Clinical trial NCT03635996
Conditions: Paroxysmal Supraventricular Tachycardia
Keywords: Paroxysmal supraventricular tachycardia cardiac monitoring atrioventricular nodal reentrant tachycardia atrioventricular reciprocating tachycardia calcium channel blocker conversion rate
Sponsor: Milestone Pharmaceuticals Inc.
Start date: 2018-12-10; Completion date: 2020-11-13
Enrollment: 169 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the safety of etripamil nasal spray (NS) 70 mg when self-administered by patients with an episode of Paroxysmal Supraventricular Tachycardia in an outpatient setting (i.e., without medical supervision).

Detailed description:
The NODE-302 study is an extension of the NODE-301 efficacy study. It is a multi-centre, open label study designed to evaluate the safety of etripamil NS 70 mg when self-administered by patients for spontaneous episodes of PSVT in an outpatient setting. All patients randomized in the NODE-301 study and who meet the inclusion and exclusion criteria of the NODE-302 study are eligible for the NODE-302 study.

After each episode of PSVT, patients will have the option to continue in the NODE-302 study and manage subsequent episodes of PSVT with etripamil NS 70 mg if they do not meet any withdrawal criteria.

Each episode of PSVT 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 ECG.

The study will include a Qualification Visit, a Treatment Period(s) , a Follow-up Visit(s) ,a Final Study Visit and if necessary an Early Termination Visit if the patient withdraws from the study after taking etripamil NS 70 mg and had a Follow-up Visit, or the patient withdraws from the study and did not take etripamil NS 70 mg.

Arms: arm 1: The dose of etripamil to be evaluated in NODE-302 is 70 mg.
Interventions: intervention 1: Etripamil NS 70 mg intervention 2: Aptar Pharma Nasal Spray Bidose System
Intervention descriptions: intervention 1: All patients will receive a total of 200 micro-liters of etripamil NS 70 mg via the Aptar Pharma Nasal Spray Bidose System each time they self-administer study drug. intervention 2: Patients will self-administer the study drug using the Aptar Pharma Nasal Spray Bidose System. The devices will be prefilled and packaged into child-resistant boxes.Instructions for its use will be provided in the study drug box.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
Multi-Centre, Open-Label, Safety Study of Etripamil Nasal Spray in 
Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia 
 
The NODE-302 Trial 
(Extension of NODE-301) 
 
Investigational Product: Etripamil (MSP-2017) 
Protocol Number: MSP-2017-1158 
 
 
 
 
Sponsor: 
Milestone Pharmaceuticals Inc. 
1111 Dr. Frederik-Philips Blvd., Suite 420 
Saint-Laurent, QC H4M 2X6, Canada 
Telephone: +1-514-336-0444 
 
Version Number: 2.0 
Original Protocol: 18 May 2018 
Amendment 1: 18 October 2018 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Milestone Pharmaceuticals Inc. except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical study for Milestone 
Pharmaceuticals Inc. You are allowed to disclose the contents of this document only to your 
Institutional Review Board or Independent Ethics Committee and study personnel directly 
involved with conducting this protocol. Persons to whom the information is disclosed must be 
informed that the information is confidential and proprietary to Milestone Pharmaceuticals Inc. 
and that it may not be further disclosed to third parties. 
 


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PROCEDURES IN CASE OF EMERGENCY OR SERIOUS ADVERSE 
EVENT REPORTING 
Emergency Contact Information 
Role in Study 
Name 
Address/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 during the Treatment Period(s) through the Final Study Visit or Early Termination 
Visit (whichever is later) 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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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, Open-Label, Safety Study of Etripamil Nasal Spray in Spontaneous 
Episodes of Paroxysmal Supraventricular Tachycardia 
The NODE-302 Trial (Extension of NODE-301) 
SHORT TITLE:  Safety Study of Intranasal Etripamil for the Termination of Spontaneous 
Episodes of Paroxysmal Supraventricular Tachycardia 
The NODE-302 Trial (Extension of NODE-301) 
PROTOCOL NUMBER:  MSP-2017-1158 
INVESTIGATIONAL PRODUCT:  Etripamil (MSP-2017) 
PHASE:  3 
INDICATION:  Paroxysmal supraventricular tachycardia (PSVT) 
OBJECTIVES: 
The primary objective of this study is to evaluate the safety of etripamil nasal spray (NS) 70 mg 
when self-administered by patients with an episode of PSVT in an outpatient setting (i.e., without 
medical supervision). 
The secondary objective of this study is to evaluate the safety and efficacy of etripamil NS 70 mg 
for the treatment of multiple episodes of PSVT. 
POPULATION: 
The NODE-302 study is designed to obtain safety data to contribute to the etripamil safety 
database. Only patients randomized in the NODE-301 study are potentially eligible for the 
NODE-302 study. However, it is expected that among the randomized patients from the 
NODE-301 study, there will be at least 125 high-risk patients who are defined as follows: 
 70 years of age; or 
 60 years of age with either first degree atrioventricular (AV) block (PR interval 
200 milliseconds) or concomitant use of medication known to affect cardiac conduction 
(i.e., beta-blockers, diltiazem, verapamil). 
If these high-risk patients are underrepresented in the NODE-301 study (i.e., 125 patients), 
additional high-risk patients will be recruited into the NODE-302 study to reach 125 high-risk 
patients enrolled. These high-risk patients will receive a test dose of etripamil NS 70 mg and will 
be evaluated for enrollment in the NODE-302 study according to the same process described in 
the NODE-301 study. 


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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. Signed the NODE-302 written informed consent; 
3. Previously randomized in the NODE-301 study: 
o Received the study drug to treat symptoms the patient believed were consistent with an 
episode of PSVT during the NODE-301 study, irrespective of the study drug efficacy; 
OR 
o Did not experience an episode of PSVT or did not use the study drug at the time of the 
NODE-301 study completion; 
4. Willing and able to comply with all aspects of the study; 
5. 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 urine pregnancy test result at the Qualification Visit and at the Follow-up Visit(s), 
and must use an approved form of contraception between the 2 visits. Approved forms of 
contraception include hormonal intrauterine devices and 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: 
o Premenopausal females with 1 of the following: 
a. Documented hysterectomy, 
b. Documented bilateral salpingectomy, or 
c. Documented bilateral oophorectomy, or 
o Postmenopausal females, defined as having amenorrhea for at least 12 months without an 
alternative medical cause; and 
6. Male patients, except those who are surgically sterile, must use an approved highly effective 
form of contraception during the 3 days after study drug administration. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Evidence of new severe arrhythmia discovered since the NODE-301 Test Dose Randomization 
Visit, including those reported on the Cardiac Monitoring System (CMS) report of the 
outpatient PSVT event treated with the study drug in the NODE-301 study, including but not 
limited to: 
a. Third-degree AV block, Mobitz II second-degree AV block, or Wenckebach with 
bradycardia 40 bpm; 


