. 
6. 
Additional eligibility criteria apply to pass the test dose at the Test Dose Randomization Visit only. 
7. 
Eligibility assessments at Follow-up Visits based on review of patient’s concomitant medications or changes in health 
status.  
8. 
If possible. The Telephone Coach will guide the patient through the study procedures. For the Test Dose Randomization 
Visit only, the Telephone Coach should be contacted once the 10 minutes of baseline recording with the CMS is 
complete. If the patient is unable to reach the Telephone Coach, he/she may proceed with the procedures using the 
printed and electronic guides. 
9. 
Including height and weight.  
10. Vital signs will be obtained within 10 minutes pre-test dose and every 5 minutes (±1 minute) for 30 minutes post-test 
dose. 
11. Blood and urine tests will be performed on all patients who pass the test dose and are randomized. 
12. For females of childbearing potential. Serum pregnancy test required at the Screening Visit and at the Final Study Visit, 
and a urine test required at the Test Dose Randomization Visit. 
13. The paper speed for these recordings should be 25 mm/sec. A continuous on-screen ECG monitoring (at least 2-leads) is 
required from the beginning until the end of the test dose for the Test Dose Randomization Visit. 
14. A 12-lead ECG will be performed on all patients who pass the test dose and are randomized. 
15. Before randomization, all patients will be trained on VMs and will receive a test dose of etripamil NS 70 mg to evaluate 
tolerability. The test dose procedures are described in the MoOP. Patients who pass the test dose will be randomized. If 
the patient fails the first test dose and the Investigator can identify a potential reversible cause for the failure, a second 
test dose may be administered within a 14-day window from the initial test dose. If the Investigator cannot identify a 
reversible cause, or if the potential cause cannot be modified (e.g., necessary antihypertensive drug to control blood 
pressure), patients will not be randomized and will complete a Final Study Visit. Patients who fail the test dose will be 
part of the Test Dose Only Population. During each patient’s Test Dose Randomization Visit, the test dose CMS ECG 
data will be reviewed by the cardiac monitoring core laboratory, and a report will be sent to the site. The operational 
aspects of the use of the CMS during the test dose are described in the MoOP. 
16. Randomized patients will be trained on how to identify and report symptoms, use of the Telephone Coach, set up and use 
of the CMS, performance of VMs, self-administration of study drug (as described in the MoOP), recording time of study 
drug administration, use of patient diary, and reporting AEs to the sites during the study for evaluation. A caregiver may 
assist in these procedures. 
17. The study kit will include the blinded study drug (placebo or etripamil NS), a CMS, a study identification card, patient’s 
study instructions, and other study-related material. Randomized patients will also be provided with a patient diary to be 
completed after experiencing a PSVT episode. 
18. The interpretation of the CMS ECG will be provided by the cardiac monitoring core laboratory to the site in a report 
based on the mobile system’s proprietary arrhythmia detection algorithms and automatic ECG collection. During each 
patient’s Test Dose Randomization Visit, the cardiac monitoring core laboratory will generate a summary test dose report 
within approximately 1 to 2 hours of the receipt of the ECG data. This report will be used by the site to determine if the 
patient passes or fails the test dose and if the eligibility criteria to be randomized in the study have been met. During the 
Treatment Period, the cardiac monitoring core laboratory will generate a summary report within 48 hours of the receipt 
of ECG data. The operational aspects are described in the MoOP. These reports will be sent to the site and the Medical 
Monitor. 
19. The CMS recording during an episode of PSVT should continue for at least 5 hours, regardless of treatment outcome. 
20. During the Treatment Period, study drug should only be administered if the VM does not resolve the patient’s symptoms. 
The patient will push the CMS event marker button to record the time of dosing immediately prior to self-administering 
the study drug intranasally as instructed. If symptoms of the PSVT episode have not resolved within 20 minutes after 
study drug administration, patients may seek appropriate medical care. 
AE = adverse event; CMS = Cardiac Monitoring System; ECG = electrocardiogram; EDC = electronic data capture; 
IRT = Interactive Response Technology; MoOP = manual of operations and procedures; NS = nasal spray; 
PSVT = paroxysmal supraventricular tachycardia; VM = vagal maneuver. 
 
 

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APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Gamma-glutamyl transferase 
Bicarbonate 
Aspartate aminotransferase 
Calcium 
Urea nitrogen 
Glucose 
Chloride 
Potassium 
Creatinine 
Total bilirubin 
Magnesium 
Direct bilirubin 
Inorganic phosphorus 
Estimated glomerular filtration rate 
Sodium 
 
Total protein 
 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Erythrocyte count 
Leukocyte cell count and differential 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
 
Additional Hematology 
Mean cell volume  
Mean cell hemoglobin concentration 
Mean cell hemoglobin 
 
 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
pH 
Nitrite 
Specific gravity 
Protein 
 
Urobilinogen 
 
 
Urine and Serum Pregnancy Test (for females of childbearing potential only)