Clinical trial NCT03464019
Conditions: Paroxysmal Supraventricular Tachycardia
Keywords: Paroxysmal supraventricular tachycardia cardiac monitoring atrioventricular nodal reentrant tachycardia atrioventricular reciprocating tachycardia calcium channel blocker administered at home conversion rate
Sponsor: Milestone Pharmaceuticals Inc.
Start date: 2018-06-18; Completion date: 2023-01-20
Enrollment: 1097 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a three-part, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etripamil nasal spray (NS) self-administered by participants who experienced an episode of paroxysmal supraventricular tachycardia (PSVT) in an at-home setting.

NODE-301 Part 1 included participants that received the randomized study drug to treat an episode of PSVT until the 150th positively adjudicated PSVT episode. Part 2 (also referred as the RAPID study) included participants that did not receive the randomized study drug in Part 1 and newly enrolled participants until the 180th positively adjudicated PSVT episode in Part 2. The study continued for approximately 6 months after the 180th positively adjudicated PSVT episode in Part 2 and this extension is referred to as Part 3 (also referred to as RAPID Extension).

Detailed description:
NODE-301 was a three-part, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etripamil NS self-administered by participants who experienced an episode of PSVT in an at-home setting. Each episode was documented by an ambulatory Cardiac Monitoring System (CMS) that was placed on the chest by the participants or caregiver when symptoms begin and recorded at least 5 hours of continuous electrocardiogram (ECG).

This was an event-driven study. The study comprised of three parts: Parts 1, 2, and 3.

NODE-301 Part 1 included participants that received the randomized study drug to treat an episode of PSVT until the 150th positively adjudicated PSVT episode (January 15th, 2020). Participants were randomized to etripamil 70 mg or placebo in a 2:1 ratio. Participants had a Test Dose Randomization Visit where they received 70 mg etripamil in sinus rhythm and a Treatment Period during which they could administer the randomized study drug during a perceived episode of PSVT.

Part 2 (also referred as the RAPID study) included participants that did not use the randomized study drug to treat a perceived episode of PSVT before the Part 1 data cutoff and newly enrolled participants. Before randomization in the RAPID study, all participants received a Test Dose of etripamil consisting of an initial dose of etripamil 70 mg followed by a second dose of etripamil 70 mg 10 minutes later to evaluate tolerability and to train participants on the study procedures. After a successful Test Dose, participants in Part 2 were randomized to etripamil or placebo in a 1:1 ratio. When experiencing a PSVT episode, participants were instructed to administer a first dose of randomized study drug (70 mg etripamil or placebo) followed 10 minutes later, if PSVT symptoms persisted, by a second dose of study drug (70 mg etripamil or placebo). After having administered the randomized study drug for a perceived episode of PSVT, participants could enter an open-label period during which they had the possibility to treat a second episode of PSVT with open-label etripamil (70 mg etripamil with optional second dose of 70 mg etripamil).

Part 2 continued until the 180th positively adjudicated PSVT episode (the data on which the primary efficacy analysis of RAPID was conducted) (July 20th 2022). The study continued for approximately 6 months after the 180th positively adjudicated PSVT episode in Part 2 and this extension is referred to as Part 3 (also referred to as RAPID Extension). The design of Parts 2 and 3 were the same and therefore their results are combined in this publication.

NODE-301 study comprised 6 arms:

* 2 arms consisting of participants enrolled in Part 1 that treated a perceived episode of PSVT with randomized study drug (etripamil NS 70 mg or placebo) in a 2:1 ratio.
* 1 arm consisting of participants that only received the Test Dose in Part 1.
* 2 arms consisting of participants enrolled in Parts 2 and 3 that treated a perceived episode of PSVT with randomized study drug (etripamil NS 70 mg with optional second dose of 70 mg etripamil or placebo) in a 1:1 ratio and could be enrolled in the open-label period to treat an additional PSVT episode with etripamil
* 1 arm consisting of participants that only received the Test Dose in Parts 2 and 3.

Arms: arm 1: Self-administration of a single dose etripamil 70 mg for a perceived episode of PSVT. arm 2: Self-administration of a single dose of placebo for a perceived episode of PSVT. arm 3: Single test dose of etripamil 70 mg in sinus rhythm arm 4: Self-administration of 70 mg etripamil for a perceived episode of PSVT followed 10 minutes later by an optional second dose of 70 mg etripamil, if symptoms persisted. Participants could be enrolled in the open-label period to treat an additional PSVT episode with etripamil. arm 5: Self-administration of placebo for a perceived episode of PSVT followed 10 minutes later by an optional second dose of placebo, if symptoms persisted. Participants could be enrolled in the open-label period to treat an additional PSVT episode with etripamil. arm 6: Repeat Test Dose of etripamil 70 mg (2X 70mg) 10 minutes apart in sinus rhythm
Interventions: intervention 1: Etripamil intervention 2: Placebo intervention 3: Etripamil Test Dose
Intervention descriptions: intervention 1: Etripamil administered via the Aptar Pharma Nasal Spray Bidose System, supplied as prefilled devices packaged into child-resistant boxes with instructions for use provided in the study drug box. intervention 2: Placebo administered via the Aptar Pharma Nasal Spray Bidose System, supplied as prefilled devices packaged into child-resistant boxes with instructions for use provided in the study drug box. intervention 3: During the Test Dose, etripamil administered via the Aptar Pharma Nasal Spray Bidose System, supplied as prefilled devices packaged into child-resistant boxes with instructions for use provided in the study drug box.

Protocol documents:
Prot_002.pdf: 
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. 
 
 


Milestone Pharmaceuticals Inc. 
Clinical Study Protocol MSP-2017-1138 
Confidential & Proprietary 
 
Version 5.0, 09 July 2019 
71
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) 

SAP_003.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
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 
 
Investigational Product: 
MSP-2017 (etripamil) 
Protocol Number: 
MSP-2017-1138 (NODE-301) 
Phase: 
3 
Original Protocol: 
08 November 2017 V1 
Amendment 1 
05 January 2018 V2 
Amendment 2 
20 February 2018 V3 
Amendment 3 
04 October 2018 V4 
Amendment 4 
09 July 2019 V5 
Statistical Analysis Plan Version: 
2.0 
Statistical Analysis Plan Date: 
13 Jan 2020  
 
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/Institutional Ethics Committee and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Milestone Pharmaceuticals Inc. and that it may not be further disclosed 
to third parties. 
 




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TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................... 6 
2. 
STUDY CHARACTERISTICS................................................................................. 6 
2.1 
Study Objectives ........................................................................................................ 6 
2.1.1 
Primary Objective ............................................................................................... 6 
2.1.2 
Secondary Objectives .......................................................................................... 6 
2.1.3 
Exploratory Objectives ....................................................................................... 6 
2.2 
Study Design .............................................................................................................. 6 
2.2.1 
Treatment Regimen and Dosage ......................................................................... 8 
2.2.2 
Drug Randomization ........................................................................................... 8 
3. 
EFFICACY ASSESSMENTS ................................................................................... 9 
3.1 
Primary Efficacy Endpoint ........................................................................................ 9 
3.2 
Secondary Efficacy Endpoints ................................................................................... 9 
3.3 
Exploratory Efficacy Endpoints ................................................................................ 9 
3.4 
Adjudication Process ................................................................................................. 9 
4. 
SAFETY ASSESSMENTS ..................................................................................... 11 
4.1 
Adverse Events ........................................................................................................ 12 
4.2 
Serious Adverse Event ............................................................................................. 12 
4.3 
Pregnancy Reporting ............................................................................................... 12 
4.4 
Clinical Laboratory Evaluations .............................................................................. 12 
4.5 
Vital Signs ............................................................................................................... 12 
4.6 
Electrocardiograms .................................................................................................. 13 
4.7 
Physical Examinations ............................................................................................. 13 
5. 
STATISTICAL METHODOLOGY ........................................................................ 13 
5.1 
Procedures for Handling Missing Data.................................................................... 14 
5.2 
Definition of Censoring Data................................................................................... 14 
5.3 
Control of type 1 error ............................................................................................. 15 
5.4 
Statistical Methods................................................................................................... 15 
5.5 
Analysis Populations ............................................................................................... 15 
5.5.1 
Efficacy Population ........................................................................................... 15 
5.5.2 
Modified intent-to-treat (mITT) Population ..................................................... 16 
5.5.3 
Test Dose Only Population ............................................................................... 16 
5.5.4 
Safety Population .............................................................................................. 16 
5.5.5 
Overall Safety Population ................................................................................. 16 
5.6 
Subject Disposition .................................................................................................. 16 


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5.7 
Protocol Deviation ................................................................................................... 16 
5.8 
Demographic and Baseline Characteristics ............................................................. 16 
5.9 
Prior/Concomitant Medications ............................................................................... 17 
5.10 
Study Drug Administration ..................................................................................... 17 
5.11 
Analysis of Efficacy ................................................................................................ 17 
5.11.1 Primary Efficacy Analysis ................................................................................ 17 
5.11.2 Secondary Efficacy Analysis ............................................................................ 18 
5.11.3 Exploratory Efficacy Analysis .......................................................................... 20 
5.12 
Analysis of Safety .................................................................................................... 20 
5.12.1 Adverse Events ................................................................................................. 20 
5.12.2 Clinical Laboratory Tests .................................................................................. 21 
5.12.3 Vital Signs ......................................................................................................... 21 
5.12.4 Electrocardiograms and Cardiac Monitoring System recordings ..................... 22 
5.12.5 Physical Examination ........................................................................................ 22 
6. 
INTERIM ANALYSIS ............................................................................................ 22 
7. 
SAMPLE SIZE DETERMINATION ...................................................................... 23 
8. 
CHANGE FROM PROTOCOL .............................................................................. 23 
9. 
PROGRAMMING SPECIFICATIONS .................................................................. 24 
APPENDIX A:  SCHEDULE OF PROCEDURES ............................................................. 25 
APPENDIX B:  TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION ........................................................................................................ 27 
APPENDIX C:   PSVT SYMPTOMS RECORDS IN ECRF ............................................. 29 
APPENDIX D: CLINICALCLINICAL LABORATORY ANALYTES ............................ 30 
APPENDIX E: SUBGROUPS OF INTEREST ................................................................... 31 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term  
Definition 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
AV 
Atrioventricular  
AVNRT  
Atrioventricular Nodal Reentry Tachycardia 
AVRT  
Atrioventricular Reentrant Tachycardia 
CI 
Confidence Interval 
CMS 
Cardiac Monitoring System 
DBP 
Diastolic Blood Pressure 
DSMC 
Data Safety Monitoring Committee  
EEAC 
ECG 
ECG Events Adjudication Committee 
Electrocardiogram 
eCRF 
Electric Case Report Form 
EDC 
Electronic Data Capture 
EP 
Electrophysiology 
HR 
Heart Rate 
IRT 
Interactive Response Technology 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Medical Monitor 
MoOP 
Manual of Operations and Procedures 
NS 
Nasal Spray  
OR 
Odds Ratio 
PAC 
Premature atrial contraction  
PSVT 
Paroxysmal Supraventricular Tachycardia 
PT 
Preferred Term 
PVC 
Premature ventricular contraction 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SOC 
System Organ Class 
SR 
Sinus Rhythm 
TEAE 
Treatment Emergency Adverse Event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper Limit of Normal 
VM 
Vagal Maneuver 


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1. 
INTRODUCTION 
This document provides a description of the statistical methods and procedures to be implemented 
for the analyses of data from the Milestone NODE-301 study (protocol number MSP-2017-1138). 
No deviations from this Statistical Analysis Plan are anticipated. However, if any deviations occur, 
they will be documented in the final clinical study report. No deviation from the primary analyses 
will be considered. 
2. 
STUDY CHARACTERISTICS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
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 Paroxysmal 
supraventricular tachycardia (PSVT) in an outpatient setting. 
2.1.2 
Secondary Objectives 
The secondary objective of this study is to evaluate the safety of etripamil NS 70 mg when self-
administered by patients without medical supervision. 
2.1.3 
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 
  To evaluate the safety and efficacy of etripamil NS 70 mg in various subgroups of interest 
(e.g., concomitant medications). 
2.2 
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).  
The study will comprise of 2 parts, Part 1 and Part 2. 
Part 1 will consist of patients dosed with the double-blind study drug or discontinued from the 
study on or before the date of 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 primary, secondary, and exploratory 
efficacy analyses for patients in Part 1 only and safety analyses on all enrolled patients. Data 
from patients in Part 1 only will be unblinded after data is locked for the pivotal analysis. 


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Part 2 will consist of patients not  included in Part 1, i.e., Part 2 will consist of patients who were 
not dosed with double-blind study drug or had not discontinued the study before the date of the 
adjudication of the 150th positively adjudicated PSVT episode or were randomized after this 
date. The data from patients in Part 2 will be combined with that from Part 1 and will be included 
in exploratory analyses. Analyses after Part 2 will include safety; and primary, secondary, and 
exploratory efficacy analyses for Parts 1 and 2 combined. Data from patients in Part 2 will be 
unblinded only 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 analyses 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 analyses. 
See SAP Annex 1 for more details on analyses conducted on the Part 2 dataset. 
This study will be conducted at approximately 75 sites. 
This is an event-driven study; 46 adjudicated terminations occurring within 5 hours after study 
drug administration without external interventions are required, approximately 100 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. Since the time from 
enrollment to when patients experience their first positively adjudicated episode of PSVT treated 
with study drug cannot be predicted, the study is projected to randomize up to 500 patients. The 
final number of randomized patients and adjudicated episodes of PSVT will depend on the 
frequency and timing of episodes of PSVT during the study.  
The study will include a Screening Visit, a Test Dose Randomization Visit, Follow-up Visits, a 
Treatment Period, and a Final Study Visit. Please refer to Appendix A for the schedule of 
procedures. 
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. 
Prior to 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 


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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. 
2.2.1 
Treatment Regimen and Dosage  
The dose of etripamil to be evaluated in NODE-301 is 70 mg. The same formulation will be used 
for the Test Dose Randomization Visit and for the Treatment Period. 
The formulation of placebo reproduces the same pH as the etripamil formulation. All patients 
will receive a total of 200 microL of etripamil NS 70 mg or placebo (i.e., 100 microL in each 
nostril via the Aptar Pharma Nasal Spray Bidose System). 
2.2.2 
Drug Randomization 
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. 
Prior to randomization, all patients will receive a test dose of etripamil NS 70 mg to evaluate 
tolerability and to train patients for the procedures.  The test dose administration will take place 
at the study site under medical supervision while the patient is in sinus rhythm (SR).  Patients 
who pass the test dose will be randomized in a 2:1 ratio to etripamil NS 70 mg or placebo using 
IRT.  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, ECG 
Events Adjudication Committee (EEAC), and Clinical Research Organization (CRO) 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.  


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3. 
EFFICACY ASSESSMENTS 
Efficacy assessments will be based on the Adjudication Report provided by the ECG Event 
Adjudication Committee (EEAC) evaluating all ECG data recorded by patients during a 
symptomatic episode.  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 symptoms of the episode of PSVT and treatment satisfaction in the 
Treatment Satisfaction Questionnaire for Medication (TSQM). 
3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as an adjudicated termination of a positively 
adjudicated episode of PSVT (atrioventricular nodal reentrant tachycardia [AVNRT] or 
atrioventricular reentrant tachycardia [AVRT] determination if possible) and conversion to Sinus 
Rhythm 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. 
3.2 
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 the current episode 
of PSVT and Rating of TSQM. 
3.3 
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 
 To repeat of key efficacy endpoints in various subgroup of interest (e.g., concomitant 
medications). 
3.4 
Adjudication Process 
Each episode 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 ECG captured by the CMS to the 
EEAC. 
The EEAC 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 


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EEAC will review all data for each study episode, i.e., the entire CMS recording and the clinically 
relevant data sent by the medical monitor. 
Primary Endpoint 
1) Supraventricular tachycardia (SVT) with a narrow QRS rate greater than 100 bpm that 
excludes sinus tachycardia, atrial fibrillation, atrial flutter, or a lack of a 1:1 AV 
relationship that may suggest atrial tachycardia. 
2) Time of “Drug Taken”- the time to the nearest second that the patient event marker occurs 
and labeled as “Drug Taken” by the patient as demonstrated on an ECG strip supplied by 
Preventice (cardiac monitoring core laboratory).  If no patient event marker is present, the 
time of onset of the recording will be used as the time of ‘’Drug Taken”. If multiple event 
markers are present, the earliest event marker labeled as “Drug Taken” by the patient will 
be used as the time of “Drug Taken”. 
3) SVT analysis- AVNRT shall be considered present if no P wave is visible or there is a clear 
P wave at the terminal portion of the QRS complex.  If a P wave occurs later in the ST 
segment, AVNRT or AVRT can be present at the discretion of the reader, however the 
reader may choose the option of indeterminate if either AVNRT or AVRT are possible. 
4) Time of termination- the time to the nearest second that the arrhythmia terminates, defined 
as the time of the 1st conducted sinus P wave after termination, but only if sinus rhythm 
remains the main atrial mechanism for at least 30 seconds beyond this point. If SVT 
resumes or an alternate atrial mechanism ensues within 30 seconds of the initial sinus P 
wave, termination is not present, and analysis for termination as defined above occurring 
later in the recording is required.  However, Premature atrial contraction (PAC) or 
Premature ventricular contraction (PVC) within a primary sinus mechanism do not nullify 
termination. 
5) Vagal maneuver outcome- if PSVT is converted to SR before any patient event marker 
occurs and Medical Monitor (MM) confirms that no study drug was taken, the VM will be 
considered successful and the event will be counted in the exploratory endpoint i.e., the 
number of positively adjudicated episodes of PSVT terminated by a VM.  
6) If the patient takes the drug during a period of SR, the episode will not be part of the 
efficacy dataset (Efficacy Population), if one or several episodes of PSVT are present after 
drug administration these PSVT will be counted as recurrences.  
7) If PSVT is converted to SR before any patient marker occurs, and Medical Monitor (MM) 
confirms that study drug was taken, the patient will have been considered to have taken 
study drug while in SR, and the PSVT will not be included in the efficacy population, 
which is the population used for the primary analysis. 
Any subsequent recurrences will be noted as a comment on the adjudication case report form.  
The EPs will adjudicate the following:  
The presence of:  
1) PSVT (AVNRT or AVRT determination if possible) 
Note: Sinus tachycardia, sinus rhythm, atrial tachycardia, atrial fibrillation, and atrial flutter 
will not be included in the Efficacy Population 


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2) termination of PSVT to SR for at least 30 seconds after study drug administration if PSVT was 
present  
3) elapsed time between study drug administration and PSVT termination. If termination follows 
a medical intervention (e.g., use of IV adenosine in a medical care facility) the patient will be 
censored at the time of conversion. If PSVT is still present 5 hours after study drug administration 
the patient will be censored at 5 hours. 
4) termination of PSVT due to VM without drug administration or before drug administration 
Any bias will be limited by the adjudicators being fully blinded to the patient identifiers and study 
treatment. 
Further details are provided in the NODE-301 study ECG Events Adjudication Committee Charter. 
4. 
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 safety assessments will be summarized in some or all of 
the pre-identified relevant subgroups of patients (see Appendix E .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.  
The EEAC report data will include 
1) The occurrence of sinus tachycardia, atrial fibrillation, atrial flutter, or atrial tachycardia 
lasting longer than 30 seconds. 
2) The occurrence of PVCs greater than 6 PVCs/45 seconds. 
3) Non-sustained ventricular tachycardia defined as equal or greater than 3 wide consecutive 
beats.  
4) Any significant bradycardia, i.e., sinus rate equal or less than 40 bpm  
5) Type I AV block lasting greater than 30 sec 
6) Any occurrence of Type II or III AV block (including AV dissociation or the presence of 
more than 2 non-conducted P waves in a row). 
7) Any pause equal or greater than 3 seconds.  
8) The time of onset and offset of the first occurrence of safety endpoint arrhythmias will be 
recorded to the nearest second.  Any subsequent recurrences will be noted as a comment 
on the case report form.  
 


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4.1 
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. 
4.2 
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, 
 An event that requires hospitalization or prolongation of existing 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. 
4.3 
Pregnancy Reporting 
Patients are requested to report to the Investigator any pregnancies of themselves or their partner(s) 
that occur within 30 days of study drug administration. The Investigator should report the 
pregnancy to Medpace Clinical Safety within 24 hours of notification. 
4.4 
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 C for a list of clinical laboratory analytes. 
4.5 
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 immediately before test 
dose administration. Following etripamil administration, vital signs will be obtained every 
5 minutes for 30 minutes. Vital signs will also be obtained if the patient reports any symptom 
potentially related to drop in blood pressure. 


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4.6 
Electrocardiograms 
Safety variables will include clinical arrhythmias and conduction disorders detected on surface ECG 
or CMS recordings.  
 
Electrocardiograms  
A 12-lead ECG will be performed at the Test Dose Randomization Visit within 10 minutes pre-test 
dose and 30 minutes post-test dose. PR interval and abnormal results will be reported by the PI in the 
CRF.    
 
At the Final Study Visit a 12-lead ECG will be performed and any new anomaly will be reported by 
the PI.  
 
CMS recordings: 
During the etripamil test dose, conduction disorders will be reported from the CMS recording. In 
case of first-degree AV block, the PR interval measured on the CMS recordings, will be reported.  
 
During the Treatment Period, arrhythmias, recurrence of episodes of PSVT, and conduction disorders 
will be reported from the CMS recording.  The adjudication committee will report the following 
safety endpoints; 
1) The occurrence of atrial fibrillation, atrial flutter, or atrial tachycardia lasting longer than 30 
seconds. 
2) The occurrence of PVCs greater than 6 PVCs/45 seconds. 
3) Non-sustained ventricular tachycardia defined as equal or greater than 3 wide consecutive beats. 
4) Any significant bradycardia, i.e., sinus rate equal or less than 40 bpm  
5) Type I AV block lasting greater than 30 sec 
6) Any occurrence of Type II or III AV block (including AV dissociation or the presence of more 
than 2 non-conducted P waves in a row). 
7) Any pause equal or greater than 3 seconds. 
The time of onset and offset of the first occurrence of safety endpoint arrhythmias will be recorded to 
the nearest second.  
4.7 
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. 
5. 
STATISTICAL METHODOLOGY 
The statistical analysis will comprise of 2 round of analysis, pivotal analysis and exploratory 
analysis. 
Pivotal analysis will be conducted when the 150th positively adjudicated PSVT episode take place. 
Only patients with the double-blind study drug or have discontinued the study before the 
adjudication of the 150th positively adjudicated PSVT episode will be included in the primary, 
secondary and exploratory efficacy analysis. Safety, disposition, and demographic data will be 
presented for all enrolled patients.   