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b. Significant symptomatic sinus bradycardia heart rate (HR) 40 bpm or sinus pauses 
(3 seconds);  
c. Any significant ventricular arrhythmia (premature ventricular beats and couplets 
[>6 premature ventricular contractions per 45 seconds electrocardiogram (ECG)] are 
considered significant); or 
d. Atrial fibrillation (event lasting longer than 30 seconds) or atrial flutter; 
2. Any drug-related or procedure-related serious adverse event (AE) during the NODE-301 
study; 
3. Any severe AE in the NODE-301 study that was severe enough to preclude administration of 
etripamil NS 70 mg in the NODE-302 study; 
4. Any new drug prescribed after the end of the patient’s participation in the NODE-301 study 
that could lower blood pressure or decrease AV node conduction; 
5. Systolic blood pressure <90 mmHg after a 5-minute rest in sitting position at the NODE-302 
Qualification Visit; 
6. Any symptoms consistent with clinically severe hypotension such as presyncope, medically 
significant lightheadedness, syncope, nausea, or vomiting; 
7. New therapy with digoxin, amiodarone, or any Class I or III antiarrhythmic drug added after 
the end of the patient’s participation in the NODE-301 study; 
8. New evidence of ventricular pre-excitation (e.g., delta waves, short PR interval, 
Wolff-Parkinson-White syndrome) on the ECG since randomization in the NODE-301 study; 
9. New symptoms of congestive heart failure defined by the New York Heart Association 
Class II to IV since randomization in the NODE-301 study;  
10. New stroke since randomization in the NODE-301 study; 
11. New evidence of a significant physical or psychiatric condition including drug abuse, which, 
in the opinion of the Investigator, could jeopardize the safety of the patient or impede the 
patient’s capacity to follow the study procedures since randomization in the NODE-301 study; 
12. New syncope since randomization in the NODE-301 study, especially if observed during the 
monitoring of the event treated in the NODE-301 study; 
13. New evidence of hepatic dysfunction, defined as alanine aminotransferase or aspartate 
aminotransferase >3 × the upper limit of normal (ULN) or total bilirubin >2 × ULN, unless 
due to Gilbert syndrome, observed at the NODE-302 Qualification Visit; 
14. New evidence of renal dysfunction as determined by an estimated glomerular filtration rate 
assessed at the NODE-302 Qualification Visit as follows: 
a. <60 mL/min/1.73 m2 for patients <60 years of age, 
b. <40 mL/min/1.73 m2 for patients 60 and <70 years of age, or 
c. <35 mL/min/1.73 m2 for patients 70 years of age;  


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15. Participation in any investigational drug or device study or the use of any investigational drug 
or device since the Final Study Visit in the NODE-301 study. 
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; 
 The patient took the study drug in both the NODE-301 and the NODE-302 studies for 
symptoms not associated with an episode of PSVT; 
 Occurrence of any medical condition, AE, or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the protocol; 
 Requirement of a prohibited concomitant medication and/or change in the use of chronic 
therapies, such as concomitant beta-blockers, calcium channel blockers, and medications that 
can lower blood pressure; 
 Patient failure to comply with protocol requirements or study-related procedures; 
 Termination of the study by Milestone or a regulatory authority; or 
 The patient self-administered a total of 11 doses of etripamil NS 70 mg in the NODE-302 
study. 
Patients who withdraw from the study after taking etripamil NS 70 mg and had a Follow-up Visit 
will be required to undergo an Early Termination Visit. 
Patients who withdraw from the study and did not take etripamil NS 70 mg will be required to 
undergo an Early Termination Visit. 
Patients who withdraw after taking the study drug but did not have a Follow-up Visit will be 
required to undergo a Final Study Visit. 
STUDY DESIGN AND DURATION: 
The NODE-302 study is an extension of the NODE-301 efficacy study. It is a multi-centre, 
open-label study designed to evaluate the safety of etripamil NS 70 mg when self-administered by 
patients for spontaneous episodes of PSVT in an outpatient setting. All patients randomized in the 
NODE-301 study and who meet the inclusion and exclusion criteria of the NODE-302 study are 
eligible for the NODE-302 study. 
After each episode of PSVT, patients will have the option to continue in the NODE-302 study and 
manage subsequent episodes of PSVT with etripamil NS 70 mg if they do not meet any withdrawal 
criteria. 
Each episode of PSVT 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. 


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The study will include the following: 
Qualification Visit 
The Qualification Visit may coincide with the NODE-301 Final Study Visit, or it may be 
conducted at a future time. During the Qualification Visit, the Investigator will review the patient’s 
recent medical status and verify the patient’s eligibility for the NODE-302 study. 
Treatment Period(s) 
Following the Qualification Visit, eligible patients will enter the Treatment Period(s). During the 
Treatment Period(s), patients will perform a sequence of steps, including etripamil NS 70 mg 
self-administration when patients identify symptoms of an episode of PSVT. Each patient will 
have the option to manage up to a maximum of 11 episodes of PSVT with etripamil NS 70 mg in 
the NODE-302 study. However, each patient will receive only 1 study kit including 1 dose of 
study drug at a time, and a new study kit will be dispensed at the Follow-up Visit. 
Follow-up Visit(s) 
Every time the patient self-administers study drug (up to a maximum of 11 doses of etripamil NS 
70 mg in the NODE-302 study), the patient will be instructed to return to the site within 7 days 
after study drug administration for a complete assessment by the Investigator and will receive 
another study kit including 1 dose of study drug, if the patient does not meet any withdrawal 
criteria. 
Final Study Visit 
A complete assessment will be performed by the Investigator. 
Early Termination Visit 
The Early Termination Visit will occur under the following circumstances: the patient withdraws 
from the study after taking etripamil NS 70 mg and had a Follow-up Visit, or the patient withdraws 
from the study and did not take etripamil NS 70 mg. In these cases, the patient should come to the 
site to return the study kit and the Investigator should close the case with Interactive Response 
Technology. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Investigational Product and Dosage: The formulation of etripamil is for intranasal administration 
and will consist of MSP-2017 (etripamil), water, acetic acid, disodium ethylene-diamine-tetra-
acetic acid, and sulfuric acid. The dose of etripamil to be evaluated in the NODE-302 study is 
70 mg.  
Mode of Administration: All patients will receive a total of 200 L of etripamil NS 70 mg 
(i.e., 100 L in each nostril via the Aptar Pharma Nasal Spray Bidose System) each time they 
self-administer study drug. The devices will be prefilled and packaged into child-resistant boxes. 
Instructions for its use are provided in the Manual of Operations and Procedures and will be 
provided in the study drug box. 


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DURATION OF TREATMENT:  
The NODE-302 study will be operational until the end of the development program (i.e., when a 
sufficient number of documented study drug administrations have been achieved for inclusion in 
the etripamil safety database). 
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 Treatment Period(s), safety variables will be recorded. 
EFFICACY VARIABLES:  
Efficacy assessments will be based on the data derived from CMS recordings. The Adjudication 
Committee will evaluate the complete CMS 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 sinus rhythm (SR) after study drug administration, will be adjudicated and 
the primary variable, the time to conversion, will be adjudicated for the primary efficacy analysis. 
STATISTICAL ANALYSES: 
Analysis Populations 
The Safety Population will include all patients who take the study drug. 
The Efficacy Population will include all patients who use the study drug to treat a positively 
adjudicated episode of PSVT. This population will not include patients who take the study drug 
for symptoms not associated with an episode of PSVT. 
Analysis of Efficacy 
The efficacy analyses will be performed on the Efficacy Population. The primary efficacy variable 
is the time to conversion of an episode of PSVT to SR after study drug administration. 
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. 
SAMPLE SIZE DETERMINATION: 
There is no statistical hypothesis in this uncontrolled open-label safety study. Based on the 
anticipated randomization of 500 patients in the NODE-301 study, it is estimated that 300 to 
500 patients will be eligible for the NODE-302 study. The final number of episodes of PSVT in 
the NODE-302 study will depend on the frequency and timing of episodes of PSVT during the 
study. The NODE-302 study will be operational until the end of the development program 
(i.e., when a sufficient number of documented study drug administrations have been achieved for 
inclusion in the etripamil safety database). 


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If the population includes fewer than 125 high-risk patients at the end of the NODE-301 study, 
new patients meeting the high-risk categories will be eligible to enroll in the NODE-302 study to 
ensure the following: 
 125 high-risk patients being enrolled (i.e., having received a test dose); and 
 75 of the enrolled high-risk patients having subsequently self-administered etripamil NS 
70 mg during an episode of PSVT, with 20 of them being 70 years of age. 
MONITORING COMMITTEES: 
Steering Committee 
A single Steering Committee will be responsible for the scientific oversight of both the NODE-301 
and NODE-302 studies. The Steering Committee Chair will review the original protocol and 
potential amendments. 
Data and Safety Monitoring Committee 
A single Data and Safety Monitoring Committee (DSMC) will operate for both the NODE-301 
and NODE-302 studies. 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. 
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.  
The EPs will adjudicate the following: 
1. The presence of PSVT (AV nodal reentrant tachycardia or AV reentrant tachycardia 
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 Vagal Maneuver 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 Adjudication Committee will review the secondary ECG safety endpoints (i.e., arrhythmia 
and conduction disorders). 
SITES:  This study will be conducted at the same sites as the NODE-301 study. 


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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 ....................................... 2 
Signature Page ................................................................................................................................ 3 
Investigator Agreement ................................................................................................................... 4 
Synopsis .......................................................................................................................................... 5 
Table of Contents .......................................................................................................................... 13 
List of Tables ................................................................................................................................ 17 
List of Figures ............................................................................................................................... 18 
List of Abbreviations and Definition of Terms............................................................................. 19 
1 Introduction and Background Information ............................................................................. 21 
1.1 
Phase 1 Study ................................................................................................................ 21 
1.2 
Phase 2 Study ................................................................................................................ 21 
1.3 
Rationale ........................................................................................................................ 25 
2 Study Objectives ..................................................................................................................... 26 
2.1 
Primary Objective ......................................................................................................... 26 
2.2 
Secondary Objective ..................................................................................................... 26 
3 Study Description.................................................................................................................... 27 
3.1 
Summary of Study Design ............................................................................................ 27 
3.2 
Study Visits ................................................................................................................... 27 
3.2.1 Qualification Visit ............................................................................................. 27 
3.2.2 Treatment Period(s) ........................................................................................... 28 
3.2.3 Follow-up Visit(s) ............................................................................................. 29 
3.2.4 Final Study Visit ................................................................................................ 29 
3.2.5 Early Termination Visit ..................................................................................... 30 
4 Selection and Withdrawal of Patients ..................................................................................... 31 
4.1 
Inclusion Criteria ........................................................................................................... 31 
4.2 
Exclusion Criteria .......................................................................................................... 32 
4.3 
Withdrawal Criteria ....................................................................................................... 33 
5 Study Treatments .................................................................................................................... 35 
5.1 
Rationale for Study Dose .............................................................................................. 35 
5.2 
Randomization and Blinding ......................................................................................... 35 


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5.3 
Drug Supplies ................................................................................................................ 35 
5.3.1 Formulation and Packaging ............................................................................... 35 
5.3.2 Study Drug Administration ............................................................................... 36 
5.3.3 Treatment Compliance ...................................................................................... 36 
5.3.4 Storage and Accountability ............................................................................... 36 
5.3.5 Study Drug Handling and Disposal ................................................................... 37 
5.4 
Prior and Concomitant Medications and/or Procedures ................................................ 37 
5.4.1 Excluded Medications and/or Procedures ......................................................... 37 
5.4.2 Documentation of Prior and Concomitant Medication Use .............................. 37 
6 Site Study Procedures ............................................................................................................. 38 
6.1 
Qualification Visit ......................................................................................................... 38 
6.2 
Treatment Period(s) ....................................................................................................... 38 
6.3 
Follow-up Visit(s) ......................................................................................................... 39 
6.4 
Final Study Visit ............................................................................................................ 40 
6.5 
Early Termination Visit ................................................................................................. 40 
7 Efficacy Assessments.............................................................................................................. 41 
7.1 
Adjudication Process ..................................................................................................... 41 
8 Safety Assessments ................................................................................................................. 42 
8.1 
Adverse Events .............................................................................................................. 42 
8.1.1 Adverse (Drug) Reaction .................................................................................. 43 
8.1.2 Unexpected Adverse Drug Reaction ................................................................. 43 
8.1.3 Assessment of Adverse Events by the Investigator .......................................... 43 
8.2 
Serious Adverse Events ................................................................................................. 44 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 45 
8.4 
Pregnancy Reporting ..................................................................................................... 46 
8.5 
Expedited Reporting ...................................................................................................... 46 
8.6 
Medical Device Complaints .......................................................................................... 47 
8.7 
Clinical Laboratory Evaluations .................................................................................... 47 
8.8 
Vital Signs ..................................................................................................................... 47 
8.9 
Electrocardiograms ........................................................................................................ 47 
8.10 Physical Examinations .................................................................................................. 47 
9 Statistics .................................................................................................................................. 48 