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Exploratory analysis will be conducted when the study is finished. Data from all enrolled patients 
will be included in this round of analysis.  
Based on the results of the pivotal analysis from Part 1, the exploratory analysis 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 analysis. 
5.1 
Procedures for Handling Missing Data  
All observed data will be used in the analyses and missing data will not be imputed. 
Partial dates will be imputed for the purposes of defining TEAEs as follows:   
• 
For a missing start day where the month and year are present, the start day will be set to 
the first day of the month. 
• 
For a missing start day and month where the year is present, the start day and month will 
be set to January 1st. 
• 
For a missing end day where the month and year are present, the end day will be set to 
the last day of the month. 
• 
For a missing end day and month where the year is present, the end day and month will 
be set to December 31st. 
Partial and completely missing dates will be imputed for the purposes of classifying concomitant 
medications as follows:   
• 
Partial dates will be imputed following the same algorithm as above for TEAEs. 
• 
For an entirely missing start date (i.e. day, month, and year are missing), the start date 
will be set to the date of informed consent signed unless the stop date is prior to the date of 
informed consent signed, in which case the start date will be set to the stop date. 
For an entirely missing stop date (i.e. day, month, and year are missing), the medication will be 
treated as ongoing. 
5.2 
Definition of Censoring Data 
The censoring rules will apply to the primary efficacy endpoint. 
For adjudicated episodes of PSVT, the EEAC will indicate at what time-point a patient episode 
should be censored. This should correspond to the time of first conducted p wave starting a 30-
second of SR after any medical intervention (e.g., use of IV adenosine in a medical care facility) 
or to the last available recorded time, at 5 hours if the PSVT is not terminated at 5 hours 
For patients without an adjudicated episode (i.e., patients presenting another type of tachycardia 
or no arrhythmia), the EEAC will determine the time to termination of this non-qualifying 
tachycardia and the episode will be censored at this time. If the tachycardia is not terminated at 
the end of the recording or if there were no tachycardia observed at all, the episode will be 
censored at the end of recording.  


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5.3 
Control of type 1 error 
All statistical analyses will be tested at nominal alpha of 0.01, unless specified otherwise.   
For label claim, in order to control the overall type 1 error to no more than 0.01, a gatekeeper 
strategy will be used as proposed below: 
1. Test the primary efficacy endpoint of time to conversion in the Efficacy Population at alpha of 
0.01.  
If statistically significant: 
2. Test the secondary efficacy endpoints TSQM Overall Satisfaction, Effectiveness and 
Convenience Scores in the Efficacy population at alpha of 0.01 using Holm’s approach.  
For Holm’s adjustment, the p-values are first ordered from the smallest to the largest. 
Suppose that p(1) represents the smallest p-value, p(2) the next-smallest p-value, p(3) the 
third-smallest p-value. The test begins by comparing the smallest p-value, p(1) to 0.01/3. If 
this p(1) is less than 0.0033, the treatment effect for the endpoint associated with this p-value 
is considered significant. The test then compares the next-smallest p-value, p(2) to an 
endpoint-specific alpha of 0.01/2 for the second smallest p-value. If p(2) < 0.01, then the 
treatment effect for the endpoint associated with this p(2) is also considered significant. The 
test then compares the next ordered p-value, p(3) to 0.01. 
The procedure stops, whenever a step yields a non-significant result. Once an ordered p-
value is not significant, the remaining larger p-values are not evaluated, and it cannot be 
concluded that a treatment effect is shown for those remaining comparisons. 
5.4 
Statistical Methods 
Summary tabulations will be presented that will display descriptive statistics for each treatment 
group. For continuous variables, descriptive statistics will include the number of subjects (n), 
mean, standard deviation, minimum, median, and maximum values. For categorical variables, 
descriptive statistics will include the number and percentage of subjects in each category.  
5.5 
Analysis Populations 
5.5.1 
Efficacy Population 
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, or PSVT episodes that resolve prior to taking study drug). The subjects will be 
included in the treatment arm in which they were randomized. 
 


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5.5.2 
Modified intent-to-treat (mITT) Population 
The mITT Population includes all randomized patients who take the randomized study drug,.  
The subjects will be included in the treatment arm in which they were randomized. 
 
5.5.3 
Test Dose Only Population 
The Test Dose Only (TD) Population includes all patients who receive a Test Dose but do not 
self-administer double blind randomized drug (Overall safety population, minus the safety 
population).  
5.5.4 
Safety Population 
The Safety Population includes all randomized patients who take the randomized study drug. The 
subjects will be included in the treatment arm according to actual received treatment. 
5.5.5 
Overall Safety Population 
The Overall Safety Population includes all patients who  take any study drug i.e., the Safety 
Population and the Test Dose Only Population combined. 
5.6 
Subject Disposition 
The numbers and percentages of subjects will be provided for subject disposition and for each 
study population.  
For randomized subjects who discontinue from the study, the primary reason for discontinuation 
will be listed and summarized by treatment group. 
For TD patients who do not proceed to randomization, the primary reason for discontinuation will 
be listed. 
5.7 
Protocol Deviation 
Protocol deviations are specified in the protocol deviation plan. A listing of all protocol deviations 
will be provided. 
5.8 
Demographic and Baseline Characteristics 
Summary statistics will be provided by treatment group for demographic characteristics 
(e.g., age, gender, race, and ethnicity) and for baseline disease variables (e.g., age at 
confirmation of PSVT, demonstrated history of sustained PSVT, number of PSVT in the past 
year, number of visits to emergency department in life time, and past disease or surgery). A 
listing of all demographic data will be provided. Summary statistics for demographic of special 
interest will be provided. Please refer to Appendix E for special interest subgroup. 


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Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
21.0) and summarized by treatment group. A listing of all medical history will be provided. 
5.9 
Prior/Concomitant Medications 
All prior and concomitant medications administered during the study will be coded using the 
Global March 2018 B3 version of the World Health Organization Drug Dictionary. Prior 
medications include medications that are started and stopped prior to the start date and time of 
the test dose. Concomitant medications include medications that start any time and are taken at 
any time after the start date and time of the test dose until the end of the follow-up period. 
Medications missing both start and stop dates or having a start date prior to the start of test study 
drug and missing stop date will be counted as concomitant. 
The number and percentage of subjects taking prior and concomitant medications will be 
summarized by Anatomical Therapeutic Chemical (ATC) class and preferred name by treatment 
group.  
A listing of all medications including the reported term, preferred term, ATC class, start and stop 
dates, and other relevant data will be provided. 
5.10 
Study Drug Administration 
eCRF data detailing the administration of the test dose and the administration of the study drug 
(etripamil or placebo) to randomized patients will be listed. If the study drug device is not fully 
deployed, half dose will be reported. 
5.11 
Analysis of Efficacy 
The primary and secondary 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 primary efficacy variable is the time to conversion of an episode of PSVT to SR after study 
drug administration. 
5.11.1 
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 intervention will be censored as described under section 5.2. 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. 


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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 every 30 minutes thereafter through 300 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, and descriptive statistics presented. The Kaplan-
Meier estimate of the time at which 25%, 50%, and 75% of adjudicated episodes of PSVT 
conversions occur will be calculated.   
Sample SAS code: 
**************************************************************************  
Note: STATUS = censored status (1 = censored, 0 = event occurred) 
TREATMENT = treatment group (0 = Placebo, 1= MSP-2017 70 mg)  
*************************************************************************;  
PROC LIFETEST timelist=3 5 10 15 20 30 60 90 120 150 180 210 240 270 300; 
 
TIME MINUTES*STATUS (1); 
 
STRATA TREATMENT; 
RUN; 
PROC PHREG; 
 
CLASS TREATMENT; 
 
MODEL TIME*STATUS (1) = TREATMENT; 
RUN; 
PROC FREQ; 
 
TABLES TIME * TREATMENT; 
 
EXACT OR; 
RUN; 
5.11.1.1. Sensitivity analysis 
A sensitivity analysis for the primary efficacy endpoint of time to conversion will be performed 
including all patients in the mITT Population, i.e., all patients with ‘misidentification of PSVT by 
the patient” as well as the patients who had an adjudicated PSVT who took the study drug.  
An additional sensitivity analysis for the primary efficacy endpoint of time to conversion will be 
performed on patient subgroups identified in Appendix E.  For each one of the variable identifying 
the subgroups (for example, Country, Sex, Age groups, etc.), a Cox model with each subgroup 
variable as factor, treatment and the interaction subgroup-by-treatment will be performed to 
evaluate the impact of each subgroup on efficacy. Hazard ratio and 95% CI will be presented 
within each subgroup in summary tables as well as in Forest plots.   
Censoring rules as described in section 5.2 will be followed. 
 
5.11.2 
Secondary Efficacy Analysis 
For the secondary efficacy endpoint analysis, collection of specific symptoms (i.e., heart 
palpitations, rapid pulse feeling, chest pain, anxiety, shortness of breath, dizziness, and fainting) 
associated with the termination of an episode of PSVT by the study drug will be summarized by 
treatment group.  


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The second question from TSQM will be used for the analysis of relief of specific symptoms 
which are collected for an episode. Specific symptoms are collected as a Yes/No answer for a 
patient episode in the eCRF, these symptoms include Rapid Pulse, Palpitations, Shortness of 
Breath, Chest Tightness, Feeling Dizzy or Lightheaded, Fainting or Passing Out, and Anxiety.  
The effect of etripamil on each symptom will be analyzed by taking the score on TSQM question 
2 “How Satisfied are you with the way the medication relieves your symptoms”, and comparing 
the average score between treatment groups ONLY for patients who checked “Yes” for whether 
the symptom was present.    
Treatment satisfaction will be analyzed by comparing the score of TSQM for effectiveness, 
convenience, and global satisfaction domain in the 2 treatment groups. Please refer to Appendix 
B for TSQM. 
TSQM scale scores range from 0 to 100 and no computed score should be lower or higher than 
these limits. Of note, a score can be computed for a domain only if no more than one item is 
missing from that domain. The calculations specific to each domain are presented in detail 
below: 
Effectiveness:  
([(Question 1 + Question 2 + Question 3) − 3] divided by 18) × 100 
If one item is missing: ([(Sum(the two completed items) – 2] divided by 12) * 100 
Convenience:  
([(Question 4 + Question 5 + Question 6) − 3] divided by 18) × 100 
If one item is missing: ([(Sum(the two completed items) – 2] divided by 12) * 100 
Global satisfaction:  
([(Question 7 + Question 8 + Question 9) − 3] divided by 14) × 100 
If either Item 7 or 8 is missing ([(Sum(the two completed items)) – 2] divided by 10) * 100 
If Item 9 is missing ([(Sum(Item7 and Item8)) – 2] divided by 8) * 100 
The Effectiveness, Convenience and Global satisfaction scores, and the TSQM question 2 for 
patients with specific symptoms will be analyzed using an ANOVA model. In the ANOVA 
model, the scores will be the dependent variable and treatment will be factor. The least square 
means, 95% confidence intervals and p-value will be presented.  
Sample SAS code: 
PROC MIXED; 
 
CLASS TREATMENT; 
 
MODEL SCORE = TREATMENT; 
 
LSMEANS TREATMENT; 
RUN; 


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5.11.3 
Exploratory Efficacy Analysis 
Exploratory efficacy endpoint analysis includes descriptive statistics of the number of patients 
who received any concomitant procedures, and the number of patients with PSVT terminated by 
additional medical intervention. These descriptive statistics will be presented by treatment group. 
Descriptive statistics of the number of positively adjudicated episodes of PSVT converted by 
performing a VM will be provided. Specifically, the number of patients and episodes with VM 
performed, and the number of patients and episodes with a successful VM.    
5.12 
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. All safety analysis will 
be performed on the Safety Population, the TD Population or the Overall Safety Population, as 
appropriate (i.e. specified in the specifications programming document).  
5.12.1 
Adverse Events 
Adverse event verbatim text will be coded and classified by system organ class (i.e., body 
system) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) 
21.0.  
Summarization of adverse events (AEs) and treatment emergent adverse events (TEAEs) 
 will include subject incidence of the following: 
 Any AE, 
 Treatment Emergent Adverse Events (TEAEs); defined as AEs with a start date occurring 
0 to 24 hours after test dose and prior to randomized study drug dose or with a start date 
occurring 0 to 24 hours after randomized study drug dose, 
 AEs by maximum severity, 
 Drug-related AEs, 
 Drug-related AEs by maximum severity, 
 Serious Adverse Events (SAEs), 
 Drug-related Serious Adverse Events, 
 AEs leading to Death, 
 AEs leading to study drug discontinuation, 
 Drug-related AEs leading to study drug discontinuation, 
 Test-Dose Emergent AEs (TDEAE); defined as AEs with a start date occurring 0 to 24 
hours after test dose, and prior to randomized study drug dose, 
 Randomized-Treatment Emergent AEs (RTEAE): defined as AEs with a start date 
occurring 0 to 24 hours after randomized out patient drug administration. 


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 AEs with a start date occurring 0 to 48 hours after randomized out patient drug 
administration. 
 AEs with a start date occurring 0 to 7 days after randomized out patient drug administration. 
Adverse events (AEs) are defined as those AEs with onset after the first dose of test study drug 
or existing events that worsened after the first test study drug dose during the study. Events 
reported with a partial onset date (e.g., month and year are reported but the day is missing) will 
be considered to be treatment-emergent if it cannot be confirmed that the event onset was prior to 
the first dose of study drug based on the available date entries.  Events with partial onset times 
which occur on the same day as a test dose or drug administration day will be considered to 
occur after drug administration. 
An overall summary table will contain the number and percentage of subjects ever having one of 
the above listed subsets of AEs.  Detailed tables of study populations will be presented with 
relevant Test-Dose Emergent or Randomized-Treatment Emergent AEs. AEs will be 
summarized overall (both treatment groups combined) and where relevant for each treatment 
group.  AEs will be presented by MedDRA system organ class (SOC) and preferred term (PT) 
with the number and percentage of subjects. If a subject has more than 1 occurrence of the same 
AE, he/she will be counted only once within that preferred term and system organ class in the 
summary tables. The maximum severity occurrence of a repeat AEas well as the relationship of 
the AE to the study drug will be used for the analyses.  AEs which are listed as possibly, 
probably, or definitively related will be classified as related, AEs listed as not related or unlikely 
related will be classified as not related. 
AEs related to study drug, severe AEs, SAEs, and AEs leading to study drug discontinuation will 
be summarized in the same manner. That is, summaries will be provided for the numbers and 
percentages of subjects by SOC and PT. 
All AEs will be included in by-subject listings. Specific by-subject listings of SAEs and AEs 
leading to study drug discontinuation will be provided. The number of days between test dose or  
randomized-treatment drug dose and when the AE occurred will be presented (i.e., relative study 
day), as will duration of the AE. 
5.12.2 
Clinical Laboratory Tests 
Clinical laboratory results (mean, , minimum, maximum, standard deviation) will be summarized 
by treatment. The change and percentage change from the screening visit to final study visit will 
be summarized by treatment. Incidence of laboratory (<LLN and >ULN) will be summarized. 
Listings of all clinical laboratory tests will be provided. 
5.12.3 
Vital Signs  
Vital signs results (n, mean, median, minimum, maximum, standard deviation, median,) will be 
summarized by visit and treatment. and visit.  The changes and percentage of change (n, mean, 
median, minimum, maximum, standard deviation) in HR, SBP, and DBP from pre-test dose to 5, 
10, 15, 20, 25, and 30 minutes post-test dose will be summarized. 


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5.12.4 
Electrocardiograms and Cardiac Monitoring System recordings 
Electrocardiograms results will be summarized by visit and treatment. The change in PR interval 
(mean, median, min, max, SD) from 10 minutes pre-test dose to 30 minutes post-test dose will be 
summarized.  A listing of all ECG results will be provided. 
Moreover, the number of subjects and percentage of subjects with conduction disorders will be 
reported from the CMS recordings. The number of subjects and percentage of subjects with first-
degree AV block will be reported. For those patients with first-degree AV block, the PR interval 
measured on the CMS recordings will be reported in terms of mean, SD, min, max. These data 
will also 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 alter AV 
conduction). These data will be reported in the Overall Safety Population.   
For episodes after a patient is randomized, the number of subjects and percentage of subjects 
with arrhythmias, recurrence of episodes of PSVT, and conduction disorders will be reported 
from the adjudication of CMS recordings. These data will be reported in the Overall Safety 
Population when the CMS data is collected but study drug was not taken (successful vagal 
maneuver, or other reason for not taking study drug).  These data will also be reported in the 
Safety population by treatment for CMS data which is collected after administration of study 
drug. 
 
The following adjudicated data will be summarized: 
 
1) N (%) of subjects with occurrence of atrial fibrillation, atrial flutter, or atrial tachycardia 
lasting longer than 30 seconds. 
2) N (%) of subjects with occurrence of PVCs greater than 6 PVCs/45 seconds. 
3) N (%) of subjects with non-sustained ventricular tachycardia defined as equal or greater than 3 
wide consecutive beats. 
4) N (%) of subjects with any sinus rate equal or less than 40 bpm and Type I AV block greater 
than 30 seconds. 
5) N (%) of subjects with any occurrence of Type II or III AV block (including AV dissociation 
or the presence of more than 2 non-conducted P waves in a row). 
6) N (%) of subjects with any pause equal or greater than 3 seconds. 
5.12.5 
Physical Examination 
Physical examination data at each evaluation will be listed.  
6. 
INTERIM ANALYSIS 
No interim analysis has been planned. 


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7. 
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 positively adjudicated 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.  
8. 
CHANGE FROM PROTOCOL 
The definition of Test Dose Only Population has been further specified in the SAP.  Also in the 
SAP and tables, the Test Dose Population will be referred to as the ‘Test Dose Only Population’. 
In the protocol it states ‘The Test Dose Population includes all patients who receive the test dose 
of etripamil NS 70 mg. The Test Dose 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 intention was for this to be the population of patients who receive the Test Dose Only (no 
randomized drug).  As written, the protocol could be interpreted as the TD population being the 
same as the Overall Safety Population.  For further specificity, the SAP defines the TD 
population as ‘The Test Dose Only (TD) Population includes all patients who receive a Test 
Dose but do not receive randomized drug (Overall safety population, minus the safety 
population).’  Furthermore, subgroup analyses are being conducted on selected safety and 
efficacy endpoints in multiple populations, as most appropriate to the tested endpoint, not in the 
Test Dose Only population. 


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The protocol states that for secondary efficacy 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 the TSQM in the 2 treatment groups.  Additional 
clarification on this analysis was added to the SAP in Section 5.11.2.   
In this protocol the timing of an AE is important to clinical relevance, due to the acute nature of 
the indication and the study treatment.  In order to make safety tables more informative, and to 
avoid comparing data from fundamentally different patient populations (those in sinus rhythm 
during a test dose, and those in PSVT or possible PSVT during an episode) tables will often 
present Test-Dose Emergent AEs (those occurring within 0 to 24 hours post Test Dose, and 
before a randomized study drug administration), and Randomized-Treatment Emergent AEs 
(those occurring within 0 to 24 hours post randomized study drug treatment) rather than all AEs.  
Summaries of all AEs regardless of timing will be included in the tables for reference.   
9. 
PROGRAMMING SPECIFICATIONS 
The programming specifications, including the mock-up validity listings, analysis tables, figures, 
and data listings, as well as the derived database specifications, will be prepared in stand-alone 
documents. The programming specification documents will be finalized prior to database lock. 
All analyses will be conducted using SAS® version 9.4 or higher. 
 
 


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APPENDIX A:  SCHEDULE OF PROCEDURES 
Table 1. 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 Coach 
 
 
 
X8 
 
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 
 
X18 
Review the CMS report19 
 
X 
 
 
X 
Identify PSVT episode 
 
 
 
X 
 
Apply and start CMS 
 
X 
 
X20 
 
Perform VM 
 
X 
 
X 
 
Administer study drug and 
record time of dosing 
 
 
 
X21 
 
Complete patient paper 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 
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). 
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 


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(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 paper 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. 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 pre-test dose and every 5 minutes 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 monitoring ECG will remain until 
the end of the test 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 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 paper 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. 
18. Only if patients took the study drug in the NODE-301 study. 
19. 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 report of the 
patient’s ECG data that will state whether or not any protocol-defined ECG test failure criteria were met. This report is 
expected to be made available within 1 to 2 hours of the receipt of ECG data and will be used by the site to determine if 
patients pass or fail the test dose and eligibility for randomization. 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, the Medical Monitor, and the Sponsor. 
20. The CMS recording during an episode of PSVT should continue for at least 5 hours, regardless of treatment outcome. 
21. During the Treatment Period, study drug should only be administered if the VM does not resolve the patient’s symptoms. 
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:  TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION 
1. How satisfied or dissatisfied are you with the ability of the medication to treat your 
condition? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
2. How satisfied or dissatisfied are you with the way the medication relieves your symptoms? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
3. How satisfied or dissatisfied are you with the amount of time it take the medication to start 
working? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
4. How easy or difficult is it to use the medication in its current form? 
1. Extremely Difficult 
2. Very Difficult 
3. Difficult 
4. Somewhat Easy 
5. Easy 
6. Very Easy 
7. Extremely Easy 
5. How easy or difficult is it to plan when you will use the medication each time? 
1. Extremely Difficult 
2. Very Difficult 
3. Difficult 
4. Somewhat Easy 


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5. Easy 
6. Very Easy 
7. Extremely Easy 
6. How convenient or inconvenient is it to take the medication as instructed? 
1. Extremely Inconvenient 
2. Very Inconvenient 
3. Inconvenient 
4. Somewhat Convenient 
5. Convenient 
6. Very Convenient 
7. Extremely Convenient 
7. Overall, how confident are you that taking this medication is a good thing for you? 
1. Not at All Confident 
2. A Little Confident 
3. Somewhat Confident 
4. Very Confident 
5. Extremely Confident 
8. How certain are you that the good things about your medication outweigh the bad things? 
1. Not at All Certain 
2. A Little Certain 
3. Somewhat Certain 
4. Very Certain 
5. Extremely Certain 
9. Taking all things into account, how satisfied or dissatisfied are you with this medication? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 


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APPENDIX C:   PSVT SYMPTOMS RECORDS IN ECRF 
List of available PSVT symptoms: 
 Repaid pulse 
 Palpitations 
 Shortness of breath 
 Chest tightness, pain or pressure 
 Feeling dizzy or lightheaded 
 Fainting or passing out 
 Anxiety 
 
 


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APPENDIX D: 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) 
 


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APPENDIX E: SUBGROUPS OF INTEREST  
1. US, Canada, Other. 
2. Male, female 
3. Patients ≥70 years old, Patients ≥70 years old with concomitant cardiovascular treatment 
(agent or treatment identified as for a cardiovascular indication; i.e. PSVT prophylaxis, anti-
hypertensive, or other cardiovascular treatments), Patients ≥60 and < 70 years old receiving 
concomitant cardiovascular treatment. 
4. Patients currently receiving any of the following classes of concomitant medication regardless 
of indication: Beta-blockers, Calcium channel blockers. 
5. Patient receiving any concomitant medication indicated for antihypertensive treatment: 
Monotherapy, Bi-therapy, Triple therapy or more, Dihydropyridine calcium channel blocker 
(e.g., amlodipine), Beta-blocker. 
6. Type of PSVT: AVNRT, AVRT, Unknown. 

Prot_000.pdf: 


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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 
Cameron Szakacs 
cszakacs@milestonepharma.com/+1-704-848-5355 
Responsible Physician 
Francis Plat 
fplat@milestonepharma.com/+1-514-336-0444, ext. 225 
Medical Monitor 
Silvia Shardonofsky 
Roberto Marchioli 
safety@milestonepharma.com/+1-514-336-0444, ext. 235 
roberto.marchioli@iqvia.com/+39 085 9049103 
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 immediately, without undue delay, and under no 
circumstances later than 24 hours after learning 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 
SAE Reporting Line 
(USA/Canada): +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
(EU): +49 89 89 55 718 44 
Safety Fax  
(USA/Canada): +1-866-336-5320 or +1-513-570-5196 
(EU): +49 89 89 55 718 104 
E-mail: medpace-safetynotification@medpace.com 
 
Medical Monitors: 
Silvia Shardonofsky, MD 
Telephone: +1-514-336-0444, ext. 235; E-mail: safety@milestonepharma.com 
Roberto Marchioli, MD 
Telephone: +39 085 9049103; E-mail: roberto.marchioli@iqvia.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 RAPID Study (NODE-301 Part 2) 
 
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. 
 