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9.1 
Analysis Populations ..................................................................................................... 48 
9.2 
Statistical Methods ........................................................................................................ 48 
9.2.1 Patient Disposition and Demographic/Baseline Characteristics ....................... 48 
9.2.2 Study Drug Administration and Concomitant Medications .............................. 48 
9.2.3 Analysis of Efficacy .......................................................................................... 48 
9.2.3.1 Primary efficacy analysis .................................................................... 48 
9.2.3.2 Secondary efficacy analyses ............................................................... 49 
9.2.4 Analysis of Safety ............................................................................................. 49 
9.2.5 Sample Size Determination ............................................................................... 49 
10 Data Management and Record Keeping ................................................................................. 50 
10.1 Data Management ......................................................................................................... 50 
10.1.1 Data Handling ................................................................................................... 50 
10.1.2 Computer Systems ............................................................................................. 50 
10.1.3 Data Entry ......................................................................................................... 50 
10.1.4 Medical Information Coding ............................................................................. 50 
10.1.5 Data Validation ................................................................................................. 50 
10.2 Record Keeping ............................................................................................................. 51 
11 Investigator Requirements and Quality Control ..................................................................... 52 
11.1 Ethical Conduct of the Study ........................................................................................ 52 
11.2 Institutional Review Board/Independent Ethics Committee ......................................... 52 
11.3 Informed Consent .......................................................................................................... 52 
11.4 Study Monitoring Requirements ................................................................................... 52 
11.5 Disclosure of Data ......................................................................................................... 53 
11.6 Retention of Records ..................................................................................................... 53 
11.7 Monitoring Committees ................................................................................................ 53 
11.7.1 Steering Committee ........................................................................................... 53 
11.7.2 Data and Safety Monitoring Committee ........................................................... 54 
11.7.3 Adjudication Committee ................................................................................... 54 
11.8 Audits and Inspections .................................................................................................. 54 
11.9 Publication Policy ......................................................................................................... 54 
11.10 Financial Disclosure ...................................................................................................... 55 
12 Study Administrative Information .......................................................................................... 56 


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12.1 Protocol Amendments ................................................................................................... 56 
12.2 Address List ................................................................................................................... 56 
12.2.1 Sponsor .............................................................................................................. 56 
12.2.2 Contract Research Organization ........................................................................ 56 
12.2.3 ECG Core Laboratory for CMS Safety Reports ................................................ 56 
12.2.4 ECG Core Laboratory for Primary Endpoint Adjudication .............................. 56 
12.2.5 Study Drug Distribution and Accountability .................................................... 56 
12.2.6 Medpace Clinical Safety ................................................................................... 57 
12.2.7 Biological Specimens ........................................................................................ 57 
13 References ............................................................................................................................... 58 
Appendix A:  Schedule of Procedures .......................................................................................... 59 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 61 


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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 ............... 22 
Table 2. 
Schedule of Procedures ............................................................................................... 59 
 
 


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LIST OF FIGURES 
Figure 1. Kaplan-Meier Plot of Conversion 15 Minutes After Study Drug Administration...... 23 
Figure 2. Mean (Standard Error) Systolic Blood Pressure (mmHg) Over Time ........................ 24 
Figure 3. Dose Response Maximal Efficacy Model................................................................... 25 
 


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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 
CMS 
Cardiac Monitoring System 
CMS safety report 
Analysis of the ECG tracing by a core laboratory for cardiac safety 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
DSMC 
Data and Safety Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
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 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PSVT 
Paroxysmal supraventricular tachycardia 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SR 
Sinus rhythm 


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Abbreviation 
Definition 
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 milliseconds.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 patients. 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 a 
dose-related trend for etripamil, to determine the minimal effective dose of etripamil, and to 
evaluate the safety of etripamil in an outpatient 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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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 AEs 
were severe and 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 (Figure 2). 
Compared with baseline, SBP measurements taken from 2 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 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 (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 
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 
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 NS 70 mg as a viable 
alternative treatment option.  
The goal of this open-label extension study of the Phase 3 NODE-301 study is to demonstrate the 
safety 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 evaluate the safety of etripamil NS 70 mg when 
self-administered by patients with an episode of PSVT in an outpatient setting (i.e., without 
medical supervision). 
2.2 
Secondary Objective 
The secondary objective of this study is to evaluate the safety and efficacy of etripamil NS 70 mg 
for the treatment of multiple episodes of PSVT. 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
The NODE-302 study is an extension of the NODE-301 efficacy study. It is a multi-centre, 
open-label study designed to evaluate the safety of etripamil NS 70 mg when self-administered by 
patients for spontaneous episodes of PSVT in an outpatient setting. All patients randomized in the 
NODE-301 study and who meet the inclusion and exclusion criteria of the NODE-302 study are 
eligible for the NODE-302 study. This study will be conducted at the same sites as the NODE-301 
study. 
After each episode of PSVT, patients will have the option to continue in the NODE-302 study and 
manage subsequent episodes of PSVT with etripamil NS 70 mg if they do not meet any withdrawal 
criteria. 
Each episode of PSVT 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 include the following: 
 A Qualification Visit, 
 Treatment Period(s), 
 Follow-up Visit(s), and 
 A Final Study Visit or an Early Termination Visit. 
3.2 
Study Visits 
3.2.1 
Qualification Visit 
The Qualification Visit may coincide with the NODE-301 Final Study Visit, or it may be 
conducted at a future time. During the Qualification Visit, the Investigator will review the patient’s 
recent medical status and verify the patient’s eligibility for the NODE-302 study (see Sections 4.1 
and 4.2). Patients will be asked to sign the NODE-302 informed consent form before 
commencement of any study-related assessments or procedures, and the signed informed consent 
form will be applicable for the initial and all subsequent episodes of PSVT.  
Although patients in the NODE-301 study signed the informed consent form and qualify for the 
NODE-302 study, mandatory assessments must be carried out to confirm ongoing eligibility and 
inclusion in the NODE-302 study. 
The results of the safety laboratory testing (hematology, chemistry, and urinalysis) performed 
either at the NODE-301 Final Study Visit or specifically for the NODE-302 Qualification Visit, 
will not be available to the Investigator at the Qualification Visit, but this will not prevent the 
Investigator from enrolling patients in the NODE-302 study. However, if there is an exclusionary 
safety laboratory result upon availability of these results, the patient will be asked to return to the 
site and be withdrawn from the NODE-302 study. 


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If the patient is entering the NODE-302 study after taking the study drug to treat an episode of 
PSVT in the NODE-301 study, the CMS safety report (see List of Abbreviations for definition) 
for the treated episode must be available for evaluation at the Qualification Visit. 
Patients will each have a unique identification number during the study. 
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 administer study drug. Patients will be trained to 
complete a patient diary (PSVT symptoms and Treatment Satisfaction Questionnaire for 
Medication [TSQM]) after each PSVT episode treated with study drug. Standardized training will 
be described in the Manual of Operations and Procedures (MoOP). 
3.2.2 
Treatment Period(s) 
Following the Qualification Visit, eligible patients will enter the Treatment Period(s). During the 
Treatment Period(s), patients will perform a sequence of steps, including etripamil NS 70 mg 
self-administration when patients identify symptoms of an episode of PSVT. Each patient will 
have the option to manage up to a maximum of 11 episodes of PSVT with etripamil NS 70 mg in 
the NODE-302 study. However, each patient will receive only 1 study kit including 1 dose of study 
drug at a time, and a new study kit will be dispensed at the Follow-up Visit.  
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. The CMS recording should continue for at least 
5 hours regardless of treatment outcome; 
3. Perform a VM. If the VM is successful in relieving symptoms, the patient will not 
self-administer the study drug but will keep the CMS device on for 5 hours. The episode of 
PSVT and the results of the VM will be analyzed by the cardiac monitoring core laboratory. 
The patient will remain in the study for a subsequent episode of PSVT; 
4. Administer etripamil NS 70 mg 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 etripamil NS 70 mg 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 the symptoms of PSVT and their evolution, as well as overall treatment 
satisfaction, in a patient diary and TSQM; 