Cameron Szakacs, PhD 
Senior Director, Drug Development 
Milestone Pharmaceuticals Inc. 
 
Guy Rousseau, PhD 
Vice President, Regulatory Affairs 
Milestone Pharmaceuticals Inc. 
 
 
Cameron 
Szakacs
Digitally signed by 
Cameron Szakacs 
Date: 2022.01.17 13:33:24 
-05'00'
Guy Rousseau
Digitally signed by Guy Rousseau 
Date: 2022.01.17 13:39:29 -05'00'
Francis Plat
Digitally signed by Francis Plat 
Date: 2022.01.17 15:46:09 -05'00'


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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, as applicable, the Food and Drug 
Administration Regulations, Food and Drug Act, or the Regulation (EU) No 536/2014 of the 
European parliament and of the Council of 16 April 2014 on clinical trials on medical products for 
human use, and repealing Directive 2001/20/EC, and 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 RAPID Study (NODE-301 Part 2) 
SHORT TITLE: Efficacy and Safety of Etripamil for the Termination of Spontaneous PSVT. 
The RAPID Study 
PROTOCOL NUMBER: MSP-2017-1138 
INVESTIGATIONAL PRODUCT: Etripamil (MSP-2017) 
EUdraCT NUMBER: 2018-000308-41 
PHASE: 3 
INDICATION: Paroxysmal supraventricular tachycardia (PSVT) 
OBJECTIVES: 
The primary objective of the RAPID study is to determine whether etripamil nasal spray (NS) 
self-administered by patients is superior to placebo at terminating episodes of PSVT in an at-
home setting. 
The secondary objective of this study is to evaluate the safety of etripamil 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,  
• To evaluate the safety and efficacy of etripamil NS in various subgroups of interest (e.g., 
concomitant medications), and 
• To evaluate the safety and efficacy of a treatment regimen of etripamil NS which allows a 
repeat dose of etripamil to terminate episodes of PSVT in an at-home setting. 
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; 






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4. Third-degree AV block, Mobitz II second-degree AV block, or Wenckebach with bradycardia 
≤40 bpm; 
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 ventricular arrhythmia considered significant by the Investigator; or 
7. Atrial fibrillation, atrial flutter or atrial tachycardia (event lasting longer than 30 seconds); 
8. Refusal of second dose of etripamil test dose regimen. 
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 dosing regimen 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. 
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 self-administered by patients who experience an episode of 
PSVT in an at-home 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 describes the conduct of NODE-301 up to the date of the adjudication of the 150th 
positively adjudicated PSVT episode (January 15th, 2020).  
• Part 2 describes the conduct of NODE-301 following the completion of Part 1. 
NODE-301 – Part 1  
Part 1 was conducted under protocol versions 1 through 5, and has been completed. Part 1 has 
the same general study design as Part 2 of the study, with the key differences being that Part 2 
includes a repeat dosing option during the randomized Treatment Period, as well as during an 
added Open-Label Treatment Period (test dose procedures have been amended in Part 2 to assess 
a repeat dose of etripamil NS 70 mg).  


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NODE-301 – Part 2 (the RAPID Study) 
RAPID (NODE-301 Part 2) will consist of:  
• New patients enrolled following protocol version 6.0 (and subsequent versions) 
implementation 
• Patients enrolled prior to protocol version 6.0 implementation and who had not 
dosed with the double-blind study drug, or had not discontinued the study before 
the adjudication of the 150th positively adjudicated PSVT episode in Part 1. 
The RAPID study will test the treatment effect of etripamil (a dosing regimen of either single 
dose or second dose, if symptoms persist after 10 minutes), in a population of patients having a 
perceived episode of PSVT in an at-home setting, as measured by time to conversion to sinus 
rhythm for at least 30 seconds. 
Enrollment into RAPID will continue until the adjudication of the 180th positively adjudicated 
PSVT episode in Part 2 patients treated with double-blind study drug during the Randomized 
Treatment Period required for the study’s pivotal analysis. See the sample size determination 
section (Section 9.2.6) for additional details. RAPID will continue for approximately 6 months 
after the date of the adjudication of the 180th positively adjudicated PSVT episode. All patients 
not unblinded as part of the RAPID pivotal analysis will be unblinded at the end of the study. 
The study will include a Screening Visit, a Test Dose Randomization Visit, Monthly Follow-up 
Visits, a Randomized Treatment Period, a Randomized Treatment Period Follow-Up Visit, an 
Open-Label 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 
See Section 6.2 for a full list of Test Dose Randomization Visit procedures. As detailed in that 
section, it is permitted to conduct the Screening and Test Dose Randomization Visit procedures 
on the same day, using a local laboratory to conduct preliminary clinical safety evaluations. 
Newly Enrolled Patients: The initial Test Dose Randomization Visit for newly enrolled patients 
should occur within 28 days after the Screening Visit. If the Test Dose Randomization visit cannot 
be conducted within 35 days after the Screening Visit, new blood and urine samples must be 
collected and sent for central laboratory evaluations at the Test Dose Randomization Visit prior 
to Test Dose procedures. Patients who pass the Test Dose criteria and are randomized will be 
instructed to not use double-blind study medication until it is confirmed that no exclusionary 
criteria were met following the analysis of the newly collected samples. 
Patients previously enrolled under NODE-301 Part 1: A Test Dose Randomization Visit to assess 
the safety of a second dose of etripamil NS 70 mg is required for patients previously enrolled 
under NODE-301 Part 1. This visit should occur at the time of reconsent of patients for Version 
6 and subsequent versions of the protocol. 
Before randomization, all patients will receive a test dose of the etripamil NS dosing regimen (an 
initial dose of etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg not earlier 


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than 10 minutes and not later than 15 minutes after the first dose) to evaluate tolerability and to 
train patients on the study procedures. All patients who pass the test dose of the etripamil NS 
dosing new regimen will be given a study kit, which includes the blinded study drug (2 devices 
pre-filled with placebo or etripamil NS 70 mg), a CMS, a study identification card, patient’s study 
instructions, and other study-related material. 
Monthly Follow-up Visits 
Follow-up Visits will occur approximately monthly from the time of randomization until the 
patient has completed the study (i.e., during the Randomized and Open-Label Treatment Periods). 
These visits can be conducted by patients returning to the investigative site or by the site personnel 
contacting patients by telephone. 
Randomized Treatment Period 
When randomized patients identify symptoms of an episode of PSVT, they will perform a 
sequence of steps, including placement of CMS device on his/her chest and study drug 
self-administration. A caregiver may help the patient with these procedures, and this should be 
annotated in the electronic case report form. Self-administration of the study drug regimen during 
a PSVT episode is as follows: an initial dose of etripamil NS 70 mg (or placebo) followed by a 
second dose 10 minutes later if the patient continues to experience PSVT symptoms. 
Randomized Treatment Period Follow-Up Visit  
A Randomized Treatment Period Follow-Up Visit will occur at the study site within 14 days after 
a patient self-administers study drug during the Randomized Treatment Period. Patients without 
tolerability issues will be entered into the Open-Label Treatment Period. 
Open-Label Treatment Period  
All patients will perform a sequence of steps, including etripamil 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. Self-administration 
of the study drug regimen during a PSVT episode is as follows: an initial dose of etripamil NS 
70 mg followed by a second dose 10 minutes later if the patient continues to experience PSVT 
symptoms (patients who are symptom-free before 10 minutes do not repeat dosing). 
Final Study Visit 
A Final Study Visit will occur at the study site within 14 days after a patient self-administers 
study drug during the Open-Label Treatment Period, or if for any other reason the patient has 
completed participation in the study. 
End of Study Telephone Follow-Up 
An End of Study Telephone Follow-Up Visit will be completed approximately 30 days after the 
Final Study Visit to assess adverse events (AEs). This visit is not required for patients who did 
not use study drug within 14 days prior to their Final Study Visit.  


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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 RAPID study is 70 mg per nasal 
spray device, using the dosing regimens described previously. The same formulation will be used 
for the Test Dose Randomization Visit and for the Treatment Periods. 
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: Each nasal spray device delivers 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 kit. 
DURATION OF TREATMENT: 
This is an event-driven study. 
Part 1: Was completed with 431 patients enrolled (completed a test dose), 419 patients 
randomized, and 156 randomized patients presenting with a positively adjudicated episode of 
PSVT. 
Part 2: A total sample size of 180 patients with a positively adjudicated PSVT episode, 
randomized at a range of 1:1 to 2:1 ratio (active : control) provides at least 90% power to detect 
a significant treatment difference for the primary endpoint at a two-sided significance level of 
0.05. Since the time from enrollment to when patients experience their first perceived episode of 
PSVT treated with study drug is unknown, the study is projected to randomize an additional 500 
patients for a total between Part 1 and RAPID (Part 2) of over 900 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 RAPID study (Part 2) will 
continue until the adjudication of the 180th positively adjudicated PSVT episode. RAPID will 
continue for approximately 6 months after the date of the adjudication of the 180th positively 
adjudicated PSVT episode.   
EFFICACY VARIABLES:  
The primary efficacy endpoint is defined as time to an adjudicated termination of a positively 
adjudicated episode of PSVT and conversion to sinus rhythm (SR) for at least 30 seconds within 
30 minutes of start of study drug dosing. 
Additional efficacy endpoints include: 
• Time to conversion at time points prior to, and later than, 30 minutes; 
• Time to conversion in patients with the option of repeat administration; 
• The percentage of patients requiring additional medical intervention in emergency department 
to terminate an episode of PSVT  


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• 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;  
• Rating of TSQM; 
• The repeat of key efficacy endpoints in various subgroups of interest (e.g., concomitant 
medications). 
SAFETY VARIABLES: 
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.  
During the Treatment Periods, safety variables will be recorded, as detailed in Sections 6.5 and 
6.7. 
STATISTICAL ANALYSES: 
The estimand of the study is the rapid conversion of PSVT to sinus rhythm in an at-home setting. 
Data from the two etripamil arms (single dose arm, and optional second dose arm) will be pooled 
for comparison to pooled data from the two placebo arms (single dose arm, and optional second 
dose arm) for all primary analyses. Sensitivity analyses looking at individual arms may be 
conducted.  
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 for a perceived episode of PSVT. 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 etripamil NS during a Test Dose 
and Randomization Visit, 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 randomized study drug for 
a perceived episode of PSVT. The subjects will be included in the treatment arm (placebo or 
double-blind study drug) according to actual received treatment. The safety population also 
includes all patients who take Open-Label Study medication for a perceived episode of PSVT. 


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The Overall Safety Population includes the Safety Population and the Test Dose Only Population. 
Planned Analyses 
The main estimator (primary efficacy endpoint) for the study will be time to adjudicated 
termination of a positively adjudicated episode of PSVT and conversion to SR for at least 30 
seconds within 30 minutes of study drug dosing.  
The main estimate (primary analysis of the primary endpoint) will be derived by Kaplan Meier 
estimates of time to conversion at 30 minutes using the Wilcoxon test. Patients who received 
medical interventions for treatment of PSVT will be censored at Minute 31. Patients who have 
not achieved conversion by Minute 30 will be censored by Minute 31. The hazard ratio 
(active/control) and the two-sided 95% confidence interval (CI) will be calculated using Cox 
regression model with treatment effect.  
A type I error control strategy using a hierarchical gatekeeping approach among sensitivity 
estimators (secondary endpoints) will be defined in the statistical analysis plan.  
Sensitivity estimators will include the following;  
• Tests of the duration of treatment effect, via Kaplan Meier estimates of time to 
conversion at 5, 10, 15, 45, 60, 90, 120, 180, 240, and 300 minutes. 
• Tests of the impact of a treatment regimen which includes an optional second dose, 
via comparisons of efficacy in the single dose regimen arms versus optional 
second dose arms, and comparisons of the proportion of patients who take a 
second dose within the optional second dose etripamil and placebo arms. 
• Tests of the ‘at-home setting’ component of the estimand, via comparison of the 
proportion of patients who seek additional medical intervention, rescue 
medication, or emergency medical care.  
• Tests of clinical benefits, via comparison of patient reported treatment 
effectiveness and overall satisfaction, as measured by the TSQM-9 and other 
patient reported symptoms.  
• Tests of the robustness of analysis method, via landmark analyses of conversion 
rates at 3, 5, 10, 15, 20, 30, 45, 60, and 90 minutes after drug administration.  
• Tests of the robustness of analysis method, via use of alternative censoring 
methods for patients who receive additional medical intervention, including a 
composite strategy (analyzed via Wei Lin Weiss method) and treatment policy 
(with patients censored at time of conversion due to medical intervention).  
• Tests of the robustness of statistical method, via use of Log-rank method for the 
main estimator, and sensitivity estimators using Kaplan Meier analyses.  
The methods for deriving sensitivity estimates will be provided in the statistical analysis plan. 
SAMPLE SIZE DETERMINATION: 
Part 1 was completed with 431 patients enrolled (completed a test dose), 419 patients randomized, 
and 156 presenting with a positively adjudicated episode of PSVT. 


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For RAPID, it is assumed that 35% of the episodes of PSVT will be converted to SR in the 
placebo group and 54% in the etripamil group by 30 minutes. These assumptions are based on 
results obtained in Part 1 of the NODE-301 study. A total sample size of 180 patients in Part 2 
with a positively adjudicated PSVT episode, randomized at a range of 1:1 to 2:1 ratio (active : 
control) provides at least 90% power to detect a significant treatment difference for the primary 
endpoint at a two-sided significance level of 0.05. This sample size was calculated based on 
internal modeling of the Part 1 data where etripamil had a higher conversion rate (54% versus 
35% at 30 minutes), and also a more rapid conversion rate (32% versus 14% at 10 minutes).  
Assuming a type I error rate of alpha = 0.05 and a ratio in the number of positively adjudicated 
episodes of PSVT etripamil:placebo between 1:1 and 2:1, a minimum of 80 positive conversion 
events will be required. Based on internal modeling, 180 patients with a positively adjudicated 
PSVT episode and 80 positive conversion events will attain greater than 90% power on the 
primary variable of time to conversion (using a 2-sided Wilcoxon test).  
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 4 and up to 6 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 episode of PSVT 
recorded during the Randomized and Open-Label Treatment Period of the study. 
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 loss of recording signal (if applicable), time of a successful medical 


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intervention (e.g., use of IV adenosine in a medical care facility), or if termination is not observed 
within 5 hours 
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 approximately 175 sites in North America and Europe. 
SPONSOR: 
Milestone Pharmaceuticals Inc. 
1111 Dr. Frederik-Philips Blvd., Suite 420 
Montreal, 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 ....................................... 2 
Signature Page ................................................................................................................................ 3 
Investigator Agreement ................................................................................................................... 4 
Synopsis .......................................................................................................................................... 5 
Table of Contents .......................................................................................................................... 16 
List of Tables ................................................................................................................................ 19 
List of Figures ............................................................................................................................... 20 
List of Abbreviations and Definition of Terms............................................................................. 21 
1 Introduction and Background Information ............................................................................. 23 
1.1 
Phase 1 Studies .............................................................................................................. 23 
1.2 
Phase 2 Study ................................................................................................................ 24 
1.3 
Phase 3 Study ................................................................................................................ 28 
1.4 
Rationale ........................................................................................................................ 30 
2 Study Objectives ..................................................................................................................... 32 
2.1 
Primary Objective ......................................................................................................... 32 
2.2 
Secondary Objective ..................................................................................................... 32 
2.3 
Exploratory Objectives .................................................................................................. 32 
3 Study Description.................................................................................................................... 33 
3.1 
Summary of Study Design ............................................................................................ 33 
3.1.1 NODE-301 – Part 1 ........................................................................................... 33 
3.1.2 NODE-301 – Part 2 (The RAPID Study) .......................................................... 33 
3.2 
Study Visits (RAPID Study) ......................................................................................... 36 
3.2.1 Screening Visit .................................................................................................. 36 
3.2.2 Test Dose Randomization Visit ......................................................................... 36 
3.2.3 Monthly Follow-up Visits ................................................................................. 37 
3.2.4 Randomized Treatment Period .......................................................................... 38 
3.2.5 Randomized Treatment Period Follow-Up Visit .............................................. 39 
3.2.6 Open-Label Treatment Period ........................................................................... 40 
3.2.7 Final Study Visit ................................................................................................ 41 
3.2.8 End of Study Telephone Follow-Up Visit ......................................................... 41 
3.3 
Common Study End Date (CSED) ................................................................................ 41 
3.4 
Conduct of RAPID Study during COVID-19 pandemic ............................................... 42 


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4 Selection and Withdrawal of Patients ..................................................................................... 43 
4.1 
Inclusion Criteria ........................................................................................................... 43 
4.2 
Exclusion Criteria .......................................................................................................... 43 
4.3 
Withdrawal Criteria ....................................................................................................... 45 
5 Study Treatments .................................................................................................................... 47 
5.1 
Treatment Groups .......................................................................................................... 47 
5.2 
Rationale for Dosing ..................................................................................................... 47 
5.3 
Randomization and Blinding ......................................................................................... 48 
5.4 
Unblinding ..................................................................................................................... 49 
5.5 
Drug Supplies ................................................................................................................ 49 
5.5.1 Formulation and Packaging ............................................................................... 49 
5.5.2 Study Drug Administration ............................................................................... 50 
5.5.3 Treatment Compliance ...................................................................................... 50 
5.5.4 Storage and Accountability ............................................................................... 50 
5.5.5 Study Drug Handling and Disposal ................................................................... 51 
5.6 
Prior and Concomitant Medications and/or Devices ..................................................... 51 
5.6.1 Excluded Medications and/or Devices .............................................................. 51 
5.6.2 Documentation of Prior and Concomitant Medication Use .............................. 51 
6 Site Study Procedures ............................................................................................................. 52 
6.1 
Screening Visit .............................................................................................................. 52 
6.2 
Test Dose Randomization Visit ..................................................................................... 52 
6.3 
Monthly Follow-up Visits ............................................................................................. 55 
6.4 
Randomized Treatment Period ...................................................................................... 56 
6.5 
Randomized Treatment Period Follow-Up Visit .......................................................... 56 
6.6 
Open-Label Treatment Period ....................................................................................... 56 
6.7 
Final Study Visit ............................................................................................................ 57 
6.8 
End of Study Telephone Follow-Up Visit ..................................................................... 57 
7 Efficacy Assessments.............................................................................................................. 58 
7.1 
Primary Efficacy Endpoint ............................................................................................ 58 
7.2 
Additional Efficacy Endpoints ...................................................................................... 58 
7.3 
Adjudication Process for Randomized Treatment Period ............................................. 58 
7.4 
Adjudication Process for Open-Label Treatment Period .............................................. 59 
8 Safety Assessments ................................................................................................................. 60 
8.1 
Adverse Events .............................................................................................................. 60 


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8.1.1 Adverse (Drug) Reaction .................................................................................. 61 
8.1.2 Unexpected Adverse Drug Reaction ................................................................. 61 
8.1.3 Assessment of Adverse Events by the Investigator .......................................... 61 
8.1.3.1 Assessment of severity ........................................................................ 61 
8.1.3.2 Causality assessment ........................................................................... 61 
8.1.4 Follow-up of Adverse Events ............................................................................ 62 
8.1.5 Adverse Events of Special Interest (AESI) ....................................................... 63 
8.2 
Serious Adverse Event .................................................................................................. 63 
8.3 
Serious Adverse Event Reporting – Procedures for Investigators ................................ 64 
8.4 
Pregnancy Reporting ..................................................................................................... 65 
8.5 
Expedited Reporting ...................................................................................................... 66 
8.6 
Medical Device Complaints .......................................................................................... 66 
8.7 
Clinical Laboratory Evaluations .................................................................................... 66 
8.8 
Vital Signs ..................................................................................................................... 66 
8.9 
Electrocardiograms ........................................................................................................ 66 
8.10 Physical Examinations .................................................................................................. 67 
9 Statistics .................................................................................................................................. 68 
9.1 
Analysis Populations ..................................................................................................... 68 
9.2 
Statistical Methods ........................................................................................................ 68 
9.2.1 Patient Disposition and Demographic/Baseline Characteristics ....................... 68 
9.2.2 Study Drug Administration and Concomitant Medications .............................. 69 
9.2.3 Analysis Populations ......................................................................................... 69 
9.2.4 Main Estimator (Primary efficacy endpoint and analysis) ................................ 69 
9.2.4.1 Sensitivity estimators .......................................................................... 70 
9.2.5 Analysis of Safety ............................................................................................. 70 
9.2.6 Sample Size Determination ............................................................................... 70 
10 Data Management and Record Keeping ................................................................................. 72 
10.1 Data Management ......................................................................................................... 72 
10.1.1 Data Handling ................................................................................................... 72 
10.1.2 Computer Systems ............................................................................................. 72 
10.1.3 Data Entry ......................................................................................................... 72 
10.1.4 Medical Information Coding ............................................................................. 72 
10.1.5 Data Validation ................................................................................................. 72 
10.2 Record Keeping ............................................................................................................. 72 


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11 Investigator Requirements and Quality Control ..................................................................... 74 
11.1 Ethical Conduct of the Study ........................................................................................ 74 
11.2 Institutional Review Board/Independent Ethics Committee ......................................... 74 
11.3 Informed Consent .......................................................................................................... 74 
11.4 Study Monitoring Requirements ................................................................................... 74 
11.5 Disclosure of Data ......................................................................................................... 75 
11.6 Retention of Records ..................................................................................................... 75 
11.7 Data Protection .............................................................................................................. 75 
11.8 Monitoring Committees ................................................................................................ 76 
11.8.1 Steering Committees ......................................................................................... 76 
11.8.2 Data and Safety Monitoring Committee ........................................................... 76 
11.8.3 Adjudication Committee ................................................................................... 76 
11.9 Audits and Inspections .................................................................................................. 77 
11.10 Publication Policy ......................................................................................................... 77 
11.11 Financial Disclosure ...................................................................................................... 77 
12 Study Administrative Information .......................................................................................... 78 
12.1 Protocol Amendments ................................................................................................... 78 
12.2 Address List ................................................................................................................... 78 
12.2.1 Sponsor .............................................................................................................. 78 
12.2.2 Contract Research Organization(s) ................................................................... 78 
12.2.3 ECG Core Laboratory for Test Dose CMS Data and CMS Monitoring ........... 78 
12.2.4 ECG Core Laboratory for Adjudication ............................................................ 78 
12.2.5 Study Drug Distribution and Accountability .................................................... 78 
12.2.6 Medpace Clinical Safety ................................................................................... 79 
12.2.7 Biological Specimens ........................................................................................ 79 
13 References ............................................................................................................................... 80 
Appendix A: Schedule of Procedures ........................................................................................... 81 
Appendix B: Clinical Laboratory Analytes .................................................................................. 84 
Appendix C: Adverse Events of Special Interest .......................................................................... 85 
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 ............................................................................................... 81 


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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 
Figure 4. Kaplan-Meier Plot of Conversion up to 5 Hours (Efficacy Population, Primary 
Analysis, Primary Endpoint, NODE-301 Part 1 ......................................................... 30 
Figure 5. RAPID Study Design .................................................................................................. 35 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse events of special interest 
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 