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6. If the symptoms of PSVT have not resolved within 20 minutes after study drug administration, 
the patient may seek appropriate medical care and follow these steps: 
a. 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 etripamil 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; and 
b. The CMS should not be removed, and recording should continue for at least 5 hours 
after study drug administration; and 
7. Schedule a Follow-up Visit within 7 days of study drug administration and/or episode of PSVT. 
The interpretation of the CMS ECG will be provided by the cardiac monitoring core laboratory to 
the site. The operational aspects are described in the MoOP. These reports will be sent to the site 
and the Medical Monitor.  
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. 
3.2.3 
Follow-up Visit(s) 
Every time the patient self-administers study drug (up to a maximum of 11 doses of etripamil NS 
70 mg in the NODE-302 study), the patient will be instructed to return to the site within 7 days 
after study drug administration for a complete assessment by the Investigator and will receive 
another study kit including 1 dose of study drug, if the patient does not meet any withdrawal criteria 
(see Section 4.3). This assessment will include a review of the CMS safety report for the treated 
episode of PSVT, so this report must be available for evaluation at the Follow-up Visit(s). The 
CMS safety report must be reviewed before an additional drug kit is dispensed. 
If the patient used the CMS for an episode of PSVT that subsequently was terminated by a 
successful VM (i.e., the patient did not use the study drug), the patient will be instructed to return 
to the site within 7 days after the episode to ensure that all data has been downloaded from the 
CMS. 
3.2.4 
Final Study Visit 
The Final Study Visit will occur under the following circumstances: 
 The required number of episodes of PSVT are observed in the study and the study is completed, 
 The patient has started treatment with a prohibited medication, 
 The Sponsor decides to terminate the study for any reason, 
 The patient self-administers 11 doses of the study drug in the NODE-302 study, 
 The patient is deemed to have completed participation in the study for any other reason, or 
 The patient withdraws after taking etripamil NS 70 mg but did not have a Follow-up Visit yet. 
A complete assessment will be performed by the Investigator (see Section 6.4). 


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3.2.5 
Early Termination Visit 
The Early Termination Visit will occur under the following circumstances: 
 The patient withdraws from the study after taking etripamil NS 70 mg and had a 
Follow-up Visit; or 
 The patient withdraws from the study and did not take etripamil NS 70 mg.  
In these cases, the patient should come to the site to return the study kit and the Investigator should 
close the case with Interactive Response Technology (IRT) (see Section 6.5). 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
The NODE-302 study is designed to obtain safety data to contribute to the etripamil safety 
database. Only patients randomized in the NODE-301 study are potentially eligible for the 
NODE-302 study. However, it is expected that among the randomized patients from the 
NODE-301 study, there will be at least 125 high-risk patients who are defined as follows: 
 70 years of age; or 
 60 years of age with either first degree AV block (PR interval 200 milliseconds) or 
concomitant use of medication known to affect cardiac conduction (i.e., beta-blockers, 
diltiazem, verapamil). 
If these high-risk patients are underrepresented in the NODE-301 study (i.e., 125 patients), 
additional high-risk patients will be recruited into the NODE-302 study to reach 125 high-risk 
patients enrolled (see Section 9.2.5). These high-risk patients will receive a test dose of etripamil 
NS 70 mg and will be evaluated for enrollment in the NODE-302 study according to the same 
process described in the NODE-301 study. 
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. Signed the NODE-302 written informed consent; 
3. Previously randomized in the NODE-301 study: 
o Received the study drug to treat symptoms the patient believed were consistent with an 
episode of PSVT during the NODE-301 study, irrespective of the study drug efficacy; 
OR 
o Did not experience an episode of PSVT or did not use the study drug at the time of the 
NODE-301 study completion; 
4. Willing and able to comply with all aspects of the study; 
5. 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 
urine pregnancy test result at the Qualification Visit and at the Follow-up Visit(s), and must 
use an approved form of contraception between the 2 visits. Approved forms of contraception 
include hormonal intrauterine devices and 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; 


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The following categories define females who are NOT considered to be of childbearing 
potential: 
o Premenopausal females with 1 of the following: 
a. Documented hysterectomy, 
b. Documented bilateral salpingectomy, or 
c. Documented bilateral oophorectomy, or 
o Postmenopausal females, defined as having amenorrhea for at least 12 months without an 
alternative medical cause; and 
6. Male patients, except those who are surgically sterile, must use an approved highly effective 
form of contraception during the 3 days after study drug administration. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Evidence of new severe arrhythmia discovered since the NODE-301 Test Dose Randomization 
Visit, including those reported on the CMS report of the outpatient PSVT event treated with 
the study drug in the NODE-301 study, including but not limited to: 
a. Third-degree AV block, Mobitz II second-degree AV block, or Wenckebach with 
bradycardia 40 bpm; 
b. Significant symptomatic sinus bradycardia HR 40 bpm or sinus pauses (3 seconds);  
c. Any significant ventricular arrhythmia (premature ventricular beats and couplets 
[>6 premature ventricular contractions per 45 seconds ECG] are considered 
significant); or 
d. Atrial fibrillation (event lasting longer than 30 seconds) or atrial flutter; 
2. Any drug-related or procedure-related SAE during the NODE-301 study; 
3. Any severe AE in the NODE-301 study that was severe enough to preclude administration of 
etripamil NS 70 mg in the NODE-302 study; 
4. Any new drug prescribed after the end of the patient’s participation in the NODE-301 study 
that could lower blood pressure or decrease AV node conduction; 
5. Systolic blood pressure <90 mmHg after a 5-minute rest in sitting position at the NODE-302 
Qualification Visit; 
6. Any symptoms consistent with clinically severe hypotension such as presyncope, medically 
significant lightheadedness, syncope, nausea, or vomiting; 
7. New therapy with digoxin, amiodarone, or any Class I or III antiarrhythmic drug added after 
the end of the patient’s participation in the NODE-301 study; 
8. New evidence of ventricular pre-excitation (e.g., delta waves, short PR interval, 
Wolff-Parkinson-White syndrome) on the ECG since randomization in the NODE-301 study; 


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9. New symptoms of congestive heart failure defined by the New York Heart Association Class II 
to IV since randomization in the NODE-301 study;  
10. New stroke since randomization in the NODE-301 study; 
11. New evidence of a significant physical or psychiatric condition including drug abuse, which, 
in the opinion of the Investigator, could jeopardize the safety of the patient or impede the 
patient’s capacity to follow the study procedures since randomization in the NODE-301 study; 
12. New syncope since randomization in the NODE-301 study, especially if observed during the 
monitoring of the event treated in the NODE-301 study; 
13. New evidence of hepatic dysfunction, defined as alanine aminotransferase or aspartate 
aminotransferase >3 × the upper limit of normal (ULN) or total bilirubin >2 × ULN, unless 
due to Gilbert syndrome, observed at the NODE-302 Qualification Visit; 
14. New evidence of renal dysfunction as determined by an estimated glomerular filtration rate 
assessed at the NODE-302 Qualification Visit as follows: 
a. <60 mL/min/1.73 m2 for patients <60 years of age, 
b. <40 mL/min/1.73 m2 for patients 60 and <70 years of age, or 
c. <35 mL/min/1.73 m2 for patients 70 years of age;  
15. Participation in any investigational drug or device study or the use of any investigational drug 
or device since the Final Study Visit in the NODE-301 study. 
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; 
 The patient took the study drug in both the NODE-301 and the NODE-302 studies for 
symptoms not associated with an episode of PSVT; 
 Occurrence of any medical condition, AE, or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the protocol; 
 Requirement of a prohibited concomitant medication and/or change in the use of chronic 
therapies, such as concomitant beta-blockers, calcium channel blockers, and medications that 
can lower blood pressure; 
 Patient failure to comply with protocol requirements or study-related procedures; 
 Termination of the study by Milestone or a regulatory authority; or 
 The patient self-administered a total of 11 doses of etripamil NS 70 mg in the NODE-302 
study. 
Patients who withdraw from the study after taking etripamil NS 70 mg and had a Follow-up Visit 
will be required to undergo an Early Termination Visit. 
Patients who withdraw from the study and did not take etripamil NS 70 mg will be required to 
undergo an Early Termination Visit. 


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Patients who withdraw after taking the study drug but did not have a Follow-up Visit will be 
required to undergo a Final Study Visit. 


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5 
STUDY TREATMENTS 
5.1 
Rationale for Study Dose 
The choice of the etripamil NS 70 mg dose has been made according to the data obtained in the 
etripamil 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 L 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 the NODE-302 study. 
5.2 
Randomization and Blinding 
This is an open-label study and no randomization will be performed. 
5.3 
Drug Supplies 
Milestone will provide sufficient quantities of etripamil NS 70 mg for the study. The lot numbers 
of supplied study drug will be recorded in the final Clinical Study Report (CSR). 
5.3.1 
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, and sulfuric acid. The dose of 
etripamil to be evaluated in the NODE-302 study is 70 mg. 
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) 


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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. Study drug will be uniquely identified with a generated kit 
identifier. The kit identifier for each patient will be recorded in the electronic data capture (EDC) 
system for the study. 
Bellwyck Pharma Services is the study drug distributor and will facilitate the delivery and resupply 
of study drug to the investigational sites. The Investigator or designee must contact the IRT when 
any unscheduled replacements of study drug are required. 
5.3.2 
Study Drug Administration 
All patients will receive a total of 200 L of etripamil NS 70 mg (i.e., 100 L in each nostril via 
the Aptar Pharma Nasal Spray Bidose System [BDS]) each time they self-administer study drug. 
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. 
5.3.3 
Treatment Compliance 
For this 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 Follow-up Visit(s) and Final Study Visit or Early Termination Visit. The patient will 
be questioned about the study 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. 
5.3.4 
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 or Early 
Termination 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 
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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. 
5.3.5 
Study Drug Handling and Disposal 
The final accountability of study drug will be performed by the Clinical Research Associate (CRA) 
at the sites. The sites will be allowed to destroy study drug after CRA accountability. If no study 
drug remains, this will be indicated in the drug accountability log. 
5.4 
Prior and Concomitant Medications and/or Procedures 
5.4.1 
Excluded Medications and/or Procedures 
Current participation in any investigational drug or device study or the use of any investigational 
drug or device within 30 days of the Qualification Visit is prohibited (except participation in the 
NODE-301 study). 
The use of digoxin, amiodarone, or any Class I or III antiarrhythmic drug is prohibited in the 
NODE-302 study. 
The effects of concomitant beta-blockers, calcium channel blockers, and medications that can 
lower blood pressure will be evaluated for each patient in the NODE-301 study. The use of these 
chronic drugs that were shown to be well tolerated by patients in the NODE-301 study (i.e., during 
the test dose and during an episode of PSVT if applicable) should not be modified in the 
NODE-302 study. No new test dose will be performed in the NODE-302 study; therefore, if a 
change in the use of these chronic therapies is necessary, the patient should be withdrawn from the 
study.  
Drugs commonly used for the chronic prophylactic treatment of episodes of PSVT 
(e.g., beta-blockers, verapamil, and diltiazem) cannot be started after inclusion of the patient in the 
NODE-302 study. If the patient requires a prohibited medication during the NODE-302 study for 
a medical diagnosis other than PSVT, the Investigator should consider withdrawing the patient 
from the study unless the medical condition(s) may be appropriately stabilized with alternatives. 
The use of any drugs of abuse that, in the opinion of the Investigator, would impact the validity of 
the study results is prohibited. 
5.4.2 
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 
Qualification Visit 
The Qualification Visit may coincide with the NODE-301 Final Study Visit, or it may be 
conducted at a future time. The following procedures are mandatory for inclusion in the 
NODE-302 study:  
 Obtain informed consent for the NODE-302 study; 
 Confirm eligibility based on inclusion/exclusion criteria; 
 Review any post-dose AEs that occurred in the NODE-301 study; 
 Evaluate any medical intervention that occurred during the Treatment Period in the NODE-301 
study; 
 Record concomitant medications; 
 Evaluate the patient’s current medical status since the NODE-301 study; 
 Perform physical examination (including height and weight); 
 Obtain and record vital signs (blood pressure and HR); 
 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; 
 Review the CMS safety report, if the patient took the study drug in the NODE-301 study; 
 Collect urine samples for on-site pregnancy test for females of childbearing potential; and 
 Each eligible patient will receive a study kit, which includes the study drug (etripamil NS), a 
CMS, a study identification card, patient’s study instructions, and other study-related material. 
If the Qualification Visit occurs within 48 hours of the NODE-301 Final Study Visit, the results 
from the NODE-301 Final Study Visit procedures may be reviewed and used to confirm other 
inclusion/exclusion criteria and/or procedures in the NODE-302 Qualification Visit, as applicable. 
If the Qualification Visit occurs after 48 hours of the NODE-301 Final Study Visit, the study 
procedures performed at the NODE-301 Final Study Visit cannot be used and must be repeated. 
See the MoOP for further details. 
6.2 
Treatment Period(s) 
During the Treatment Period(s), the patient will perform a sequence of steps described in 
Section 3.2.2, including etripamil NS 70 mg administration when the patient identifies symptoms 
of an episode of PSVT. Each patient will have the option to manage multiple episodes of PSVT 
(up to a maximum of 11 doses of etripamil NS 70 mg) in the NODE-302 study. 
The interpretation of the CMS ECG will be provided by the cardiac monitoring core laboratory to 
the site. The operational aspects are described in the MoOP. These reports will be sent to the site 
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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. 
In all cases, the presence of an episode of PSVT and termination will be reported to the Investigator 
by the cardiac monitoring core laboratory as well as potential arrhythmia or conduction issues 
identified on the 5-hour recording.  
6.3 
Follow-up Visit(s) 
All patients who experience an episode of PSVT and self-administer the study drug will be 
instructed to return to the site within 7 days after each episode. The following procedures will be 
performed: 
 Evaluate the patient’s medical status; 
 Review/have patient complete the patient diary entries of scoring scales; 
 Record any AEs;  
 Collect/return the study kit, if applicable: 
a. Used study drug, and 
b. Used study identification card; 
 Record concomitant medications; 
 Obtain and record vital signs (blood pressure and HR); 
 Collect urine sample for central laboratory urinalysis, only at the first Follow-up Visit for 
which the patient took the study drug; 
 Collect blood sample for safety laboratory testing (hematology, chemistry, and serum 
pregnancy test for females of childbearing potential) by the central laboratory, only at the first 
Follow-up Visit for which the patient took the study drug; 
 Collect urine samples on-site for pregnancy test for females of childbearing potential; 
 Review the CMS safety report; 
 Evaluate any medical intervention during the Treatment Period(s); and 
 Ensure the patient continues to be eligible for the study. 
If the patient decides to continue in the NODE-302 study, a new study kit, which will contain a 
new study drug and a study identification card (if previous one was used), will be dispensed to the 
patient. The patient will be provided with a new diary (TSQM and relief of symptoms numeric 
scoring scales). The CMS will be checked to ensure that all data was downloaded and transmitted 
to the core laboratory at the Follow-up Visit prior to being given back to the patient. 
In addition, an on-site Follow-up Visit must occur due to the following: 
 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, the CMS will be checked to ensure that all data 
was downloaded and transmitted to the core laboratory and patients should remain in the study 
for subsequent episodes of PSVT. 