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Abbreviation 
Definition 
SAE 
Serious adverse event 
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 at-home setting.  
Etripamil is an investigational drug that has not received marketing authorization by any regulatory 
authority.  
1.1 
Phase 1 Studies 
Study MSP-2017-1096 evaluated the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of etripamil, with the aim of determining the maximum tolerated dose or 
maximum feasible dose (MFD) of 2 different formulations administered via the intranasal (IN) 
route in healthy adult male subjects. All etripamil doses were generally well tolerated, and there 
was no difference in the safety profile and PK between the 2 etripamil formulations (MSP-2017A 
and MSP-2017B). The study of formulation A was stopped at 60 mg, and formulation B was 
studied at 105 mg and 140 mg (formulation B was the dosage form selected for future clinical 
studies). 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. 
MSP-2017-1205 (NODE-102) study was a randomized, double-blind, placebo-controlled, single 
dose, 4-way crossover, single dose Phase I study to assess the PK, PD, and safety and tolerability 
of IN etripamil at three dose levels and placebo in healthy Japanese and non-Japanese adults. The 
primary objective was to assess the safety and tolerability of etripamil in healthy Japanese and 
non-Japanese volunteers. The secondary objectives were to assess the PK and PD of etripamil in 


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healthy Japanese and non-Japanese volunteers and the exploratory objectives were to assess the 
PK and PD of etripamil in healthy male and female volunteers. 
A maximum of 24 participants, 12 Japanese and 12 non-Japanese, were planned and enrolled in 
the study and 23 completed the study (1 Japanese subject discontinued prematurely due to the 
development of an adverse event). After signing the ICF, potential participants underwent 
screening procedures within 28 days of Day 1. Participants were admitted to the clinical unit on 
Day -1 and screening procedures were repeated to confirm their eligibility. Participants fasted 
overnight for at least 10 hours. On Day 1, participants were randomized to 1 of 3 treatment 
sequences (Placebo-70 mg-35 mg, 35 mg-Placebo-70 mg, or 70 mg-35 mg-Placebo) and received 
either a single intranasal dose of etripamil or placebo followed by a 2-week washout period 
between doses. Etripamil NS up to 105 mg was administered using the Phase 3 formulation Aptar 
Bi-dose nasal spray device (i.e., up to 3 sprays of 100 µL of 350 mg/mL etripamil formulation in 
each nostril). After the third period, all participants received a dose of 105 mg etripamil. The total 
study duration was approximately 3 months, including the screening and follow-up. Blood for PK 
assessments was collected before each dose and at 0.5, 1.5, 3, 5, 7, 10, 15, 25, 50, 90, 360, 720, 
and 1440 minutes after dosing. Urine for PK analysis was collected before dosing and over the 
intervals of 0-2 hours, 2-4 hours, 4-6 hours, 6-12 hours, and 12-24 hours after dosing. Vital signs 
and ECGs were measured at the corresponding PK time points. 
Slightly more Japanese participants experienced a TEAE compared with non-Japanese participants 
and there were more TEAEs at the 105 mg dose compared with the 35 mg and 70 mg doses. 
However, at the 35 mg and 70 mg doses, the percentage of participants with TEAEs was within 
the range of values associated with placebo treatment. The most frequent TEAEs (>10%) were 
increased lacrimation, burning nose sensation, and rhinorrhea, occurring at all doses (including 
placebo). Each of these was considered by the investigator as related to treatment. Most TEAEs 
were mild or moderate in intensity, except 1 instance of burning nose sensation (non-Japanese 
participant at 105 mg etripamil dose) which was severe. There were no serious adverse events. 
One Japanese participant discontinued due to TEAEs (tearing, facial burning sensation, 
rhinorrhea). There were no trends in clinical laboratory changes and there were no TEAEs due to 
changes in clinical laboratory values. There were no meaningful changes in vital signs. Changes 
in ECGs were generally transient and judged to be not clinically significant by the Investigator.  
In both Japanese and non-Japanese participants, etripamil exposure increased in a dose-
proportional manner between 35 mg and 70 mg, while exposure at the highest dose of 105 mg was 
similar to what was seen at 70 mg. 
1.2 
Phase 2 Study 
NODE-1 (MSP-2017-1109) was a Phase 2 study conducted in the electrophysiology laboratory 
(EPL) as a proof-of-concept and dose response study in patients with documented history of PSVT. 
This Phase 2 study assessed the ability of etripamil to terminate an episode of PSVT induced in 
the EPL and was also designed to identify the dose(s) that will be taken in subsequent studies. The 
primary objective was to demonstrate the superiority of at least 1 dose of IN etripamil over placebo 
in terminating an episode of PSVT induced in the EPL. The secondary objectives were to establish 
a dose-related trend for etripamil, to determine the minimal effective dose of etripamil, and to 
evaluate the safety of etripamil in a clinical setting. 


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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 
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 








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adjudicated episode of PSVT and conversion to sinus rhythm for at least 30 seconds. The primary 
efficacy endpoint was evaluated using the time to conversion of an episode of PSVT to sinus 
rhythm after study drug administration as the primary efficacy variable. The study included a 
Screening Visit, a Test Dose Randomization Visit, Follow-up Visits, a Treatment Period, and a 
Final Study Visit. Before randomization, all patients received a test dose of etripamil NS 70 mg to 
evaluate tolerability. The test dose administration took place at the study site under medical 
supervision while the patient was in sinus rhythm (SR). Patients who passed the test dose were 
randomized in a 2:1 ratio to etripamil NS 70 mg or placebo. During the Treatment Period, all 
randomized patients performed a sequence of steps upon self-identifying symptoms of an episode 
of PSVT, including contacting a Telephone Coach for assistance on study procedures, applying a 
CMS on their chest, performing a vagal maneuver (VM), and study drug self-administration.  
The presence of an episode of PSVT and termination were evaluated by an independent 
Adjudication Committee. The Adjudication Committee’s evaluations were done using the 
complete CMS ECG recorded during the patient’s PSVT episode. 
In NODE-301 Part 1, 419 out of 431 patients (97%) who received the test dose were randomized 
into the study. 198 patients self-administered the study drug for a perceived episode of PSVT of 
which 156 patients (79%) had positively adjudicated PSVT episodes; 107 (68.6%) patients 
received etripamil and 49 (31.4%) patients received placebo. The study did not achieve its primary 
endpoint of time to conversion of PSVT to SR compared to placebo following study drug 
administration (Figure 4) over the 5-hour observation period. The hazard ratio HR (95% CI) was 
1.086 (0.726, 1.623); p=0.12 in favor of etripamil. The median time to conversion was 25 minutes 
(95% CI: 16, 43) for etripamil vs. 50 minutes (95% CI: 31,101) for placebo. Early drug effect was 
observed, including the conversion of 54% of etripamil patients compared to 35% of placebo 
patients within 30 minutes after study drug administration (p=0.02), a time period consistent with 
etripamil's pharmacological activity. Patients who received placebo went to the emergency 
department to receive rescue medication earlier and more often than those who received etripamil, 
contributing to confound results from the latter time period of the statistical analysis of the primary 
endpoint at 5 hours. 




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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 nonclinical safety program and clinical studies continue to demonstrate that etripamil, overall, 
displays a favorable safety profile. No important risks for etripamil have been identified during 
the etripamil development program. The important potential risks for etripamil are cardiac effects 
(second- or third-degree atrioventricular (AV) block, sinus pauses ≥3 sec , sinus bradycardia, and 
exacerbation of congestive heart failure), syncope, symptomatic hypotension and hypersensitivity 
reactions.   
The goal of this double-blind Phase 3 NODE-301 study is to demonstrate the safety and 
effectiveness of etripamil NS in the treatment of spontaneous episodes of PSVT when 
self-administered by patients in an at-home setting. 


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


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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 self-administered by patients who experience an episode of 
PSVT in an at-home 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 approximately 
175 sites. 
This is an event-driven study. The study will comprise of 2 parts, Part 1 and Part 2.  
• Part 1 describes the conduct of the NODE-301 study up to the date of the adjudication 
of 150th positively adjudicated PSVT episode (January 15th, 2020); 
• Part 2 describes the conduct of the NODE-301 study after the completion of Part 1. 
3.1.1 
NODE-301 – Part 1  
Part 1 was completed with 431 patients enrolled (completed a test dose), 419 patients randomized 
into the study, and 156 randomized patients presenting with a positively adjudicated episode of 
PSVT for the pivotal analysis. The design and conduct of Part 1 the NODE-301 study can be found 
in Protocol versions 1 through 5. Part 1 has the same general study design as Part 2 of the study, 
with the key differences being that Part 2 includes a repeat dosing option during the Randomized 
Treatment Period, as well as during an added Open-Label Treatment Period (test dose procedures 
have been amended in Part 2 to assess a repeat dose of etripamil NS 70 mg). 
3.1.2 
NODE-301 – Part 2 (The RAPID Study)  
The RAPID Study will consist of: 
• New patients enrolled following protocol version 6.0 (and subsequent versions) 
implementation.  
• Patients enrolled prior to protocol version 6.0 implementation and who had not dosed with 
the double-blind study drug, or had not discontinued the study before the adjudication of 
the 150th positively adjudicated PSVT episode in Part 1. 
The RAPID study will test the treatment effect of etripamil (a dosing regimen of either single 
dose or second dose, if symptoms persist after 10 minutes), in a population of patients having a 
perceived episode of PSVT in an at-home setting, as measured by time to conversion. 
Composition of the study arms are determined as follows: 
• Single-dose - Patients enrolled during Part 1 who complete the study (i.e., dose with study 
drug for a perceived episode of PSVT) prior to implementation of Version 6 of the protocol 
will comprise the patients utilizing a single dose of double-blind study drug (2:1 
randomization of etripamil:placebo). 
• Dosing regimen - Newly enrolled patients (i.e., post-implementation of protocol Version 
6) who pass a test dose regimen of etripamil (an initial dose of etripamil NS 70 mg followed 


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by a second dose of etripamil NS 70 mg not earlier than 10 minutes and not later than 15 
minutes after the first dose) will be randomized to a dosing regimen that permits a second 
dose of study drug, if symptoms are still present at 10 minutes, to treat a perceived episode 
of PSVT (1:1 randomization of etripamil:placebo).   
o Patients enrolled during Part 1 of the study who have not dosed with study drug or 
withdrawn from the study prior to implementation of Version 6 of the protocol, and 
who pass a test dose regimen of etripamil will be re-randomized to the dosing 
regimen, as described above for newly enrolled patients.    
• Data from the single dose arm will be pooled with data from the dosing regimen arm for 
both etripamil and placebo groups for the primary analysis.   
RAPID has the same inclusion/exclusion criteria as Part 1, with the exception of a few 
clarifications or modifications. The most substantial changes in study design between NODE 301 
Part 1 and RAPID are as follows: 
• Dosing regimen – Patients in RAPID will be randomized to a dosing regimen that will 
permit a second dose of study drug to be self-administered 10 minutes after the first dose, 
if symptoms persist at 10 min, to treat perceived episodes of PSVT.   
• Test Dose procedures – All patients enrolling in RAPID will be required to pass a test dose 
regimen consisting of two (2) doses of etripamil NS 70 mg administered 10 minutes apart 
(in sinus rhythm) prior to randomization.  
• Open-Label Treatment Period – RAPID study includes an Open-Label Treatment Period 
following the Randomized Treatment Period of the study.    
o Patients comprising the single dose arms of the RAPID study will not be entered 
into the Open-Label Treatment Period of the RAPID study (participation of patients 
in the single dose-arms of the study will end prior to implementation of Version 6 
of the protocol).   
The RAPID study design is presented in Figure 5 below. 
 




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3.2 
Study Visits (RAPID Study) 
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 a 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 between the Investigator and Medical 
Monitor. 
3.2.2 
Test Dose Randomization Visit 
See Section 6.2 for a full list of Test Dose Randomization Visit procedures. As detailed in that 
section, it is permitted to conduct the Screening and Test Dose Randomization Visit procedures 
on the same day, using a local laboratory to conduct preliminary clinical safety evaluations. 
Newly Enrolled Patients: The initial Test Dose Randomization Visit for newly enrolled patients 
should occur within 28 days after the Screening Visit. If the Test Dose Randomization visit cannot 
be conducted within 35 days after the Screening Visit, new blood and urine samples must be 
collected and sent for central laboratory evaluations at the Test Dose Randomization Visit prior to 
Test Dose procedures. Patients who pass the Test Dose criteria and are randomized will be 
instructed to not use double-blind study medication until it is confirmed that no exclusionary 
criteria were met following the analysis of the newly collected samples. 
Patients previously enrolled under NODE-301 Part 1: A Test Dose Randomization Visit to assess 
the safety of a second dose of etripamil NS 70 mg is required for patients previously enrolled under 
NODE-301 Part 1. This visit should occur at the time of reconsent of patients for Version 6 of the 
protocol and subsequent versions of the protocol. 
Before randomization, all patients will self-administer a test dose of the etripamil NS dosing 
regimen (an initial dose of etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg 
not earlier than 10 minutes and not later than 15 minutes after the first dose) to evaluate tolerability, 
and to train patients on the study procedures. Both doses of the etripamil dosing regimen must be 
administered for the test dose to be considered evaluable. 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).  


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• Patients who pass the test dose of the etripamil NS dosing regimen, as described above, will 
be randomized to in a 1:1 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 the etripamil dosing regimen 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 
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. 
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 VM, and self-administer study drug. A caregiver may help the 
patient with these procedures and this should be annotated in the electronic case report form 
(eCRF). Each randomized patient will receive a study kit, which includes the blinded study drug 
(2 devices pre-filled with placebo or etripamil NS 70 mg), a CMS, a study identification card, 
patient’s study instructions, and other study related material. Randomized patients will also be 
provided with patient questionnaires to be completed after experiencing a PSVT episode. The 
patient questionnaires collect information about the timing and symptoms of the patient’s PSVT 
episode and includes a Treatment Satisfaction Questionnaire for Medication (TSQM-9). 
Standardized training will be described in the MoOP. 
3.2.3 
Monthly Follow-up Visits 
Follow-up Visits will occur approximately monthly from the time of randomization until the 
patient has completed the study (i.e., throughout the Randomized and Open-Label Treatment 
Periods). These visits can be conducted by patients returning to the investigative site or by the site 
personnel contacting patients by telephone. During this visit, sites will review patient concomitant 
medications and health status 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 


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of an episode of PSVT. Routine monthly Follow-up Visits are highly recommended but are not 
mandatory. A missing Follow-up Visit will be considered a deviation of the protocol; however, 
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 preferred that 
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. 
3.2.4 
Randomized 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 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 each dose of study drug, as applicable. The CMS should not be removed, 
and the recording should continue for at least 5 hours after study drug administration; 
a. The patient should be seated prior to self-administering the first dose of study drug, 
(each dose consists of 2 sprays of study drug from a single device, one spray in each 
nostril).   
b. If symptoms of PSVT do not resolve within 10 minutes after the first dose of study 
drug, the patient should administer a second dose of study drug by using the 
additionally-provided nasal spray device. The second dose of study drug should be 
taken not earlier than 10, and not later than 15 minutes after the first dose. The patient 
may gently blow their nose to remove any excess fluid build-up immediately prior to 
self-administration of the second dose. The patient will push the CMS event marker 
button immediately prior to self-administering the second dose.  
c. In the event that a full dose (i.e., 2 sprays, one in each nostril) of study drug is not 
administered during the first dose (e.g., due to misuse of device or device malfunction), 
the patient should wait at least 10 minutes before self-administering a second dose, if 
needed.  




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3.2.6 
Open-Label Treatment Period  
All patients will perform a sequence of steps, including etripamil NS 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. 
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 etripamil NS 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 etripamil NS 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 each dose of etripamil NS 70 mg, as applicable. The CMS should not be 
removed, and the recording should continue for at least 5 hours after study drug administration; 
a. The patient should be seated prior to self-administering the first dose of etripamil NS 
70 mg, (each dose consists of 2 sprays of etripamil from a single device, one spray of 
etripamil NS 35 mg in each nostril).   
b. If symptoms of PSVT do not resolve within 10 minutes after the first dose of etripamil 
NS 70 mg, the patient should administer a second dose of etripamil NS 70 mg by using 
the additionally-provided nasal spray device. The second dose of etripamil should be 
taken not earlier than 10, and not later than 15 minutes after the first dose. The patient 
may gently blow their nose to remove any excess fluid build-up immediately prior to 
self-administration of the second dose. The patient will push the CMS event marker 
button immediately prior to self-administering the second dose.  
c. In the event that a full dose (i.e., 2 sprays, one in each nostril) of etripamil NS 70 mg 
is not administered during the first dose (e.g., due to misuse of device or device 
malfunction), the patient should wait at least 10 minutes before administering a second 
dose, if needed.  
d. Patients should not self-administer a second dose of study drug if they are experiencing 
tolerability issues believed related to the first dose (e.g., symptoms of 
lightheadedness/dizziness). 
5. Complete the provided patient questionnaires.   
a. Questionnaire regarding details of the PSVT episode being treated should be completed 
as soon as possible after termination of the treated PSVT episode;  
b. Completion of TSQM-9 should be completed as soon as possible after termination of 
the treated PSVT episode; 
6. If the symptoms of PSVT have not resolved within 30 minutes after the start of etripamil NS 
70 mg administration, patients may seek appropriate medical care and follow the steps below: 




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3.4 
Conduct of RAPID Study during COVID-19 pandemic 
To ensure the safety of trial participants in RAPID, new processes or modification of listed 
processes may be put in place to reduce the risks associated with the COVID-19 pandemic. These 
potential changes include, but are not limited to, the use of tele-medicine to conduct study visit 
procedures, conduct of study procedures outside of the clinical site (i.e., at a patient’s home) by 
site personnel or by trained but non-study personnel, allowing the Screening and Test Dose 
Randomization Visits to be conducted on the same day by using local clinical laboratory results to 
allow preliminary enrollment of the patient into the study, and the distribution of investigational 
products by alternative secure delivery methods. In the event alternative process are implemented, 
the process and the reason for the implementation for the contingency measure will be documented 
by the sponsor and clinical investigators. 
 




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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 chronic therapy with oral amiodarone, or have taken oral 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 ventricular tachycardia); 
10. Current congestive heart failure defined by the New York Heart Association Class II to IV;  
11. History of Acute Coronary Syndrome or stroke within 6 months of Screening; 
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 End-Stage Renal Disease as determined by an estimated glomerular filtration rate 
assessed at the Screening Visit of <15 mL/min/1.73m2, or requiring hemodialysis; 
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; 
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; or 
17. Previously enrolled in a clinical trial for etripamil and received study drug during a perceived 
episode of PSVT. 
 
Before randomization in the RAPID study, all patients will receive a test dose of an etripamil NS 
dosing regimen (an initial dose of etripamil NS 70 mg followed by a second dose of etripamil NS 
70 mg not earlier than 10 minutes and not later than 15 minutes after the first dose) to evaluate 
tolerability and to train patients on the study procedures.  
Both doses of the etripamil dosing regimen must be administered for the test dose to be considered 
evaluable. The second dose of etripamil NS 70 mg should not be administered if the patient reports 
tolerability issues (e.g., unacceptable local irritation, or symptoms of hypotension) immediately 
prior to the administration of the second dose, or if, in the investigator’s opinion, there are concerns 
observed on the patient’s continuous ECG monitoring or with the patient’s vital signs that would 
preclude the second dose of etripamil NS 70 mg. If patients report feeling lightheaded/presyncope, 
they should be instructed to lie down and put their feet up until the symptoms resolve. 




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• 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 Overall 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 an etripamil dosing regimen (an initial 
dose of etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg not before 10 
minutes and not later than 15 minutes after the first dose) 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 1:1 ratio to etripamil dosing regimen or placebo using IRT. 
5.2 
Rationale for Dosing 
The rationale of dosing of etripamil NS in RAPID is based on observations in the Phase 1, Phase 
2 and early Phase 3, NODE-301 Part 1 study data. 
Phase 1 
In the MSP-2017-1096 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). Previous published data indicate that a PR prolongation of approximately 8 to 
10% appears to be a pharmacodynamic marker associated with the conversion of PSVT to normal 
sinus rhythm5,6. One of the cohorts evaluated the effects of two 30 mg doses given 10 minutes 
apart and demonstrated that drug exposure and PR interval increased and remained elevated for a 
longer period as compared to the single 30 mg dose.  
In the MSP-2017-1205 (NODE-102) randomized, double-blind, placebo-controlled, ethnobridging 
PK/PD study, 35, 70 and 105 mg doses were evaluated. Etripamil exposure increased in a dose 
proportional manner between 35 and 70 mg but not between the 70 and 105 mg doses. Inter-patient 
variability and a correlation with weight were observed. The PR interval and HR were increased 
within 10 minutes and correlated to PK parameters. The pharmacodynamic effect of etripamil 
began to decrease starting at 15 minutes and lasted for up to 30-45 minutes based on the duration 
of PR prolongation exceeding 10% from baseline.  
In Phase 1 studies, an increase in TEAEs, mainly related to nasal irritation, was observed at doses 
higher than 70 mg. 
Phase 2 
Four doses (35, 70, 105, and 140 mg) were tested in the NODE-1 Phase 2 study. The 3 highest 
doses (70, 105, and 140 mg) were statistically significantly superior compared with placebo for 
terminating induced PSVT in the EPL within 15 minutes of dosing; in addition, the time to 
conversion of PSVT to SR was shorter with these doses compared with placebo. The Emax model 
of dose response indicates that these 3 doses are at the plateau of the dose response, whereas the 
35 mg dose is in the ascending portion of the curve (see Section 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 


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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 was selected as the only dose for NODE-301 Part 1. 
Phase 3 
A post hoc efficacy analysis of the NODE-301 Part 1 study demonstrated early etripamil activity, 
with a conversion rate of 54% of etripamil patients vs. 35% of placebo patients converted to SR 
by 30 minutes after drug administration, i.e., approximately a 19% absolute difference, consistent 
with a rapid onset of action, similar to what was observed in Phase 2 (NODE-1) and consistent 
with the PK of the drug. The study also showed that treatment with a 70 mg dose was safe and 
well tolerated over 5 hours following treatment in more than 100 patients in PSVT.  
These clinical data led to the adoption of a new dosing regimen for the RAPID study (NODE-301 
Part 2) in an attempt to increase the exposure and pharmacodynamic effect of etripamil. This 
dosing regimen allows patients to receive a second dose of etripamil NS 70 mg 10 minutes after 
the first dose if the symptoms of PSVT persist, thus administering a total of 140 mg etripamil NS 
only to patients who do not respond to etripamil NS 70 mg at 10 minutes. In addition, the split-
dose regimen reduces the volume of spray administered at one time in the nostrils, compared to 
what would be required to administer a higher dose of drug via a single spray. 
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 
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.  
Patients previously enrolled in Part 1 who subsequently pass a test dose of the etripamil dosing 
regimen will be re-randomized in RAPID (1:1 etripamil to placebo).  
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: 


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• 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 using an emergency code (provided in a sealed envelope to each site at study 
start-up) to unblind a patient within the IRT system. 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 intranasal (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 RAPID study is 70 mg per nasal spray device, 
using the dosing regimens described previously. The same formulation will be used for the Test 
Dose Randomization Visit and for the Randomized and Open-Label Treatment Periods 
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. All Open-Label study drug (i.e., study drug used for Test Dose 
and for Open-Label Treatment Periods) will be uniquely identified with individual kit identifiers. 
The kit identifier for each patient will be recorded in the electronic data capture (EDC) system for 
the study. 
The study drug distributor 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. 