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6.4 
Final Study Visit 
At the Final Study Visit, the following procedures will be performed: 
 Identify reason(s) for study completion; 
 Evaluate the patient’s current medical status; 
 Review/have patient complete the patient diary entries of scoring scales, only if the patient 
took the study drug; 
 Record any AEs; 
 Evaluate any medical intervention since the last Treatment Period; 
 Collect/return the study kit, including: 
a. Used or unused study drug, 
b. Used or unused CMS, and 
c. Study identification card; 
 Perform physical examination (including height and weight); 
 Obtain and record vital signs (blood pressure and HR); 
 Record concomitant medications; 
 Review the CMS safety report; 
 Collect urine sample for central laboratory urinalysis, only if the patient took the study drug; 
 Collect blood sample for safety laboratory testing (hematology, chemistry, and serum 
pregnancy test for females of childbearing potential) by the central laboratory, only if the 
patient took the study drug; and  
 Close the case with IRT. 
6.5 
Early Termination Visit 
The following procedures will be performed for patients that withdraw from the study: 
 Identify the reason(s) for withdrawal; 
 Collect the study kit, including: 
a. Used or unused study drug, 
b. Used or unused CMS, and  
c. Study identification card; 
 Obtain the signed withdrawal form; 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 CMS 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. 
Following each PSVT episode treated with study drug, the patient will report and rate symptoms 
of the episode of PSVT and its evolution, as well as overall treatment satisfaction, in a patient diary 
and TSQM.  
7.1 
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 Data and Safety Monitoring Committee (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). 
Further details are provided in the NODE-302 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 Treatment Period(s), 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 study drug administration during the Treatment Period(s) through the Final Study Visit or Early 
Termination Visit (whichever is later). 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 qualified 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 beginning at the Treatment Period will 
be reported as an AE(s). 
Clinically significant abnormal assessments that are detected during the study (i.e., beginning at 
the Treatment Period) 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 
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. 
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 


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“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. 
8.2 
Serious Adverse Events 
An AE or 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 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 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 


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drug administration. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery will be recorded as AEs and assessed for 
seriousness; 
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 during 
the Treatment Period(s) through the Final Study Visit or Early Termination Visit (whichever is 
later) 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. 


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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 
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 
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. This is an open-label study; therefore, all reports 
sent to Investigators will be unblinded. 
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. 
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 


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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 
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 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 Qualification Visit, the first Follow-up Visit for which the patient took the study 
drug, and at the Final Study Visit if the patient took the study drug. Urine pregnancy tests will be 
performed on female patients of childbearing potential at the Qualification Visit and at the 
Follow-up Visit(s). Serum pregnancy tests will be performed by the central laboratory any time 
blood samples are sent to the central laboratory. See Appendix B for a list of clinical laboratory 
analytes. 
8.8 
Vital Signs 
Vital signs (i.e., blood pressure and HR) will be obtained at the Qualification Visit, at Follow-up 
Visit(s), and at the Final Study Visit. Vital signs will be obtained after at least a 5-minute rest in a 
seated position. 
8.9 
Electrocardiograms 
A 12-lead ECG will be performed at the Qualification Visit. 
Safety assessments will be based on the data derived from CMS recordings. The cardiac 
monitoring core laboratory will review the CMS records for each patient and will send an ECG 
strip and report to the Investigator. 
8.10 
Physical Examinations 
A physical examination (including height and weight) will be performed at the Qualification Visit 
and the Final Study 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 Safety Population will include all patients who take the study drug. 
The Efficacy Population will include all patients who use the study drug to treat a positively 
adjudicated episode of PSVT. This population will not include patients who take the study drug 
for symptoms not associated with an episode of PSVT. 
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 patients who discontinue from the study, the primary reason for discontinuation 
will be listed and summarized. 
Summary statistics will be provided for demographic characteristics (e.g., age, gender, race, and 
ethnicity) and for baseline disease variables. 
The number of etripamil administrations per patient will be reported. 
9.2.2 
Study Drug Administration and Concomitant Medications 
Log entries detailing the IN administration of the study drug to 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 taking 
concomitant medications will be summarized by anatomical therapeutic chemical classification 
and preferred term. 
9.2.3 
Analysis of Efficacy 
The efficacy analyses will be performed on the Efficacy Population. The primary efficacy variable 
is the time to conversion of an episode of PSVT to SR after study drug administration. 
9.2.3.1 
Primary efficacy analysis 
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 Kaplan-Meier estimates of time to conversion will be calculated and reported as a 
Kaplan-Meier plot. The Kaplan-Meier estimate and confidence intervals of the time at which 25%, 
50%, and 75% of an episode of PSVT conversions occur will be calculated.  