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5.5.2 
Study Drug Administration 
Each nasal spray device delivers 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 included in each study 
drug kit and are provided in the MoOP. 
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 each drug administration, 
patients are to remain in a seated position with their head upright, breathe normally, and refrain 
from blowing their nose. Patients may gently blow their nose to remove any excess fluid build-up 
prior to administration of a second dose. A second dose of study drug should be taken not earlier 
than 10, and not later than 15 minutes after the first dose. This applies to test dose procedures, as 
well as during Randomized and Open-Label Treatment Periods to treat perceived PSVT episodes 
(if symptoms of PSVT persist 10 minutes after the first dose of study drug). 
In the event that a full dose of etripamil NS 70 mg is not administered during the initial dose (e.g., 
due to misuse of device or device malfunction), the patient should wait at least 10 minutes before 
self-administering a second dose, if needed.   
Patients should not take a second dose of study drug if they are experiencing tolerability issues 
believed related to the first dose (e.g., symptoms of lightheadedness/dizziness). If patients report 
feeling lightheaded/presyncope, they should be instructed to lie down and put their feet up until 
the symptoms resolve.   
Patients will receive study drug as determined by their treatment group assignment. 
If the BDS does not deploy, it will be considered a missed or partial dose, as applicable. 
5.5.3 
Treatment Compliance 
The patient will self-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 and Open-Label Treatment Periods of the study, study drug will be self-
administered, or administered with the help of a caregiver and this should be annotated in the 
eCRF. Patients will be required to return the used BDS devices, 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 devices such as failure in 
deployment of the BDS device, 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. 


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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. 
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 without sponsor approval. 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 
Participation in any investigational drug or device study or the use of any investigational drug or 
device from within 30 days prior to the Screening Visit through the end of the study is prohibited. 
The use of digoxin or any Class I or III antiarrhythmic drug, from within less than the equivalent 
of 5 half-lives of this drug prior to the Test Dose Randomization Visit, through the end of the 
study, is prohibited. The use of oral amiodarone from within 30 days prior to the Test Dose 
Randomization Visit, through the end of the study, is prohibited. 
Drugs for chronic prophylactic treatment of episodes of PSVT (e.g., beta-blockers, verapamil, and 
diltiazem) cannot be started after randomization. Concomitant “pill-in-pocket” use of these drugs 
to treat PSVT episodes that do not resolve after treatment with study drug should not be used for 
at least 30 minutes after the start of study drug administration.  
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 
To ensure the safety of trial participants in RAPID, and to reduce the risks associated with the 
COVID-19 pandemic by reducing the number of visits the patient is required to make to the 
investigative site, it is permitted that all Screening Visit procedures and Test Dose Randomization 
Visit procedures be conducted on the same day.   
In this case, duplicate Screening Visit blood and urine samples will be collected, one set will be 
sent to the central laboratory, and the second set will be analyzed by a local laboratory. If there are 
no exclusionary results from the local laboratory, the patient will be permitted to continue with the 
Test Dose Randomization Visit procedures. If the patient successfully completes all Screening and 
Test Dose Randomization Visit procedures, the patient will be considered preliminarily enrolled 
(pending receipt of results from the central laboratory), and will be randomized into the study. The 
patient will be dispensed study medication and all study materials, but instructed not to use the 
study medication until they are informed by the investigative site that the results have been 
received from the central laboratory, there are no exclusionary results, and the patient has been 
successfully enrolled. The official date of enrollment of the patient into the study will be the date 
the site receives the results from the central laboratory. If there are exclusionary results from the 
central laboratory, the patient will return to the site, be withdrawn from the study and complete a 
Final Study Visit. 
The local laboratory will not be certified for use in the study, and the local laboratory results will 
not be entered into the study database, but will be retained in the patient’s site study file. 
The Test Dose Randomization Visit should occur within 28 days after the Screening Visit for new 
patients enrolled into the RAPID study, and should be conducted at the time of reconsent for 


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patients previously enrolled under NODE-301 Part 1. For new patients, if the Test Dose 
Randomization visit cannot be conducted within 35 days after the Screening Visit, new blood and 
urine samples must be collected and sent for central laboratory evaluations at the Test Dose 
Randomization Visit prior to Test Dose procedures. Patients who pass the Test Dose criteria and 
are randomized will be instructed to not use double-blind study medication until it is confirmed 
that no exclusionary criteria were met following the analysis of the newly collected samples. 
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. The 
patient should be instructed that if the patient is unable to reach the Telephone Coach 
during a perceived PSVT episode, 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(s) of administration of study drug; 
o Administration of etripamil NS (as described in the MoOP); 
o Completion of post-treatment patient questionnaires; 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 self-administer a test dose of etripamil dosing regimen (an initial dose of 
etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg not earlier than 10 
minutes and not later than 15 minutes after the first dose) before randomization. Patients should 
be placed in a comfortable sitting position for a minimum of 5 minutes before starting the test 
dose administration procedure and should remain in a seated position throughout the test 
procedures. 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 45 minutes after the first dose of etripamil NS 
70 mg. 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 45 minutes after the first dose of etripamil NS 70 mg. The paper speed 


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for these recordings should be 25 mm/sec. 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 (±2 minute) for 45 minutes after the first 
dose of etripamil NS 70 mg; 
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 Administer second etripamil NS 70 mg no earlier than 10 minutes, and no later than 15 
minutes after the first dose, pushing the CMS event marker button immediately prior to 
administration. 
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. 
Both doses of the etripamil dosing regimen must be administered for the test dose to be considered 
evaluable.   
The second dose of etripamil NS 70 mg should not be administered if the patient reports tolerability 
issues (e.g., unacceptable local irritation, or symptoms of hypotension) immediately prior to the 
administration of the second dose, or if, in the investigator’s opinion, there are concerns observed 
on the patient’s continuous ECG monitoring or with the patient’s vital signs that would preclude 
the second dose of etripamil NS 70 mg.  
Patients who pass the test dose will be randomized using the IRT to obtain the study kit 
assignments (patients previously randomized in Part 1 will be re-randomized in RAPID). Each 
randomized patient will receive a study kit, which includes the blinded study drug (2 devices; 
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 patient questionnaires, to be completed 
after experiencing a PSVT episode. The patient questionnaires collect information about timing 
and symptoms of the patient’s PSVT episode and includes a TSQM-9 to assess treatment 
satisfaction. 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 dosing regimen (2 doses of etripamil NS 70 mg within 10 minutes) 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 (see Section 9.1). 
6.3 
Monthly 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 be considered a deviation of the 
protocol; however, 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 during a perceived PSVT 
episode, 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 Completion of patient questionnaires; 
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 need 
to conduct an additional test dose. The Medical Monitor should 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 may 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 may be 
necessary 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 if this cannot be confidently performed 
remotely. Patients will retain their CMS and remain in the study for subsequent episodes of PSVT. 
6.4 
Randomized 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 double-blind 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 
Randomized Treatment Period Follow-Up Visit  
A Randomized Treatment Period Follow-Up Visit will occur at the study site within 14 days after 
a patient self-administers study drug during the Randomized Treatment Period. 
The following procedures will occur at this visit: 
• Collect/review the completed patient questionnaires; 
• Record any post-dose AEs; 
• Collect and evaluate the used study drug device; 
• Evaluate any medical intervention during the Treatment Period; 
• Obtain and record vital signs (blood pressure and HR); 
• Record concomitant medications; 
• Evaluate patient’s CMS report if available 
o If CMS report is not available, ensure that all data from the patient’s CMS has been 
downloaded and sent to the cardiac monitoring core laboratory; 
• Collect urine sample for pregnancy test for females of childbearing potential;  
• Assess eligibility for the Open-Label Treatment Period, and if eligible, dispense Open-Label 
etripamil and provide patient with CMS device (ensure device has been reset), and a new 
patient questionnaires. 
6.6 
Open-Label Treatment Period  
All randomized patients who have self-administered the study drug for a perceived PSVT episode 
(Randomized Treatment Period) will be instructed to perform the steps described in Section 3.2.6 
after they have identified 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. 


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6.7 
Final Study Visit 
A Final Study Visit will occur at the study site within 14 days after a patient self-administers study 
drug during the Open-Label Treatment Period , or if for any other reason the patient has completed 
participation in the study, as described in Section 3.2.7. 
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); 
• 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; 
• Collect/review the completed patient questionnaires; 
• Record any post-dose AEs; 
• 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 Periods; 
• Perform physical examination; 
• Obtain and record vital signs (blood pressure and HR); 
• Record concomitant medications; 
• Evaluate patient’s CMS report if available 
o If CMS report is not available, 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; and 
• Close the case with IRT. 
6.8 
End of Study Telephone Follow-Up Visit 
An End of Study Telephone Follow-Up Visit will be completed approximately 30 days after the 
Final Study Visit to assess AEs. This visit is not required for patients who did not use study drug 
within 14 days prior to their Final Study Visit. 
 


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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 time to an adjudicated termination of a positively 
adjudicated episode of PSVT and conversion to SR for at least 30 seconds within 30 minutes of 
start of study drug dosing.  
The primary efficacy endpoint will be evaluated using the time to conversion of an episode of 
PSVT to SR after start of study drug administration as the primary efficacy variable. 
7.2 
Additional Efficacy Endpoints 
The additional efficacy endpoints will include: 
• Time to conversion at time points prior to, and later than, 30 minutes; 
• Time to conversion in patients with the option of repeat administration; 
• The percentage of patients requiring additional medical intervention in emergency department 
to terminate an episode of PSVT  
• 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;  
• Rating of TSQM; 
• The repeat of key efficacy endpoints in various subgroups of interest (e.g., concomitant 
medications). 
7.3 
Adjudication Process for Randomized Treatment Period 
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 4 and up to 6 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 start of study drug 
administration and PSVT termination, time to loss of recording signal (if applicable), time of a 
successful medical intervention (e.g., use of IV adenosine in a medical care facility), or if 
termination is not observed within 5 hours. The Adjudication Committee will review the full 
disclosure of the 5-hour CMS recording and will report arrhythmias and conduction disturbances 
in the eCRF. 
Further details are provided in the RAPID (NODE-301 Part 2) study Adjudication Committee 
Charter. 
7.4 
Adjudication Process for Open-Label Treatment Period 
A similar process as described in Section 7.3 will be followed to adjudicate PSVT events treated 
with etripamil during the Open-Label Treatment Period. 
 


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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 Randomized and Open-Label Treatment Periods, safety variables will be recorded, as 
detailed in Sections 6.5 and 6.7. 
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 
NOTE: An AE that is expected or known from past clinical experience or class effect of the drug 
is still considered an AE and should be collected and recorded in the 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) and the procedure will be recorded in the concomitant procedures form in 
the eCRF. 
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 


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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). 
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 


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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.  
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. 
8.1.4 Follow-up of Adverse Events 
Any AE will be followed (up to a maximum of 30 days after the patient’s last dose of study drug 
in the study) to a satisfactory resolution, until it becomes stable, or until it can be explained by 
another known cause(s) (i.e., concurrent condition or medication) and clinical judgment indicates 
that further evaluation is not warranted. All findings relevant to the final outcome of an AE will 
be included in the EDC.  
Patients who have not taken any study drug within 14 days prior to their Final Study Visit do not 
need AEs followed after their Final Study Visit. AEs ongoing at the time of database lock should 
have all available information entered into the database and be followed as described in this section 
in case the AE eventually meets an SAE criterion. 


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All SAEs should be followed until satisfactory resolution, even after database lock. 
8.1.5 
Adverse Events of Special Interest (AESI) 
Due to the pathophysiology of PSVT, certain arrhythmias may occur as part of the normal course 
of the disease, particularly during the onset and conversion of PSVT episodes. CMS holter 
abnormalities should be carefully reviewed for type, duration, relation to underlying disease, and 
general clinical context when determining if an AE occurred. Investigators should consult with the 
medical monitor if they have any questions regarding potential CMS holter abnormalities or 
arrhythmias. 
Due to the mechanism of action of etripamil, patients could be at a higher risk of certain adverse 
events of special interest. Investigators should be on the alert for these events, or for symptoms 
which indicate an event may be present. An AESI may indicate that a patient should be withdrawn 
from the study and a careful evaluation of any patients with AESI is merited. Investigators should 
contact the medical monitor if any safety concerns arise. 
Investigators should follow the standard protocol process for AE and SAE reporting for these 
AESI. 
Below is a list of AEs which are considered AESIs if they occur within 24 hours of study drug 
administration (Appendix C).   
• Tachyarrhythmias 
• Bradyarrhythmias 
• AV Block – any degree 
• Syncope and related events 
• Hypersensitivity reaction 
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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For clarity, hospitalizations for planned PSVT related ablations will not be considered 
SAEs. 
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 immediately, without undue delay, and under no circumstances later than 24 hours after 
learning 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. 


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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 
(EU): +49 89 89 55 718 44 
Safety Fax  
(USA/Canada): +1-866-336-5320 or +1-513-570-5196 
(EU): +49 89 89 55 718 104 
E-mail: medpace-safetynotification@medpace.com 
Medical Monitors 
Silvia Shardonofsky, MD 
Telephone: +1-514-336-0444, ext. 235 
E-mail: safety@milestonepharma.com 
 
Roberto Marchioli, MD 
Telephone: +39 085 9049103  
Email: roberto.marchioli@iqvia.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 


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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. 
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 
All medical device complaints are to be recorded on the appropriate eCRF. 
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 and at 
the Randomized Treatment Visit Follow-Up 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, at the Randomized Treatment Follow-Up 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 within 10 minutes before test dose administration. Following start of etripamil 
administration, vital signs will be obtained every 5 minutes (±2 minute) for 45 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 


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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. The SAP may evolve over time for reasons such as protocol 
amendments or regulatory agency’s feedback. The final SAP must be finalized prior to data base 
lock. 
The estimand of the study is the rapid conversion of PSVT to sinus rhythm in an at-home setting. 
Data from the two etripamil arms (single dose arm, and optional second dose arm) will be pooled 
for comparison to pooled data from the two placebo arms (single dose arm, and optional second 
dose arm) for all primary analyses. Sensitivity analyses looking at individual arms may be 
conducted.   
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 for a perceived episode of PSVT. 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 etripamil during a Test Dose and 
Randomization Visit, 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 randomized study drug for a 
perceived episode of PSVT. The subjects will be included in the treatment arm (placebo or double-
blind study drug) according to actual received treatment. The Safety Population also includes all 
patients who take Open-Label study medication for a perceived episode of PSVT. 
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. 


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9.2.2 
Study Drug Administration and Concomitant Medications 
Log entries detailing the 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. 
9.2.3 
Analysis Populations 
The efficacy analyses will be performed on the Efficacy Population. Additional sensitivity efficacy 
analyses and exploratory efficacy analyses will be performed on the other populations.  
The safety analyses will be performed on the Safety Population for double-blind randomized 
treatment, and for the Overall Safety population for Open-Label data. Sensitivity analyses on other 
populations and subgroups may be performed as specified in the SAP, including safety analyses 
aggregating Part 1 and Part 2, and safety analyses for the Open-Label Treatment Period. 
9.2.4 
Main Estimator (Primary efficacy endpoint and analysis) 
The main estimator (primary efficacy endpoint) for the study will be time to adjudicated 
termination of a positively adjudicated episode of PSVT and conversion to sinus rhythm (SR) for 
at least 30 seconds within 30 minutes of study drug dosing. 
Data from the single dose arm will be pooled with data from the repeat dose arm for both etripamil 
and placebo groups for the primary analysis.   
Medical intervention is a key intercurrent event in the trial. For the primary analysis, a hypothetical 
strategy will be utilized; patients who receive medical intervention will be considered as treatment 
failures, and censored at the end of the observation period. Sensitivity analyses including a 
composite strategy (analyzed via Wei Lin Weiss method) and treatment policy (with patients 
censored at time of conversion due to medical intervention) may also be conducted. 
The main estimate (primary analysis of the primary endpoint) will be derived by Kaplan Meier 
estimates of time to conversion at 30 minutes, using the Wilcoxon test. Patients who received 
medical interventions for treatment of PSVT will be censored at Minute 31. Patients who have not 
achieved conversion by Minute 30 will be censored by Minute 31. The hazard ratio (active/control) 
and two-sided 95% confidence interval (CI) will be calculated using Cox regression model with 
treatment effect.  
The primary comparison will be the difference between pooled etripamil arm (pooled data from 
the single dose arm and the optional second dose arm) and pooled placebo (pooled data from the 
single dose arm and the optional second dose arm). The secondary interest of comparison will be 
the difference of between etripamil optional second dose arm and single etripamil arm. It should 
be noted that the objective of this comparison is not to achieve significant p-value due to the sample 
sizes. Rather, the objective is to assess the trend of the optional second dosing effect. 
 


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9.2.4.1 
Sensitivity estimators 
A type I error control strategy using a hierarchical gatekeeping approach among sensitivity 
estimators (secondary endpoints) will be defined in the statistical analysis plan.  
Sensitivity estimators will include the following;  
• Tests of the duration of treatment effect, via Kaplan Meier estimates of time to 
conversion at 5, 10, 15, 45, 60, 90, 120, 180, 240, and 300 minutes. 
• Tests of the impact of a treatment regimen which includes an optional second dose, 
via comparisons of efficacy in the single dose regimen arms versus optional second 
dose arms, and comparisons of the proportion of patients who take a second dose 
within the optional second dose etripamil and placebo arms. 
• Tests of the ‘at-home setting’ component of the estimand, via comparison of the 
proportion of patients who seek additional medical intervention, rescue medication, 
or emergency medical care.  
• Tests of clinical benefits, via comparison of patient reported treatment effectiveness 
and overall satisfaction, as measured by the TSQM-9 and other patient reported 
symptoms.  
• Tests of the robustness of analysis method, via landmark analyses of conversion 
rates at 3, 5, 10, 15, 20, 30, 45, 60, and 90 minutes after drug administration.  
• Tests of the robustness of analysis method, via use of alternative censoring methods 
for patients who receive additional medical intervention, including a composite 
strategy (analyzed via Wei Lin Weiss method) and treatment policy (with patients 
censored at time of conversion due to medical intervention).  
• Tests of the robustness of statistical method, via use of Log-rank method for the 
main estimator, and sensitivity estimators using Kaplan Meier analyses.  
9.2.5 
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 separately for patients in Parts 1 and 2 of the study. Additional 
safety analyses may be conducted for all patients (Parts 1 and 2).  
9.2.6 
Sample Size Determination 
Part 1 was completed with 431 patients enrolled (completed a test dose), 419 patients randomized 
and 156 presenting with a positively adjudicated episode of PSVT. 
For Part 2 (RAPID), it is assumed that 35% of the episodes of PSVT will be converted to SR in 
the placebo group and 54% in the etripamil group by 30 minutes. These assumptions are based on 
results obtained in Part 1 of the NODE-301 study.  
A total sample size of 180 patients in Part 2 with a positively adjudicated PSVT episode, 
randomized at a range of 1:1 to 2:1 ratio (active : control) provides at least 90% power to detect a 


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significant treatment difference for the primary endpoint at a two-sided significance level of 
0.05. This sample size was calculated based on internal modeling of the Part 1 data where 
etripamil had a higher conversion rate (54% versus 35% at 30 minutes), and also a more rapid 
conversion rate (32% versus 14% at 10 minutes).  
Assuming a type I error rate of alpha = 0.05 and a ratio in the number of positively adjudicated 
episodes of PSVT etripamil:placebo between 1:1 and 2:1, a minimum of 80 positive conversion 
events will be required. Based on internal modeling, 180 patients with a positively adjudicated 
PSVT episode and 80 positive conversion events will attain greater than 90% power on the 
primary variable of time to conversion (using a 2-sided Wilcoxon test).  
It is anticipated that as many as 500 additional patients may need to be randomized in RAPID to 
accrue a sufficient number of patients in the Efficacy Population within 18 months, for a total 
between Part 1 and RAPID of over 900 patients. 
 
 


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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 following versions of the following thesauri will be used: 
• 
 MedDRA v 21.0 for medical history and AEs, and 
• WHODrug Global March 2018 B3 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. 
11.7 
Data Protection 
The Sponsor complies with applicable laws and regulations, notably the General Data Protection 
Regulation related to Personal Data protection arising from company-sponsored clinical trials 
involving EU data subjects, via a set of policies relating to data protection practice and retention 
of personal information, privacy notices and security measures, all supervised by the Data 
Protection Officer. The Sponsor and its contractors have implemented various methods to assure 
the security and integrity of personal information including, but not limited to: pseudonymization, 


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logical access controls, traceability, encryption, operating systems security, data breach 
procedures, backup, business continuity, and disaster recovery. 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. The subject will be informed 
that his/her personal study-related data will be used by the Sponsor in accordance with local data 
protection law(s). The level of disclosure will be explained to the subject. The subject will be 
informed that his/her medical records may be examined by Clinical Quality Assurance auditors or 
other authorized personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.  
The Sponsor policy requires all notified breaches to be investigated, categorized, and remediation 
activities implemented. When the rights and freedoms of the data subject are affected then data 
breaches are notified to the relevant authorities and, when there is a high risk, to the data subject. 
11.8 
Monitoring Committees 
11.8.1 
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 RAPID study Steering Committee Charter. 
11.8.2 
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 RAPID study DSMC Charter. 
11.8.3 
Adjudication Committee 
The Adjudication Committee will comprise at least 4 and up to 6 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 episode of PSVT recorded during the Randomized and Open-
Label Treatment Phase of the study. 
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.  


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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 loss of recording signal (if applicable), time of a successful medical 
intervention (e.g., use of IV adenosine in a medical care facility), or if termination is not observed 
within 5 hours. 
The conclusions 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 7.3. 
Further details are provided in the RAPID study Adjudication Committee Charter.   
11.9 
Audits and Inspections 
Authorized representatives of Milestone, a regulatory authority, or an IRB/IEC may visit the site 
to perform audits or inspections, including source data verification. The purpose of a Milestone 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted and data were recorded, analyzed, 
and accurately reported according to the protocol, GCP guidelines of the ICH, and any applicable 
regulatory requirements. The Investigator should contact Milestone immediately if contacted by a 
regulatory agency about an inspection. 
11.10 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with Milestone before any study 
data are submitted for publication. Milestone reserves the right to deny publication rights until 
mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication is achieved. 
Milestone recognizes that there is a responsibility under the regulatory guidelines to ensure that 
results of scientific interest arising from this clinical trial are appropriately published and 
disseminated. A summary of the results of this trial will be made available on 
http://www.clinicaltrialsregister.eu/ (as applicable) in accordance to the legal requirements 
(EudraCT database, § 13 (9) GCP Ordinance). 
11.11 
Financial Disclosure 
Investigators are required to provide financial disclosure information to Milestone to permit 
Milestone to fulfill its obligations under 21 CFR §54 and other appropriate international 
regulations. In addition, Investigators must commit to promptly updating this information if any 
relevant changes occur during the study and for a period of 1 year after the completion of the study. 


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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 
Montreal, QC H4M 2X6, Canada 
Telephone: +1-514-336-0444 
12.2.2 
Contract Research Organization(s) 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227, USA 
Telephone: +1-800-730-5779 
 
IQVIA Biotech 
1700 Perimeter Park Drive 
Morrisville, NC 27560, USA 
Telephone: +1-866-303-4966  
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 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 
Catalent CTS, LLC  
Address: 10245 Hickman Mills Drive,  
Kansas City, MO 64137, USA 


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Telephone: +816-767-6657   
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 
(EU): +49 89 89 55 718 44 
Safety Fax  
(USA/Canada): +1-866-336-5320 or +1-513-570-5196 
(EU): +49 89 89 55 718 104 
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 
 
Medpace Reference Laboratories Belgium (MRL-BE) 
Technologielaan 19 
B-3001 Leuven, Belgium 
Telephone: +32 16 407775 
Fax: +32 16 407781 


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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. 
5. Reiter MJ, Shand DG, Pritchett EL. Comparison of intravenous and oral verapamil 
dosing. Clin Pharmacol Ther. 1982 Dec;32(6):711-20. 
6. Prystowsky EN, Niazi I, Curtis AB, Wilber DJ, Bahnson T, Ellenbogen K, et al. 
Termination of PSVT by tecadenoson (CVT-510), a Novel A1-Adenosine Receptor 
Agonist. J Am Coll Cardiol. 2003 Sep 17;42(6):1098-102. 
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
Table 2. Schedule of Procedures 
Assessment 
Screening 
Visit1 
Test Dose 
Random-
ization 
Visit2 
Monthly 
Follow-
up Visit3 
Randomi
zed 
Treat-
ment 
Period4 
 
Randomi
zed 
Treat-
ment 
Follow-
Up Visit5 
Open-
Label 
Treat-
ment 
Period4 
Final 
Study 
Visit5 
End of 
Study 
Telephone 
Follow-Up 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility 
X6 
X7 
X8 
 
 
 
 
 
Contact the Telephone 
Coach9 
 
X 
 
X 
 
X 
 
 
Demographics/medical 
history 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
X 
 
X 
 
Physical examination 
X10 
 
 
 
 
 
X 
 
Vital signs (blood 
pressure and heart rate) 
X 
X11 
 
 
X 
 
X 
 
Hematology, chemistry, 
and urinalysis12 
X 
 
 
 
 
 
X13 
 
Pregnancy test14 
X 
X 
 
 
X 
 
X 
 
12-lead ECG15 
X 
X 
 
 
 
 
X16 
 
Test dose administration17 
 
X 
 
 
 
 
 
 
Patient training on PSVT 
episode assessments18 
 
X 
X 
 
X 
 
 
 
Randomization (via IRT) 
 
X 
 
 
 
 
 
 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
Dispense study kit19 
 
X 
 
 
X 
 
 
 
Ensure CMS data down-
loaded and sent to cardiac 
monitoring core lab 
 
X 
X20 
 
X 
 
X 
 
Review the CMS report21 
 
X 
 
 
X 
 
X 
 
Identify PSVT episode 
 
 
 
X 
 
X 
 
 
Apply and start CMS 
 
X 
 
X22 
 
X22 
 
 
Perform VM 
 
X 
 
X 
 
X 
 
 
Administer study drug 
and record time of dosing 
 
 
 
X23 
 
X23 
 
 
Complete patient 
questionnaires 
 
 
 
X 
 
X 
 
 
Evaluate medical 
intervention during the 
Treatment Period 
 
 
 
 
X 
 
X 
 
Collect study kit (used 
and unused) 
 
 
 
 
X 
 
X 
 
Identify reason(s) for 
study completion or 
withdrawal 
 
 
 
 
 
 
X 
 
Close case with IRT 
 
 
 
 
 
 
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. 


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1. 
Screening Visit can be conducted with Test Dose Randomization Visit for purposes of avoiding an extra on site visit in extenuating 
circumstances 
2. 
The Test Dose Randomization Visit should occur within 28 days after the Screening Visit for newly enrolled patients and should 
occur at the time of reconsent for patients previously randomized in NODE-301 Part 1. If the Test Dose Randomization visit cannot 
be conducted within 35 days after the Screening Visit, new blood and urine samples must be collected and sent for central 
laboratory evaluations at the Test Dose Randomization Visit prior to Test Dose procedures. Patients who pass the Test Dose criteria 
and are randomized will be instructed to not use double-blind study medication until it is confirmed that no exclusionary criteria 
were met following the analysis of the newly collected samples. 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 dosing regimen 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). Screening and Test Dose Randomization Visits can be incorporated into one visit for purposes of avoiding an extra 
on site visit in extenuating circumstances 
3. 
Monthly Follow-up Visits to occur approximately monthly via site visit or telephone (site visit preferred for patients who have an 
episode of PSVT terminated by VM). 
4. 
Randomized Treatment Period occurs from randomization until patient has an episode of PSVT treated with study drug. Open-Label 
Treatment Period occurs from after Randomized Treatment Follow-up Visit until the patient has an at-home episode treated with 
Open-Label drug. 
5. 
Randomized Treatment Follow-up Visit to occur within 14 days after a patient self-administers study drug during the Randomized 
Treatment Period. Final Study Visit to occur within 14 days after the Open-label Treatment Period, or within 14 days of the test 
dose administration for patients who fail the test dose. 
6. 
Confirmation of eligibility at Screening includes confirmation of PSVT diagnosis. Acceptable source documents to confirm the 
PSVT diagnosis are provided in the MoOP. 
7. 
Additional eligibility criteria apply to pass the test dose at the Test Dose Randomization Visit only. 
8. 
Eligibility assessments at the Monthly Follow-up Visits based on review of patient’s concomitant medications or changes in health 
status. 
9. 
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. 
10. Including height and weight. 
11. Vital signs will be obtained within 10 minutes pre-test dose and every 5 minutes (±2 minute) for 45 minutes post first test dose. 
12. Blood / urine samples can be analysed locally for purposes of preliminary enrolment if Screening/Test Dose Randomization Visits 
are combined; samples also to be sent to Central lab. Central lab results will allow enrollment in study 
13. Blood and urine tests will be performed on all patients who pass the test dose and are randomized. 
14. 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 and the Randomized Treatment Follow-Up Visit. 
15. 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. 
16. A 12-lead ECG will be performed on all patients who pass the test dose and are randomized. 
17. Before randomization, all patients will be trained on VMs and will receive a test dose of etripamil regimen (an initial dose of 
etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg not earlier than 10 minutes and not later than 15 minutes after 
the first dose) 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. 
18. 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. 
19. The study kit will include the study drug (2 devices of placebo or etripamil NS), a CMS, a study identification card, patient’s study 
instructions, and other study-related material. Patients will also be provided with patient questionnaires to be completed after 
experiencing a PSVT episode. At the Randomized Treatment Follow-up Visit, Open-Label etripamil will be provided with the CMS 
device (sites to ensure device has been reset) and new patient questionnaires. 
20. Download of CMS data during Follow-Up Visit if patient applied device without dosing study drug (e.g., VM-terminated PSVT). 
21. 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 Randomized Treatment Period and the Open-Label 


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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. 
22. The CMS recording during an episode of PSVT should continue for at least 5 hours, regardless of treatment outcome. 
23. During the Randomized Treatment Period and the Open-Label 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 30 minutes after start of 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) 
 
 


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APPENDIX C: ADVERSE EVENTS OF SPECIAL INTEREST 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Depending on the nature of 
the event rapid communication by the sponsor to other parties (e.g., regulators) might also be 
warranted. These adverse events may warrant collection of additional information across the 
studies to characterize them appropriately (e.g., laboratory parameters, vital signs, 
electrocardiograms, risk factors, concomitant illnesses, and concomitant therapies). 
Due to the mechanism of action of etripamil, patients could be at risk of certain adverse events of 
special interest if they occur within 24 hours of blinded study drug/etripamil NS administration. 
Due to the pathophysiology of PSVT, certain arrhythmias may occur as part of the normal course 
of the disease, particularly during the onset and conversion of PSVT episodes.  CMS Holter 
abnormalities should be carefully reviewed by the Principal Investigator when determining if an 
AE did occur. 
 
List of Adverse Events of Special Interest 
• Tachyarrhythmias 
o Supraventricular: 
 Occurrence of Atrial Tachycardia, Atrial Fibrillation or Atrial Flutter lasting 
longer than 30 seconds 
o Ventricular:  
 Non-Sustained Ventricular Tachycardia defined as equal or greater than 3 
consecutive wide beats originating in the ventricles at a rate >100 bpm, 
terminating spontaneously 
 Ventricular Tachycardia defined as wide consecutive beats originating in 
the ventricles at a rate >100 bpm during >30 sec or requiring termination 
due to hemodynamic compromise if less than 30 sec 
• Bradyarrhythmia 
o Any rate equal or less than 40 bpm lasting > 30 sec 
o Any pause equal or greater than 3 seconds 
• Atrioventricular Block  
o New onset (i.e., not present in the ECG performed at the screening visit) of type I 
AV block lasting greater than 30 seconds 
o Any occurrence of type II or III AV block (including AV dissociation or the 
presence of more than 2 consecutive non-conducted P waves) 


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• Syncope and related events 
o Syncope: a transient, self-limited loss of consciousness with an inability to maintain 
postural tone that is followed by spontaneous recovery. 
o Pre-syncope: terminology used to describe a series of symptoms consisting of light-
headedness, muscular weakness, blurred vision, and feeling faint. To avoid any 
confusion with syncope, preferably describe the symptoms and avoid using this 
terminology if there is no loss of consciousness. 
o Loss of consciousness: a partial or complete loss of consciousness with interruption 
of awareness of oneself and one’s surroundings. When the loss of consciousness is 
temporary and there is spontaneous recovery, it is referred to as syncope 
o Dizziness: a false sense of motion or spinning, light-headedness or feeling faint, 
unsteadiness or a loss of balance, a feeling of floating, wooziness, or heavy 
headedness. The episode may last seconds or more and may recur. 
o Drop-attack: a sudden fall without loss of consciousness. 
o Hypotension: defined as a systolic blood pressure (SBP) <90 mmHg after a 5-
minute rest in sitting position; when clinically severe hypotension patients 
experience light-headedness, nausea or vomiting 
o Orthostatic hypotension: a physical finding defined as a systolic blood pressure 
decrease of at least 20 mmHg or a diastolic blood pressure decrease of at least 10 
mmHg within three minutes of standing 
• Hypersensitivity reaction 
 
 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
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 
 
Investigational Product: 
MSP-2017 (etripamil) 
Protocol Number: 
MSP-2017-1138 (NODE-301) 
Phase: 
3 
Original Protocol: 
08 November 2017 V1 
Amendment 1 
05 January 2018 V2 
Amendment 2 
20 February 2018 V3 
Amendment 3 
04 October 2018 V4 
Amendment 4 
09 July 2019 V5 
Amendment 5 
16 July 2020 V6 
Amendment 6 
01 March 2021 V7 
Amendment 7 
14 January 2022 V8 
Statistical Analysis Plan Version: 
1.00 
Statistical Analysis Plan Date: 
6 June 2022 
 
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/Institutional Ethics Committee and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Milestone Pharmaceuticals Inc. and that it may not be further disclosed 
to third parties. 
 
DocuSign Envelope ID: 4510CBA3-5B28-4486-9544-38359544272D


Milestone Pharmaceuticals Inc.  
MSP-2017-1138 NODE-301 Part 2 
CONFIDENTIAL 
V1.00 
Statistical Analysis Plan 
  
6 Jun 2022 
 
Page 2 of 38 
 
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 RAPID Study (NODE-301 Part 2) 
 
Prepared by 
David Feng, MS 
Senior Statistician 
TCM Groups, Inc. 
 
Approved by 
 
Signature 
      Date 
 
 
________________________________ 
_____________________ 
Michael Chen, PhD  
President 
TCM Groups, Inc. 
 
 
 
________________________________ 
_____________________ 
Jeff Nelson 
COO 
Milestone Pharmaceuticals Inc. 
 
 
 
________________________________ 
_____________________ 
Francis Plat, MD 
CSO 
Milestone Pharmaceuticals Inc. 
 
 
Digitally signed by Jeff 
Nelson 
Date: 2022.06.11 13:27:28 
-04'00'
DocuSign Envelope ID: 4510CBA3-5B28-4486-9544-38359544272D
6/14/2022
6/11/2022


Milestone Pharmaceuticals Inc.  
MSP-2017-1138 NODE-301 Part 2 
CONFIDENTIAL 
V1.00 
Statistical Analysis Plan 
  
6 Jun 2022 
 
Page 3 of 38 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................... 6 
2. 
STUDY CHARACTERISTICS................................................................................. 6 
2.1 
Study Objectives ........................................................................................................ 6 
2.1.1 
Primary Objective ............................................................................................... 6 
2.1.2 
Secondary Objectives .......................................................................................... 6 
2.1.3 
Exploratory Objectives ....................................................................................... 6 
2.2 
Study Design .............................................................................................................. 7 
2.2.1 
Treatment Regimen and Dosage ....................................................................... 10 
2.2.2 
Drug Randomization ......................................................................................... 11 
2.2.3 
Study Drug Administration ............................................................................... 11 
3. 
EFFICACY ASSESSMENTS ................................................................................. 12 
3.1 
Primary Efficacy Endpoint ...................................................................................... 12 
3.2 
Additional Efficacy Endpoints ................................................................................ 12 
3.3 
Adjudication Process for Randomized Treatment Period ....................................... 13 
3.4 
Adjudication Process for Open-Label Treatment Period ......................................... 13 
4. 
SAFETY ASSESSMENTS ..................................................................................... 13 
4.1 
Adverse Events ........................................................................................................ 14 
4.2 
Serious Adverse Event ............................................................................................. 14 
4.3 
Pregnancy Reporting ............................................................................................... 14 
4.4 
Clinical Laboratory Evaluations .............................................................................. 14 
4.5 
Vital Signs ............................................................................................................... 15 
4.6 
Electrocardiograms .................................................................................................. 15 
4.7 
Physical Examinations ............................................................................................. 15 
5. 
STATISTICAL METHODOLOGY ........................................................................ 15 
5.1 
Analysis Populations ............................................................................................... 15 
5.1.1 
Overall Safety Population ................................................................................. 15 
5.1.2 
Safety Population .............................................................................................. 15 
5.1.3 
Test Dose Only Population ............................................................................... 16 
5.1.4 
Modified intent-to-treat (mITT) Population ..................................................... 16 
5.1.5 
Efficacy Population ........................................................................................... 16 
5.2 
General Convention ................................................................................................. 16 
5.2.1 
Treatment Group ............................................................................................... 16 
5.2.2 
Data Presentation Convention ........................................................................... 17 
5.2.3 
Baseline Convention ......................................................................................... 17 
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5.2.4 
Software Convention......................................................................................... 17 
5.2.5 
Missing Value Imputation Convention ............................................................. 17 
5.2.6 
SAP Version Control Convention ..................................................................... 17 
5.3 
Description of Study Population .............................................................................. 18 
5.3.1 
Disposition ........................................................................................................ 18 
5.3.2 
Demographic and Baseline Characteristics....................................................... 18 
5.3.3 
Medical History................................................................................................. 18 
5.3.4 
Prior and Concomitant Medication ................................................................... 18 
5.3.5 
Study Drug Administration ............................................................................... 19 
5.4 
Efficacy Analyses .................................................................................................... 19 
5.4.1 
Primary Efficacy Endpoint Analyses ................................................................ 19 
5.4.2 
Secondary Endpoint Analyses - Patient Reported 9-Item Treatment 
Satisfaction Questionnaire for Medication and Symptom Outcomes ............... 21 
5.4.3 
Other Secondary Efficacy and Robustness/Sensitivity Analyses. .................... 22 
5.4.4 
Controlling Type I Error for Multiple Comparisons ......................................... 24 
5.5 
Analysis of Safety .................................................................................................... 24 
5.5.1 
Adverse Events ................................................................................................. 25 
5.5.2 
Clinical Laboratory Tests .................................................................................. 26 
5.5.3 
Vital Signs ......................................................................................................... 26 
5.5.4 
Electrocardiograms and Cardiac Monitoring System recordings ..................... 27 
5.5.5 
Physical Examination ........................................................................................ 27 
6. 
INTERIM ANALYSIS ............................................................................................ 28 
7. 
SAMPLE SIZE DETERMINATION ...................................................................... 28 
8. 
PROGRAMMING SPECIFICATIONS .................................................................. 28 
APPENDIX A:  SCHEDULE OF PROCEDURES ............................................................. 29 
APPENDIX B:  TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION BASED ON AN ABBREVIATED 9 ITEMS (TSQM-9) ............. 32 
APPENDIX C:   PSVT SYMPTOMS RECORDS IN ECRF ............................................. 34 
APPENDIX D: CLINICAL LABORATORY ANALYTES ............................................... 36 
APPENDIX E: SUBGROUPS OF INTEREST ................................................................... 37 
APPENDIX F: IMPUTATION OF MISSING DATES ...................................................... 38 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term  
Definition 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
AV 
Atrioventricular  
AVNRT  
Atrioventricular Nodal Reentry Tachycardia 
AVRT  
Atrioventricular Reentrant Tachycardia 
BDS 
Aptar Pharma Nasal Spray Bidose System 
CI 
Confidence Interval 
CMS 
Cardiac Monitoring System 
DBP 
Diastolic Blood Pressure 
DSMC 
Data Safety Monitoring Committee  
EEAC 
ECG 
ECG Events Adjudication Committee 
Electrocardiogram 
eCRF 
Electric Case Report Form 
EDC 
Electronic Data Capture 
EP 
Electrophysiology 
HR 
Heart Rate 
IRT 
Interactive Response Technology 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent To Treat 
MM 
Medical Monitor 
MoOP 
Manual of Operations and Procedures 
NS 
Nasal Spray  
OR 
Odds Ratio 
PAC 
Premature atrial contraction  
PSVT 
Paroxysmal Supraventricular Tachycardia 
PT 
Preferred Term 
PVC 
Premature ventricular complex  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SOC 
System Organ Class 
SR 
Sinus Rhythm 
TEAE 
Treatment Emergency Adverse Event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
TSQM-9 
An abbreviated TSQM based on 9 items 
TTC 
Time to Conversion 
ULN 
Upper Limit of Normal 
VM 
Vagal Maneuver 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) is based on Milestone Pharmaceutical’s “RAPID Study” that 
is Part 2 of NODE-301, Protocol Number MSP-2017-1138, Version 8, dated 14 January 2022.  
 
This document provides details on statistical analysis methodologies to be used to analyze the 
efficacy and safety data from Part 2 of the NODE-301 study, including definitions for study 
populations, the rules to derive variables such as censoring variables and rules to handle missing 
data, as well as details on analysis models and methods to be used.  It should be noted that this 
SAP is prepared specifically for Part 2 of the NODE-301 study (referred to as the RAPID study).  
A separate SAP for Part 1 of NODE-301 was developed and executed prior to the unblinding of 
that dataset.   
 
This document may evolve over time, for example, to reflect the requirements of protocol 
amendments or regulatory requests. However, the final SAP must be completed, approved by the 
Sponsor, submitted to regulatory agencies as applicable, and placed on file before the database is 
locked and treatment codes are unblinded. The approved plan will be used to carry out all analyses 
for the clinical study report. Deviations, if any, from the approved plan will be noted in the clinical 
study report. 
2. 
STUDY CHARACTERISTICS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective of this study is to determine whether etripamil nasal spray (NS) self-
administered by patients is superior to placebo at terminating episodes of paroxysmal 
supraventricular tachycardia (PSVT) in a at-home setting. 
2.1.2 
Secondary Objectives 
The secondary objective of this study is to evaluate the safety of etripamil NS when self-
administered by patients without medical supervision. 
2.1.3 
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, 
• To evaluate the safety and efficacy of etripamil NS in various subgroups of interest (e.g., 
concomitant medications), and 
• To evaluate the safety and efficacy of a treatment  regimen of etripamil NS which allows 
a repeat dose of etripamil NS to terminate episodes of PSVT in an at-home setting. 
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2.2 
Study Design  
NODE-301 is a multi-center, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of etripamil NS self-administered by patients who experience an episode of 
PSVT in an at-home 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 NODE-301 study will comprise of 2 parts, Part 1 and Part 2.  This SAP will pertain to Part 2 
of the NODE-301 study (the RAPID study). 
RAPID (NODE-301 Part 2) will consist of: 
• New patients enrolled following protocol version 6.0 (and subsequent versions) 
implementation 
• Patients enrolled prior to protocol version 6.0 implementation and who were not dosed 
with the double-blind study drug, or had not discontinued the study before the adjudication 
of the 150th positively adjudicated PSVT episode in Part 1. 
The RAPID study will test the treatment effect of etripamil (a dosing regimen of either single 
dose or second dose, if symptoms persist after 10 minutes), in a population of patients having a 
perceived episode of PSVT in an at-home setting, as measured by time to conversion. 
Enrollment into RAPID will continue until the 180th positively adjudicated PSVT episode in 
Part 2 patients. See the sample size determination section (Section 9.2.6 of the protocol) for 
additional details. RAPID will continue for approximately 6 months after the date of the 
adjudication of the 180th positively adjudicated PSVT episode. All patients not unblinded as part 
of the RAPID pivotal analysis will be unblinded at the end of the study. 
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Figure 1. NODE-301 Patient Flow, Part 1 and Part 2 
 
 
 
 
 
A. Primary Analysis for RAPID study will pool the Etripamil single dose and optional second 
dose arms from Part 2 only, and compare to the pooled Placebo single dose and optional 
second dose arms from Part 2 only 
B. All patients who did not have an episode by cutoff date in Part 1 remain fully blinded 
Note: PSVT and non-PSVT determined by independent adjudication committee 
 
The study will include a Screening Visit, a Test Dose Randomization Visit, Monthly Follow-up 
Visits, a Randomized Treatment Period, a Randomized Treatment Period Follow-Up Visit, an 
Open-Label Treatment Period, and a Final Study Visit. 
Screening Visit 
NODE-301 Part 1 
RAPID Study (NODE-301 
Part 2) 
A 
A 
A 
A 
B 
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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 
See Section 6.2 for a full list of Test Dose Randomization Visit procedures. As detailed in that 
section, it is permitted to conduct the Screening and Test Dose Randomization Visit procedures 
on the same day, using a local laboratory to conduct preliminary clinical safety evaluations. 
Newly Enrolled Patients: The initial Test Dose Randomization Visit for newly enrolled patients 
must occur within 28 days after the Screening Visit. 
Patients previously enrolled under NODE-301 Part 1: A Test Dose Randomization Visit to assess 
the safety of a second dose of etripamil NS 70 mg was required for patients previously enrolled 
under NODE-301 Part 1. This visit should occur at the time of reconsent of patients for Version 
6 and subsequent versions of the protocol. 
Before randomization, all patients will receive a test dose of the etripamil NS dosing regimen (an 
initial dose of etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg not earlier 
than 10 minutes and not later than 15 minutes after the first dose) to evaluate tolerability and to 
train patients on the study procedures. All patients who pass the test dose of the etripamil NS 
dosing new regimen will be given a study kit, which includes the blinded study drug (2 devices 
pre-filled with placebo or etripamil NS 70 mg), a CMS, a study identification card, patient’s study 
instructions, and other study-related material.  
Both doses of the etripamil dosing regimen must be administered for the test dose to be considered 
evaluable.  The test dose administration will take place at the study site under medical supervision 
while the patient is in sinus rhythm (SR).  
Patients who pass the test dose of the etripamil NS dosing regimenwill be randomized to in a 1:1 
ratio to etripamil or placebo using an Interactive Response Technology (IRT) system, and will be 
given a study kit, including double-blind study medication to treat a PSVT episode in an at-home 
setting. 
Monthly Follow-up Visits 
Follow-up Visits will occur approximately monthly from the time of randomization until the 
patient has completed the study (i.e., during the Randomized and Open-Label Treatment 
Periods).  
These visits can be conducted by patients returning to the investigative site or by the site 
personnel contacting patients by telephone. 
Randomized Treatment Period 
When randomized patients identify symptoms of an episode of PSVT, they will perform a 
sequence of steps, including placement of CMS device on his/her chest and study drug self-
administration. A caregiver may help the patient with these procedures, and this should be 
annotated in the electronic case report form. Self-administration of the study drug regimen 
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during a PSVT episode is as follows: an initial dose of etripamil NS 70 mg (or placebo) followed 
by a second dose 10 minutes later if the patient continues to experience PSVT symptoms 
(patients who are symptom-free before 10 minutes do not repeat dosing). 
Randomized Treatment Period Follow-Up Visit 
A Randomized Treatment Period Follow-Up Visit will occur at the study site within 7 days after 
a patient self-administers study drug during the Randomized Treatment Period. Patients without 
tolerability issues will be entered into the Open-Label Treatment Period. 
Open-Label Treatment Period 
All patients will perform a sequence of steps, including etripamil 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. Self-administration 
of the study drug regimen during a PSVT episode is as follows: an initial dose of etripamil NS 70 
mg followed by a second dose 10 minutes later if the patient continues to experience PSVT 
symptoms (patients who are symptom-free before 10 minutes do not repeat dosing). 
Final Study Visit 
A Final Study Visit will occur at the study site within 7 days after a patient self-administers 
study drug during the Open-Label Treatment Period, or if for any other reason the patient has 
completed participation in the study. 
End of Study Telephone Follow-Up 
An End of Study Telephone Follow-Up Visit will be completed approximately 30 days after the 
Final Study Visit to assess adverse events (AEs). This visit is not required for patients who did 
not use study drug within 14 days prior to their Final Study Visit. 
2.2.1 
Treatment Regimen and Dosage  
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 RAPID study is 70 mg per nasal spray device, 
using the dosing regimens described previously. The same formulation will be used for the Test 
Dose Randomization Visit and for the Treatment Periods. 
 
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: Each nasal spray device delivers 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 kit. 
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2.2.2 
Drug Randomization 
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 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. 
 
Patients previously enrolled in Part 1 who subsequently pass a test dose of the etripamil dosing 
regimen will be re-randomized in RAPID (1:1 etripamil to placebo), however they will keep the 
same patient identification number. 
 
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.  
2.2.3 
Study Drug Administration 
Each nasal spray device delivers 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 included in each 
study drug kit and are provided in the MoOP. 
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 each drug 
administration, patients are to remain in a seated position with their head upright, breathe 
normally, and refrain from blowing their nose. Patients may gently blow their nose to remove 
any excess fluid build-up prior to administration of a second dose. A second dose of study drug 
should be taken not earlier than 10 minutes, and not later than 15 minutes after the first dose. 
This applies to test dose procedures, as well as during Randomized and Open-Label Treatment 
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Periods to treat perceived PSVT episodes (if symptoms of PSVT persist 10 minutes after the first 
dose of study drug). 
In the event that a full dose of etripamil NS 70 mg is not administered during the initial dose 
(e.g., due to misuse of device or device malfunction), the patient should wait at least 10 minutes 
before self-administering a second dose, if needed. 
Patients should not take a second dose of study drug if they are experiencing tolerability issues 
believed related to the first dose (e.g., symptoms of lightheadedness/dizziness). If patients report 
feeling lightheaded/presyncope, they should be instructed to lie down and put their feet up until 
the symptoms resolve. 
Patients will receive study drug as determined by their treatment group assignment.  If the BDS 
does not deploy, it will be considered a missed or partial dose, as applicable. 
3. 
EFFICACY ASSESSMENTS 
Efficacy assessments will be based on the data derived from CMS recordings. The Adjudication 
Committee will evaluate the ECG data recorded from patients to determine if a true PSVT 
episode occurred.  To avoid potential bias, the determination of true PSVT should be made based 
on the portion of the ECG recordings excluding any ECG after study drug is administered.   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 PSVT Symptom Questionnaire and TSQM. 
3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as time to an adjudicated termination of a positively 
adjudicated episode of PSVT and conversion to SR for at least 30 seconds within 30 minutes of 
start of study drug dosing. This is calculated as the time in seconds from study drug initiation to 
termination of the PSVT episode as determined by the independent Adjudication Committee.   
3.2 
Additional Efficacy Endpoints 
The additional efficacy endpoints will include: 
• Time to conversion at time points prior to, and later than, 30 minutes; 
• Time to conversion in patients with the option of repeat administration; 
• The percentage of patients requiring additional medical intervention in emergency 
department to terminate an episode of PSVT 
• Relief of specific symptoms (i.e., heart palpitations, rapid pulse feeling, chest pain, anxiety, 
shortness of breath, dizziness, and fainting) potentially associated with the current episode 
of PSVT   
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• Rating of TSQM-9 and symptoms. 
• The repeat of key efficacy endpoints in various subgroups of interest (e.g., concomitant 
medications) See Appendix E for listing. 
3.3 
Adjudication Process for Randomized Treatment Period  
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 4 and up to 6 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. 
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 start of study drug 
administration and PSVT termination, time to loss of recording signal (if applicable), time of a 
successful medical intervention (e.g., use of IV adenosine in a medical care facility), or if 
termination is not observed within 5 hours. The Adjudication Committee will review the full 
disclosure of the 5-hour CMS recording and will report arrhythmias and conduction disturbances 
in the eCRF. 
Further details are provided in the RAPID (NODE-301 Part 2) study Adjudication Committee 
Charter. 
3.4 
Adjudication Process for Open-Label Treatment Period 
A similar process to the one used for double blind treatment will be followed to adjudicate PSVT 
events treated with etripamil during the Open-Label Treatment Period.  
4. 
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.  
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During the etripamil NS 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 safety assessments will be summarized in some or all of 
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; 
see Appendix E) for pre-defined subgroup analyses. 
Detailed AE assessments can be found in Section 8 of the protocol.   
4.1 
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. 
4.2 
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, 
• An event that requires hospitalization or prolongation of existing 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. 
4.3 
Pregnancy Reporting 
Patients are requested to report to the Investigator any pregnancies of themselves or their partner(s) 
that occur within 30 days of study drug administration. The Investigator should report the 
pregnancy to Medpace Clinical Safety within 24 hours of notification. 
4.4 
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 C for a list of clinical laboratory analytes. 
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4.5 
Vital Signs 
Vital signs (i.e., SBP, DBP, and HR) will be obtained at the Screening Visit, at the Test Dose 
Randomization Visit, at the Randomized Treatment Follow-Up 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 within 10 minutes  before test dose administration. Following etripamil 
administration, vital signs will be obtained every 5 minutes (±1 minute) for 45 minutes after the 
first dose of etripamil NS 70 mg. Vital signs will also be obtained if the patient reports any 
symptom potentially related to drop in blood pressure. 
4.6 
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.  
4.7 
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. 
5. 
STATISTICAL METHODOLOGY 
The pivotal analyses will be conducted after the 180th positively adjudicated PSVT episode is 
documented. Only patients who have dosed with double-blind study drug or have discontinued the 
study before the adjudication of the 180th positively adjudicated PSVT episode will be included in 
the primary, secondary and exploratory efficacy analyses of the pivotal analysis.  
5.1 
Analysis Populations 
5.1.1 
Overall Safety Population 
The Overall Safety Population includes all patients who take any study drug (test dose or 
randomized study drug, or both). 
5.1.2 
Safety Population 
The Safety Population includes all randomized patients who take the randomized study drug for 
a perceived episode of PSVT. The patients will be included in the treatment arm according to  
actual received treatment. The safety population also includes all patients who take the Open-
Label study medication for a perceived episode of PSVT.   
The primary safety analyses will be based on this Safety Population. 
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5.1.3 
Test Dose Only Population 
The Test Dose Only (TD) Population includes all patients who receive a Test Dose but do not 
self-administer double blind randomized drug (Overall safety population, minus the safety 
population). 
Safety data for the TD Population will also be presented. 
5.1.4 
Modified intent-to-treat (mITT) Population 
The mITT Population includes all randomized patients who take the randomized study drug for a 
perceived episode of PSVT.  The patients will be included in the treatment arm in which they are 
randomized to. 
The mITT population is expected to be the same as the Safety Population unless patients take the 
drug that is different from what they are randomized to receive.  Data for mITT may not be 
presented separately unless the two populations are differed by more than 10 patients. 
5.1.5 
Efficacy Population 
The Efficacy Population includes all mITT patients who take the study drug to treat a positively 
adjudicated episode of PSVT. This population will exclude patients who take the study drug for a 
negatively adjudicated episode of PSVT (i.e., symptoms not associated with an episode of 
PSVT) or PSVT episodes that resolve prior to first administration of study drug. These excluded 
patients will be included in mITT population.   
The primary efficacy analyses will be based on this Efficacy Population.  
5.2 
General Convention 
5.2.1 
Treatment Group 
Patients enrolled or re-enrolled after NODE-301 protocol amendment 6 (starting of the RAPID 
Study and addition of optional second dose) are randomized to one of the two treatment groups: 
Etripamil Group (Active Group) or Placebo Group (Control Group).  Most patients within each 
group will have the opportunity to take an optional second dose of study drug, self-administered 
only if PSVT episode symptoms do not resolve within 10 minutes after first dose.  A small set of 
patients (n=33) who took study drug for an episode after the Part 1 cutoff date, but prior to 
amendment 6 are in the single dose arms, reflecting their absence of an option of a repeat dose. 
Unless otherwise stated, Active Group will refer to the pooled etripamil arms in Part 2 (single 
dose arm, and optional second dose arm) and Placebo Group will refer to the pooled placebo 
arms in Part 2 (single dose arm, and optional second dose arm).  The primary comparisons will 
be between Active Group and the Placebo Group. 
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5.2.2 
Data Presentation Convention 
Unless otherwise stated, all hypothesis tests will be conducted at a two-sided significance level 
of 0.05. P-values will be presented with 3 decimals and p values that are less than 0.001 will be 
presented as <0.001. 
Continuous data will be summarized using descriptive statistics: number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum. Frequencies and percentages 
will be used to summarize categorical (discrete) data. Presentations of categorical data will 
generally suppress percentages for items where the count is zero in order to draw attention to the 
nonzero counts. In general, mean, standard deviation, median, minimum, maximum, and 
percentages will be presented with one decimal. 
Unless otherwise stated, confidence intervals, when presented, will be constructed at the two-
sided 95% level. For binomial variables, the 95% confidence intervals will be constructed using 
the normal approximation without continuity correction. 
Data listings will present all data collected on case report forms (CRFs) by study drug, center, 
and patient number. 
5.2.3 
Baseline Convention 
Unless otherwise stated, the baseline is the last observed measurement prior to or on the date of 
randomization. 
5.2.4 
Software Convention 
Unless otherwise stated the following software will be used: 
• Analyses will be performed using SAS Version 9.4;   
• All medical history and AEs will be coded using MedDRA v 21.0; 
• All prior medication and concomitant medication will be coded using WHODrug Global 
March 2018 B3. 
5.2.5 
Missing Value Imputation Convention 
Unless otherwise stated missing values will not be imputed.  Missing AE and concomitant 
medication dates will be imputed based on the methods outlined in Appendix F. 
5.2.6 
SAP Version Control Convention 
The first approved versions of the SAP will be numbered sequentially as Version 1.00. As 
mentioned in the introduction, the SAP may evolve over time due to reasons such as protocol 
amendment or regulatory feedback, the subsequent approved version will be numbered as 
sequentially as Version 1.0i. The reason for the changes must be documented in the SAP history 
log.  The final version to be used for the analysis must be filed before the data base lock and 
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labelled as Final Version 1.xy.  The Clinical Study Report will document any changes made after 
the Final Version.  
5.3 
Description of Study Population  
5.3.1 
Disposition 
Patient disposition summaries will be presented by treatment arm and will include the number of 
patients randomized, the number and percentage of randomized patients in each of the pre-
defined study populations, the number and percentage of patients who received drug during the 
open-label follow-up period,  as well as the number and percentage of patients who complete the 
study. The summaries will also include the reasons for early discontinuation from the study, and 
the alternative diagnoses for patients who were not in PSVT as the time they took study drug for 
a perceived episode.  
For TD patients who do not proceed to randomization, or randomized patients who do not 
proceed to the open-label follow-up period, the primary reason for discontinuation will be listed. 
5.3.2 
Demographic and Baseline Characteristics 
Summary statistics will be provided by treatment group for demographic characteristics 
(e.g., age, gender, race, and ethnicity) and for baseline disease variables (e.g., age at 
confirmation of PSVT, demonstrated history of sustained PSVT, number of PSVT in the past 
year, number of visits to emergency department in life time, and past disease or surgery). A 
listing of all demographic data will be provided. Summary statistics for demographic of special 
interest will be provided. Please refer to Appendix E for special interest subgroup. 
5.3.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
21.0) and summarized by treatment group. A listing of all medical history will be provided. 
5.3.4 
Prior and Concomitant Medication 
All prior and concomitant medications administered during the study will be coded using ATC 
Level 4 of the WHO Drug Dictionary March 2018 B3 version. Prior medications include 
medications that are started and stopped prior to the start date and time of the test dose. 
Concomitant medications include medications that start any time and are taken at any time after 
the start date and time of the test dose until the end of the follow-up period. Medications missing 
both start and stop dates or having a start date prior to the start of test study drug and missing 
stop date will be counted as concomitant. 
The number and percentage of patients taking prior and concomitant medications will be 
summarized by Anatomical Therapeutic Chemical (ATC) class and preferred name by treatment 
group.  
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A listing of all medications including the reported term, preferred term, ATC class, start and stop 
dates, and other relevant data will be provided. 
5.3.5 
Study Drug Administration 
The eCRF data detailing the administration of the test dose and the administration of the study 
drug (etripamil or placebo) to randomized patients will be listed. Whether a patient took one or 
two doses of study drug, and the time of second dose administration, and whether the patient was 
in PSVT when taking a second dose for a perceived episode will also be listed.  If the study drug 
device is not fully deployed for a device, half dose will be reported. 
5.4 
Efficacy Analyses  
The estimand of the study is to test the rapid treatment effect of Etripamil (a dosing regimen of 
either single or optional second dose) in a population of patients having an episode of PSVT in 
an at-home setting, as measured by time to conversion.  The main estimator is the Kaplan Meier 
analysis of time from study drug initiation to conversion from PSVT into normal sinus rhythm. 
The main estimate is the relative hazard ratio between Etripamil and Placebo treatment. A key 
intercurrent event is patients who seek rescue medical intervention prior to conversion to normal 
sinus rhythm.   
Patients enrolled or re-enrolled after NODE-301 protocol amendment 6 (starting of the RAPID 
Study and addition of optional second dose) are randomized to one of the two treatment groups: 
Etripamil Group (Active Group) or Placebo Group (Control Group).  Most patients within each 
group will have had the opportunity to self-administer an optional second dose of study drug, 
only if the PSVT episode does not resolve within 10 minutes after first dose.   A small set of 
patients who took study drug for an episode after the Part 1 cutoff date, but prior to amendment 6 
are in the single dose arms. 
Unless otherwise stated Active Group will refer to the pooled etripamil arms in Part 2 (single 
dose arm, and optional second dose arm) and Placebo Group will refer to the pooled placebo 
arms in Part 2 (single dose arm, and optional second dose arm).  The primary comparisons will 
be between the Active Group and the Placebo Group.   
In addition, analyses based on the single dose arms and the optional second dose arms will also 
be provided.  The purpose of these analyses is not to detect a significant difference, due to the 
small sample size in single dose arms;rather, these analyses are performed to evaluate any trend. 
5.4.1 
Primary Efficacy Endpoint Analyses 
The primary endpoint is Time to Confirmed Conversion by Minute 30 (TTC30) defined as time 
to adjudicated termination of a positively adjudicated episode of PSVT and conversion to sinus 
rhythm (SR) for at least 30 seconds within 30 minutes of study drug dosing. 
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5.4.1.1 Derivation of Primary Endpoint 
The following rules will be used to derive the conversion time and censoring rules for 
adjudicated episodes of PSVT: 
1. For patients who achieved a confirmed conversion by Minute 30, TTC30 will be set to the 
conversion time with the censoring indicator equal to 0 (No). 
2. For patients who fail to achieve the confirmed conversion and who have achieved the 
confirmed conversion after Minute 30, TTC30 will be set to 31 with the censoring indicator 
equal to 1 (Yes). 
3. For patients who receive medical intervention (e.g., taking or being administered a rescue 
medication or physician assisted VM) to treat their current episode before Minute 30, 
TTC30 will be set to Minute 31 with the censoring indicator equal to 1 (Yes). 
4. For patients whose recordings are interrupted (e.g., mechanical failures) before Minute 30, 
TTC30 will be set to the time when the interruptions occur with the censoring indicator 
equal to 1 (Yes). 
5. Minute 0 will be set as the time of administration of the first dose of study drug. 
5.4.1.2 Primary Analysis of Primary Endpoint 
Analysis of Primary Endpoint TTC30 will be analyzed via SAS Lifetest procedure using 
Wilcoxon test.   
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.  The Kaplan-Meier estimate 
of the time at which 25%, 50%, and 75% of adjudicated episodes of PSVT conversions occur 
will be calculated, if estimable.   
Conversion rates at 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, and 300 minutes will be summarized 
descriptively.  The percentages, the differences between the percentages, odds ratio, relative risk 
ratio, and the 2-sided 95% confidence intervals of the difference will be presented.  
Sample SAS code: 
**************************************************************************  
Note: STATUS = censored status (1 = censored, 0 = event occurred) 
TREATMENT = treatment group (0 = Placebo, 1= MSP-2017 70 mg)  
*************************************************************************;  
PROC LIFETEST timelist= 5 10 15 20 25 30; 
 
TIME TTC30*STATUS (1)/ test=WILCOXON; 
 
STRATA TREATMENT; 
RUN; 
PROC PHREG; 
 
CLASS TREATMENT; 
 
MODEL TIME*STATUS (1) = TREATMENT; 
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RUN; 
 
   
5.4.2 
Secondary Endpoint Analyses - Patient Reported 9-Item Treatment Satisfaction 
Questionnaire for Medication and Symptom Outcomes 
5.4.2.1 Treatment Satisfaction Questionnaire for Medication 9-Item  (TSQM-9) 
TSQM-9 is an abbreviated 9-item TSQM.  Ratings on TSQM-9 (please refer to Appendix B for 
TSQM) are captured in the eCRF. 
The second question from TSQM-9 will be used for the analysis of relief of specific symptoms 
which are collected for an episode. Specific symptoms are collected as a Yes/No answer for a 
patient episode in the eCRF, these symptoms include Rapid Pulse, Palpitations, Shortness of 
Breath, Chest Tightness, Feeling Dizzy or Lightheaded, Fainting or Passing Out, and Anxiety.   
Treatment satisfaction will be analyzed by comparing the score of TSQM-9 for effectiveness, 
convenience, and global satisfaction domain in the 2 treatment groups. Please refer to Appendix 
B for TSQM-9. 
TSQM-9 scale scores range from 0 to 100 and no computed score should be lower or higher than 
these limits. Of note, a score can be computed for a domain only if no more than one item is 
missing from that domain. The calculations specific to each domain are presented in detail 
below: 
Effectiveness:  
([(Question 1 + Question 2 + Question 3) − 3] divided by 18) × 100 
If one item is missing: ([(Sum(the two completed items) – 2] divided by 12) * 100 
Convenience:  
([(Question 4 + Question 5 + Question 6) − 3] divided by 18) × 100 
If one item is missing: ([(Sum(the two completed items) – 2] divided by 12) * 100 
Global satisfaction:  
([(Question 7 + Question 8 + Question 9) − 3] divided by 14) × 100 
If either Item 7 or 8 is missing ([(Sum(the two completed items)) – 2] divided by 10) * 100 
If Item 9 is missing ([(Sum(Item7 and Item8)) – 2] divided by 8) * 100 
5.4.2.2 Analyses of TSQM-9 
The Effectiveness, Convenience and Global satisfaction scores, and the TSQM-9 question 2 for 
patients with specific symptoms will be analyzed using an ANOVA model. In the ANOVA 
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model, the scores will be the dependent variable and treatment will be factor. The least square 
means, 95% confidence intervals and p-value will be presented.  
Sample SAS code: 
PROC MIXED; 
 
CLASS TREATMENT; 
 
MODEL SCORE = TREATMENT; 
 
LSMEANS TREATMENT; 
RUN; 
5.4.2.3 Individual Patient Symptoms 
Patients will be asked “How long was it from the start of your SVT episode, until you took study 
drug?”  The answers will be summarized by treatment group.  Furthermore, as soon as possible 
after the SVT episode is over, patients will rate their symptom severity (1=Mild and 5=Severe) 
and symptom outcome (Very much worse, Much worse, Minimally worse, No change, 
Minimally improved, Much improved, Very much improved) for the following 7 symptoms: 
• Rapid Pulse (my heart rate is very fast) 
• Palpitations (I can feel my heart pounding in my chest) 
• Feeling Dizzy or Lightheaded 
• Shortness of Breath (it is hard for me to catch my breath) 
• Anxiety 
• Chest Tightness, Pain, or Pressure 
• Passing Out or Fainting 
5.4.2.4 Analyses of Individual Patient Symptoms 
The severity score for each symptom will be analyzed via a ANOVA model with treatment 
effects.  In the analysis, the severity score will be imputed as 0 for patients who answer “No” to 
“Did you have this symptom.”  The treatment effects, the differences in treatment effects, and 
the two-sided 95% confidence intervals of the differences will be presented. 
Symptom outcome for each symptom will be analyze as percentage of responder where a 
responder is defined as outcome=”Much improved” or “Very much improved.”  In these 
analyses, patients who have not provide answers will be treated as non-responders.  The 
percentages of the responders, the differences in the percentages of the responders, and the two-
sided 95% confidence intervals of the differences will be presented. 
5.4.3 
Other Secondary Efficacy and Robustness/Sensitivity Analyses. 
To evaluate internal consistency and robustness/sensitivity of the efficacy assessment, the 
following sensitivity analyses will be performed: 
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1. TTC30 will be analyzed via LIFETEST based all patients in the mITT Population, i.e., all 
patients with ‘misidentification of PSVT by the patient” as well as the patients who had 
an adjudicated PSVT who took the study drug. 
2. TTC30 will be analyzed via Wei Lin Weissfeld method, on a composite endpoint where 
conversions to sinus rhythm due to additional medical intervention are considered a 
negative recurrent event, and conversions to sinus rhythm without additional medical 
intervention a positive terminating event. 
3. TTC30 will be analyzed via LIFETEST using Log-Rrank test 
4. TTC30, and TTC300 will be analyzed via LIFETEST using Wilcoxon method, with with 
patients censored at time of conversion due to medical intervention. 
5. TTC10, TTC15, TTC45, TTC60, TTC90, TTC120, TTC180, and TTC300 will be analyze 
via LIFETEST using Wilcoxon method. 
6. Analysis of the 2x70 dose reimen; Percent of patients randomized to the optional second 
dose arms who take the optional second dose within etripamil and placebo arms will be 
analyzed via PROC FREQ based on CMH (Cochran-Mantel-Haenszel ) method. 
7. Analysis of the 2x70 dose reimen; TTC30 for patients who take the optional second dose 
will be analyzed via LIFETEST using Wilcoxon method. 
8. Analysis of the 2x70 dose reimen; TTC30 for patients in the Efficacy population who 
have not taken the optional second dose will be analyzed via LIFETEST using Wilcoxon 
method. 
9. TTC30 for patients randomized into the single-dose arms (ie, not given the option of a 
repeat dose) will be analyzed via LIFETEST using Wilcoxon method. 
10. TTC30 for patients randomized into the optional second-dose arms (ie, given the option 
of a repeat dose) will be analyzed via LIFETEST using Wilcoxon method. 
11. Percent of patients who seek additional medical intervention will be analyzed via PROC 
FREQ based on CMH method together and if appropriately, by individual types of 
intervention (went to ED regardless of conversion; oral pill-in-pocket; IV medication; and 
physician administered VM).   
a. Analyzed for medical intervention after randomized treatment only  
b. Any treatment for any subject perceived episode of PSVT (includes OL treatment). 
c. Analyzed for medical intervention after randomized treatment only pooling Part 1 
and Part 2 data. 
12. TTC30 will be analyzed via LIFETEST for patient subgroups identified in Appendix E.   
For each one of the variable identifying the subgroups (for example, Country, Sex, Age 
groups, etc.), a Cox model with each subgroup variable as factor, treatment and the 
interaction subgroup-by-treatment will be performed to evaluate the impact of each 
subgroup on efficacy. Hazard ratio and 95% CI will be presented within each subgroup in 
summary tables as well as in Forest plots.  
13. TTC30 will be analyzed via LIFETEST for patients who took placebo as their double-
blind treatment and then etripamil for the open-label treatment visit.  This cross-over 
analysis will utilize the placebo adminsitration as control, and open-label administration 
as the active arm. 
14. TTC30 will be reported for the open label treatment visit in patients with positively 
adjudicated PSVT, who take etripamil during PSVT during that open label drug 
administration. 
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15. The durability of conversion will be analyzed via PROC FREQ for placebo versus 
etripamil of the percent of patients who, after converting to sinus rhythm, experience a 
recurrence of PSVT during the 5 hour observation window. 
16. If more than 10 patients in the total efficacy population have a recurrence of PSVT within 
5 hours, the impact of the definition of conversion for the primary endpoint will be tested 
by analyzing TTC30 via LIFETEST, where conversion is defined as being in sinus rhythm 
for ≥1 minute, ≥2 minutes, and ≥5 minutes.   
17. A number needed to treat analysis will be conducted on the Efficacy population and Safety 
Population, based on conversion to SR at 5, 10, 15, 30, 45, or 60 minutes.   
 
5.4.4 
Controlling Type I Error for Multiple Comparisons  
TTC30 is the only primary endpoint.  The null hypothesis (no treatment difference) with respect 
to TTC30 will be tested at a two-sided 0.05 significant level for superiority claim.  Once the 
superiority claim is made, the superiority claims for the following efficacy endpoints will also be 
tested at two-sided significance level of 0.05 in the order specified below: 
1. Kaplan Meier estimates of time to conversion over 10 minutes 
2. Kaplan Meier estimates of time to conversion over 45 minutes 
3. Percent of patients who seek additional medical intervention within 5 hour observation 
window.  This analysis will be conducted using pooled double-blind data from Part 1 and 
Part 2 of the 301 study.   
4. TSQM-9 Effectiveness 
5. TSQM-9 Global Satisfaction 
6. Kaplan Meier estimates of time to conversion over 60 minutes 
7. Improvement of symptoms of rapid pulse feeling  
8. Improvement of symptoms of heart palpitations 
9. Improvement of symptoms of anxiety 
10. Improvement of symptoms of chest pain 
11. Improvement of symptoms of shortness of breath 
12. Improvement of symptoms of dizziness and/or fainting 
To control for family-wise Type I error rate at 0,05, a null hypothesis for a efficacy variable can 
be rejected only if all null hypotheses before it are also rejected. 
5.5 
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. All safety analysis will 
be performed on the Safety Population, the TD Population or the Overall Safety Population, as 
appropriate (i.e. specified in the specifications programming document).  
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5.5.1 
Adverse Events 
Adverse event verbatim text will be coded and classified by system organ class (i.e., body 
system) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) 
21.0.  
Summarization of adverse events (AEs) and treatment emergent adverse events (TEAEs) will 
include patient incidence of the following: 
• Any AE; 
• Treatment Emergent Adverse Events (TEAEs); defined as AEs with a start date occurring 
0 to 24 hours after test dose and prior to randomized study drug dose or with a start date 
occurring 0 to 24 hours after randomized study drug dose, or with a start date occurring 0 
to 24 hours after open-label Follow-up period drug dose; 
• AEs by maximum severity; 
• Drug-related AEs; 
• Drug-related AEs by maximum severity; 
• Serious Adverse Events (SAEs); 
• Drug-related Serious Adverse Events; 
• AEs leading to death; 
• AEs leading to study drug discontinuation; 
• Drug-related AEs leading to study drug discontinuation; 
• Test-Dose Emergent AEs (TDEAE); defined as AEs with a start date occurring 0 to 24 
hours after test dose, and prior to randomized study drug dose; 
• Randomized-Treatment Emergent AEs (RTEAE): defined as AEs with a start date 
occurring 0 to 24 hours after randomized outpatient drug administration; 
• Open-Label Follow-up AEs (OLFAE);  defined as AEs with a start date occurring 0 to 24 
hours after Open label outpatient drug administration. 
• AEs with a start date occurring 0 to 48 hours after randomized drug administration or open-
label outpatient drug administration; 
• AEs with a start date occurring 0 to 7 days after randomized drug administration or open-
label outpatient drug administration. 
Adverse events (AEs) are defined as those AEs with onset after the first dose of test study drug 
or existing events that worsened after the first test study drug dose during the study. Events 
reported with a partial onset date (e.g., month and year are reported but the day is missing) will 
be considered to be treatment-emergent if it cannot be confirmed that the event onset was prior to 
the first dose of study drug based on the available date entries.  Events with partial onset times 
which occur on the same day as a test dose or drug administration day will be considered to 
occur after drug administration, see Appendix F. 
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An overall summary table will contain the number and percentage of patients ever having one of 
the above listed subsets of AEs.  Detailed tables of study populations will be presented with 
relevant  
• Test-Dose Emergent TDEAE,  
• Randomized-Treatment Emergent RTEAEs   
• Open-Label Follow-up Emergent OLFAEs.  
• AEs will be summarized overall (both treatment groups, Etripamil and Placebo combined) 
for periods when both groups receive study drug (Test-dose and Open-label treatment 
emergent AEs)  
• For each treatment group separately for Randomized-Treatment Emergent AEs.   
• AEs for patients who took a single dose of study drug compared to patients who took the 
optional second dose of study drug will be presented. 
AEs will be presented by MedDRA system organ class (SOC) and preferred term (PT) with the 
number and percentage of patients. If a patient has more than 1 occurrence of the same AE, 
he/she will be counted only once within that preferred term and system organ class in the 
summary tables. The maximum severity occurrence of a repeat AE as well as the highest grade 
relationship of the AE to the study drug will be used for the analyses.  AEs which are listed as 
possibly, probably, or definitively related will be classified as related, AEs listed as not related or 
unlikely related will be classified as not related. 
AEs related to study drug, severe AEs, SAEs, and AEs leading to study drug discontinuation will 
be summarized in the same manner. That is, summaries will be provided for the numbers and 
percentages of patients by SOC and PT. 
All AEs will be included in by-patient listings. Specific by-patient listings of SAEs and AEs 
leading to study drug discontinuation will be provided. The number of days between test dose, or  
randomized-treatment or open-label treatment drug dose and when the AE occurred will be 
presented (i.e., relative study day), as will duration of the AE. 
5.5.2 
Clinical Laboratory Tests 
Clinical laboratory results (mean,  minimum, maximum, standard deviation) will be summarized 
by treatment. The change and percentage change from the screening visit to final study visit will 
be summarized by treatment. Incidence of laboratory abnormalities (<LLN and >ULN) will be 
summarized. Listings of all clinical laboratory tests will be provided. 
5.5.3 
Vital Signs  
Vital signs results (n, mean, median, minimum, maximum, standard deviation, median,) will be 
summarized by visit and treatment..  The changes and percentage of change (n, mean, median, 
minimum, maximum, standard deviation) in HR, SBP, and DBP from pre-test dose to 5, 10, 15, 
20, 25, 30, 35, 40 and 45 minutes post-test dose will be summarized. 
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5.5.4 
Electrocardiograms and Cardiac Monitoring System recordings 
Electrocardiograms results will be summarized by visit and treatment. The change in PR interval 
(mean, median, min, max, SD) from 10 minutes pre-test dose to 45 minutes post-test dose will be 
summarized.  A listing of all ECG results will be provided. 
The change in heart rate (as measured by the CMS) from prior to drug administration to 5, 10, 
15, 20, 25, and 30 minutes after administration of double blind study drug will be summarized by 
treatment group.   
The number of patients and percentage of patients with conduction disorders will be reported 
from the CMS recordings. The number of patients and percentage of patients with first-degree 
AV block will be reported. For patients with first-degree AV block, the PR interval measured on 
the CMS recordings will be reported in terms of mean, SD, min, max. These data will also 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 alter AV conduction, see 
Appendix E). These data will be reported in the Overall Safety Population.   
For episodes after a patient is randomized, the number of patients and percentage of patients with 
arrhythmias, recurrence of episodes of PSVT, and conduction disorders will be reported from the 
adjudication of CMS recordings. These data will be reported in the Overall Safety Population 
when the CMS data is collected but study drug was not taken (successful vagal maneuver, or 
other reason for not taking study drug), and when data is collected after taking Open-label 
Follow-up period study drug.  These data will also be reported in the Safety population by 
treatment for CMS data which is collected after administration of randomized double-blind study 
drug but prior to Open-label Follow-up period study drug administration. 
 
The following adjudicated data will be summarized: 
 
1) N (%) of patients with occurrence of atrial fibrillation, atrial flutter, or atrial tachycardia 
lasting longer than 30 seconds. 
2) N (%) of patients with non-sustained ventricular tachycardia defined as equal or greater than 3 
wide consecutive beats. 
3) N (%) of patients with sustained ventricular tachycardia defined as equal or greater than 10 
wide consecutive beats 
4) N (%) of patients with any sinus rate equal or less than 40 bpm and Type I AV block greater 
than 30 seconds. 
5) N (%) of patients with any occurrence of Type II or III AV block (including AV dissociation 
or the presence of more than 2 non-conducted P waves in a row). 
6) N (%) of patients with any pause equal or greater than 3 seconds. 
7) N (%) patients bradycardia less than 40 bpm 
5.5.5 
Physical Examination 
Physical examination data at each evaluation will be listed.  
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MSP-2017-1138 NODE-301 Part 2 
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6. 
INTERIM ANALYSIS 
No interim analysis has been planned. 
7. 
SAMPLE SIZE DETERMINATION 
A total sample size of 180 patients in Part 2 with a positively adjudicated PSVT episode, 
randomized at a range of 1:1 to 2:1 ratio (active : control) provides at least 90% power to detect a 
significant treatment difference for the primary endpoint at a two-sided significance level of 
0.05. This sample size was calculated based on internal modeling of the Part 1 data where 
etripamil had a higher conversion rate (54% versus 35% at 30 minutes), and also a more rapid 
conversion rate (32% versus 14% at 10 minutes). 
Assuming a type I error rate of alpha = 0.05 and a ratio in the number of positively adjudicated 
episodes of PSVT etripamil:placebo between 1:1 and 2:1, a minimum of 80 positive conversion 
events will be required.  Based on internal modeling, 180 patients with a positively adjudicated 
PSVT episode and 80 positive conversion events will attain greater than 90% power on the 
primary variable of time to conversion (using a 2-sided Wilcoxon test). 
It is anticipated that as many as 500 additional patients may need to be randomized in RAPID to 
accrue a sufficient number of patients in the Efficacy Population within 18 months.  
8. 
PROGRAMMING SPECIFICATIONS 
The programming specifications, including the mock-up validity listings, analysis tables, figures, 
and data listings, as well as the derived database specifications, will be prepared in stand-alone 
documents. The programming specification documents will be finalized prior to database lock.  
 
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Milestone Pharmaceuticals Inc.  
MSP-2017-1138 NODE-301 Part 2 
CONFIDENTIAL 
V1.00 
Statistical Analysis Plan 
  
6 Jun 2022 
 
Page 29 of 38 
 
APPENDIX A:  SCHEDULE OF PROCEDURES 
Table 1. Schedule of Procedures 
Assessment 
Screening 
Visit1 
Test Dose 
Random-
ization 
Visit2 
Monthly 
Follow-
up Visit3 
Randomi
zed 
Treat-
ment 
Period4 
 
Randomi
zed 
Treat-
ment 
Follow-
Up Visit 
Open-
Label 
Treat-
ment 
Period4 
Final 
Study 
Visit5 
End of 
Study 
Telephone 
Follow-Up 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility 
X6 
X7 
X8 
 
 
 
 
 
Contact the Telephone 
Coach9 
 
X 
 
X 
 
X 
 
 
Demographics/medical 
history 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
X 
 
X 
 
Physical examination 
X10 
 
 
 
 
 
X 
 
Vital signs (blood 
pressure and heart rate) 
X 
X11 
 
 
X 
 
X 
 
Hematology, chemistry, 
and urinalysis12 
X 
 
 
 
 
 
X13 
 
Pregnancy test14 
X 
X 
 
 
X 
 
X 
 
12-lead ECG15 
X 
X 
 
 
 
 
X16 
 
Test dose administration17 
 
X 
 
 
 
 
 
 
Patient training on PSVT 
episode assessments18 
 
X 
X 
 
X 
 
 
 
Randomization (via IRT) 
 
X 
 
 
 
 
 
 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
Dispense study kit19 
 
X 
 
 
X 
 
 
 
Ensure CMS data down-
loaded and sent to cardiac 
monitoring core lab 
 
X 
X20 
 
X 
 
X 
 
Review the CMS report21 
 
X 
 
 
X 
 
X 
 
Identify PSVT episode 
 
 
 
X 
 
X 
 
 
Apply and start CMS 
 
X 
 
X22 
 
X22 
 
 
Perform VM 
 
X 
 
X 
 
X 
 
 
Administer study drug 
and record time of dosing 
 
 
 
X23 
 
X23 
 
 
Complete patient 
questionnaires 
 
 
 
X 
 
X 
 
 
Evaluate medical 
intervention during the 
Treatment Period 
 
 
 
 
X 
 
X 
 
Collect study kit (used 
and unused) 
 
 
 
 
X 
 
X 
 
Identify reason(s) for 
study completion or 
withdrawal 
 
 
 
 
 
 
X 
 
Close case with IRT 
 
 
 
 
 
 
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. 
Screening Visit can be conducted with Test Dose Randomization Visit for purposes of avoiding an extra on site visit in extenuating 
circumstances 
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Milestone Pharmaceuticals Inc.  
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Statistical Analysis Plan 
  
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2. 
The Test Dose Randomization Visit should occur within 28 days after the Screening Visit for newly enrolled patients and should 
occur at the time of reconsent for patients previously randomized in NODE-301 Part 1. If the Test Dose Randomization visit cannot 
be conducted within 35 days after the Screening Visit, new blood and urine samples must be collected and sent for central 
laboratory evaluations at the Test Dose Randomization Visit prior to Test Dose procedures. Patients who pass the Test Dose criteria 
and are randomized will be instructed to not use double-blind study medication until it is confirmed that no exclusionary criteria 
were met following the analysis of the newly collected samples. 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 dosing regimen 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). Screening and Test Dose Randomization Visits can be incorporated into one visit for purposes of avoiding an extra 
on site visit in extenuating circumstances 
3. 
Monthly Follow-up Visits to occur approximately monthly via site visit or telephone (site visit preferred for patients who have an 
episode of PSVT terminated by VM). 
4. 
Randomized Treatment Period occurs from randomization until patient has an episode of PSVT treated with study drug. Open-Label 
Treatment Period occurs from after Randomized Treatment Follow-up Visit until the patient has an at-home episode treated with 
Open-Label drug. 
5. 
Randomized Treatment Follow-up Visit to occur within 14 days after a patient self-administers study drug during the Randomized 
Treatment Period. Final Study Visit to occur within 14 days after the Open-label Treatment Period, or within 14 days of the test 
dose administration for patients who fail the test dose. 
6. 
Confirmation of eligibility at Screening includes confirmation of PSVT diagnosis. Acceptable source documents to confirm the 
PSVT diagnosis are provided in the MoOP. 
7. 
Additional eligibility criteria apply to pass the test dose at the Test Dose Randomization Visit only. 
8. 
Eligibility assessments at the Monthly Follow-up Visits based on review of patient’s concomitant medications or changes in health 
status. 
9. 
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. 
10. Including height and weight. 
11. Vital signs will be obtained within 10 minutes pre-test dose and every 5 minutes (±1 minute) for 45 minutes post first test dose.  
12. Blood / urine samples can be analysed locally for purposes of preliminary enrolment if Screening/Test Dose Randomization Visits 
are combined; samples also to be sent to Central lab. Central lab results will allow enrollment in study  
13. Blood and urine tests will be performed on all patients who pass the test dose and are randomized. 
14. 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 and the Randomized Treatment Follow-Up Visit. 
15. 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. 
16. A 12-lead ECG will be performed on all patients who pass the test dose and are randomized. 
17. Before randomization, all patients will be trained on VMs and will receive a test dose of etripamil regimen (an initial dose of 
etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg not earlier than 10 minutes and not later than 15 minutes after 
the first dose) 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. 
18. 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. 
19. The study kit will include the study drug (2 devices of placebo or etripamil NS), a CMS, a study identification card, patient’s study 
instructions, and other study-related material. Patients will also be provided with patient questionnaires to be completed after 
experiencing a PSVT episode. At the Randomized Treatment Follow-up Visit, Open-Label etripamil will be provided with the CMS 
device (sites to ensure device has been reset) and new patient questionnaires. 
20. Download of CMS data during Follow-Up Visit if patient applied device without dosing study drug (e.g., VM-terminated PSVT). 
21. 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 Randomized Treatment Period and the Open-Label 
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. 
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Milestone Pharmaceuticals Inc.  
MSP-2017-1138 NODE-301 Part 2 
CONFIDENTIAL 
V1.00 
Statistical Analysis Plan 
  
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22. The CMS recording during an episode of PSVT should continue for at least 5 hours, regardless of treatment outcome. 
23. During the Randomized Treatment Period and the Open-Label 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 30 minutes after start of 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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Milestone Pharmaceuticals Inc.  
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Statistical Analysis Plan 
  
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APPENDIX B:  TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION BASED ON AN ABBREVIATED 9 ITEMS (TSQM-9) 
1. How satisfied or dissatisfied are you with the ability of the medication to treat your 
condition? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
2. How satisfied or dissatisfied are you with the way the medication relieves your symptoms? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
3. How satisfied or dissatisfied are you with the amount of time it take the medication to start 
working? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
4. How easy or difficult is it to use the medication in its current form? 
1. Extremely Difficult 
2. Very Difficult 
3. Difficult 
4. Somewhat Easy 
5. Easy 
6. Very Easy 
7. Extremely Easy 
5. How easy or difficult is it to plan when you will use the medication each time? 
1. Extremely Difficult 
2. Very Difficult 
3. Difficult 
4. Somewhat Easy 
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5. Easy 
6. Very Easy 
7. Extremely Easy 
6. How convenient or inconvenient is it to take the medication as instructed? 
1. Extremely Inconvenient 
2. Very Inconvenient 
3. Inconvenient 
4. Somewhat Convenient 
5. Convenient 
6. Very Convenient 
7. Extremely Convenient 
7. Overall, how confident are you that taking this medication is a good thing for you? 
1. Not at All Confident 
2. A Little Confident 
3. Somewhat Confident 
4. Very Confident 
5. Extremely Confident 
8. How certain are you that the good things about your medication outweigh the bad things? 
1. Not at All Certain 
2. A Little Certain 
3. Somewhat Certain 
4. Very Certain 
5. Extremely Certain 
9. Taking all things into account, how satisfied or dissatisfied are you with this medication? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
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APPENDIX C:   PSVT SYMPTOMS RECORDS IN ECRF 
List of available PSVT symptoms: 
• Rapid pulse 
• Palpitations 
• Shortness of breath 
• Chest tightness, pain or pressure 
• Feeling dizzy or lightheaded 
• Fainting or passing out 
• Anxiety 
 
Screenshots of the PRO tool are provided below 
 
 
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APPENDIX D: 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) 
 
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APPENDIX E: SUBGROUPS OF INTEREST  
1. Region (North America and Europe, and by individual country where N > 10) 
2. Male, female 
3. Patient age by quartile 
4. Patients ≥70 years old,  
5. Patients ≥70 years old with concomitant cardiovascular treatment (agent or treatment identified 
as for a cardiovascular indication; i.e. PSVT prophylaxis, anti-hypertensive, or other 
cardiovascular treatments),  
6. Patients ≥60 and < 70 years old receiving concomitant cardiovascular treatment (Beta blockers, 
calcium channel blockers, ARBs or ACEs).  
7. Patients currently receiving any of the following classes of concomitant medication regardless 
of indication: Beta-blockers, Calcium channel blockers, ARBs or ACEs. 
8. Patient receiving any concomitant medication indicated for antihypertensive treatment: 
Monotherapy, Bi-therapy, Triple therapy or more, Dihydropyridine calcium channel blocker 
(e.g., amlodipine), Beta-blocker. 
9. Type of PSVT: AVNRT, AVRT, Indeterminate. 
10. Duration from onset of symptoms to taking of study drug (<=Median duration and > median 
duration) 
 
 
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APPENDIX F: IMPUTATION OF MISSING DATES 
This section describes missing date imputation methods. 
 
For Adverse Events 
If onset date is completely missing, onset date is set to date of randomization. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
• If year = year of randomization, then set month and day to month and day of randomization 
• If year < year of randomization, then set month and day to December 31. 
• If year > year of randomization, then set month and day to January 1. 
If month and year are present and day is missing: 
• If year = year of randomization and 
o If month = month of randomization then set day to day of first dose 
o If month < month of first dose then set day to last day of month 
o If month > month of first dose then set day to first day of month 
• If year < year of randomization then set day to last day of month 
• If year > year of randomization then set day to first day of month 
For all other cases, set onset date to date of randomization. 
 
For determination of TEAE, time of dosing will be truncated to minutes (exclude the seconds) to 
match what is recorded for AEs.  For example an AE with onset of 13:55 and study drug dosing 
time of 13:55:35 will be considered to be post drug administration and a TEAE. 
 
For Concomitant Medications 
Start Date: If start date is completely missing and end date is not prior to randomization, then the 
medication will be classified as concomitant. If start date is completely missing and end date is 
prior to randomization, then the medication will be classified as prior. 
 
If (year is present and month and day are missing) or (year and day are present and month is 
missing) then set month and day to January 1. If year and month are present and day is missing 
then set day to first day of month. 
 
End Date: If end date is completely missing then the medication will be classified as 
concomitant.  If (year is present and month and day are missing) or (year and day are present and 
month is missing) then set month and day to December 31. If year and month are present and day 
is missing then set day to last day of the month. 
 
Note: that if both start and end dates are missing then the medication will be classified as 
concomitant. 
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