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9.2.3.2 
Secondary efficacy analyses 
The TSQM will be reported. 
Descriptive statistics of the numbers of episodes of PSVT converted by performing a VM will be 
reported. 
Descriptive statistics of the numbers of positively adjudicated episodes of PSVT converted by 
performing a VM will be reported. 
Descriptive statistics of the number of patients that required healthcare intervention to terminate 
an episode of PSVT will be reported. 
All 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. 
9.2.5 
Sample Size Determination 
There is no statistical hypothesis in this uncontrolled open-label safety study. Based on the 
anticipated randomization of 500 patients in the NODE-301 study, it is estimated that 300 to 
500 patients will be eligible for the NODE-302 study. The final number of episodes of PSVT in 
the NODE-302 study will depend on the frequency and timing of episodes of PSVT during the 
study. The NODE-302 study will be operational until the end of the development program 
(i.e., when a sufficient number of documented study drug administrations have been achieved for 
inclusion in the etripamil safety database). 
If the population includes fewer than 125 high-risk patients at the end of the NODE-301 study, 
new patients meeting the high-risk categories (see Section 4) will be eligible to enroll in the 
NODE-302 study to ensure the following: 
 125 high-risk patients being enrolled (i.e., having received a test dose); and 
 75 of the enrolled high-risk patients having subsequently self-administered etripamil NS 70 mg 
during an episode of PSVT, with 20 of them being 70 years of age. 
 


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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. 


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10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, CMS data, inventory of 
study drug kits, 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 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 
Monitoring Committees 
11.7.1 
Steering Committee 
A single Steering Committee will be responsible for the scientific oversight of both the NODE-301 
and NODE-302 studies. The Steering Committee Chair will review the original protocol and 
potential amendments. 
Further details are provided in the NODE-302 study Steering Committee Charter. 


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11.7.2 
Data and Safety Monitoring Committee 
A single DSMC will operate for both the NODE-301 and NODE-302 studies. 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. 
Further details are provided in the NODE-302 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 Adjudication Committee will review the secondary ECG safety endpoints (i.e., arrhythmia 
and conduction disorders). 
Further details are provided in the NODE-302 study Adjudication Committee Charter. 
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 


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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, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB 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 (USA): +1-800-730-5779 
12.2.3 
ECG Core Laboratory for CMS Safety Reports 
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 
Qualification 
Visit1 
Treatment 
Period(s)2 
Follow-up 
Visit(s)3 
Final Study 
Visit4 
Early 
Termination 
Visit5 
Informed consent 
X 
 
 
 
 
Eligibility 
X6 
 
X 
 
 
Review post-dose AEs from 
NODE-301 study 
X 
 
 
 
 
Contact the Telephone Coach 
 
X7 
 
 
 
Recent medical status 
X8 
 
X 
X 
 
Concomitant medications 
X 
 
X 
X 
 
Physical examination9 
X 
 
 
X 
 
Vital signs (blood pressure 
and heart rate) 
X 
 
X 
X 
 
Hematology, chemistry, and 
urinalysis 
X10 
 
X11 
X12 
 
Pregnancy test13 
X 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
AEs 
 
X 
X 
X 
 
Dispense study kit14 
X 
 
X15 
 
 
Review CMS safety report16 
X 
 
X 
X 
 
Administer study drug and 
record time of dosing 
 
X17 
 
 
 
Review/have patient 
complete patient diary entries 
of scoring scales 
 
X 
X 
X 
 
Identify PSVT episode 
 
X 
 
 
 
Apply and start CMS 
 
X18 
 
 
 
Perform VM 
 
X 
 
 
 
Evaluate medical 
intervention during the 
Treatment Period(s) 
X19 
 
X 
X 
 
Collect study kit 
 
 
X20 
X21 
X21 
Identify reason(s) for study 
completion or withdrawal 
 
 
 
X 
X 
Close case with IRT 
 
 
 
X 
X 
Obtain signed withdrawal 
form 
 
 
 
 
X 
Note: Patients will be asked to sign the NODE-302 informed consent form before commencement of any study-related 
assessments or procedures, and the signed informed consent form will be applicable for the initial and all subsequent episodes 
of PSVT. 
1. 
The Qualification Visit of this study may coincide with the NODE-301 Final Study Visit or it may be conducted at a 
future time. Some procedures listed in the NODE-302 Schedule of Procedures Qualification Visit may refer to 
procedures conducted specifically for the NODE-301 study. If the Qualification Visit occurs within 48 hours of the 
NODE-301 Final Study Visit, the results from the NODE-301 Final Study Visit procedures may be reviewed and used to 
confirm other inclusion/exclusion criteria and/or procedures in the NODE-302 Qualification Visit, as applicable. If the 
Qualification Visit occurs after 48 hours of the NODE-301 Final Study Visit, the study procedures performed at the 
NODE-301 Final Study Visit cannot be used and must be repeated. See the MoOP for further details. 
2. 
The Treatment Period will begin immediately following the Qualification Visit. Eligible patients will perform a sequence 
of steps, including etripamil NS 70 mg self-administration when patients identify symptoms of PSVT. 
3. 
All patients who experience an episode of PSVT and self-administer the study drug will be instructed to return to the site 
within 7 days after each episode. Patients may continue to use study drug up to a maximum of 11 doses of etripamil NS 


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70 mg in the NODE-302 study. If the patient used the CMS for an episode of PSVT that subsequently was terminated by 
a successful VM (i.e., the patient did not use the study drug), the patient will be instructed to return to the site within 
7 days after the episode to ensure that all data has been downloaded from the CMS. 
4. 
A Final Study Visit will occur under different circumstances. A complete assessment will be performed by the 
Investigator. 
5. 
The Investigator should make every attempt to complete an Early Termination Visit for patients that withdraw or are 
discontinued from the study. 
6. 
Confirmation of eligibility at the Qualification Visit includes confirmation of PSVT diagnosis. Acceptable source 
documents to confirm the PSVT diagnosis are provided in the MoOP. Results from the NODE-301 Final Study Visit 
procedures may be reviewed and used to confirm other inclusion/exclusion criteria and/or procedures in the NODE-302 
Qualification Visit, as applicable. See the MoOP for further details. 
7. 
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. 
8. 
Since the NODE-301 study.  
9. 
Include height and weight. 
10. Hematology, chemistry, and urine safety tests will be performed for all patients in the NODE-301 Final Study Visit and 
these safety results may be used as baseline for the NODE-302 study if the NODE-302 Qualification Visit occurs within 
48 hours of the NODE-301 Final Study Visit. However, if the Qualification Visit occurs after 48 hours of the NODE-301 
Final Study Visit, the hematology, chemistry, and urine tests performed at the NODE-301 Final Study Visit cannot be 
used and must be repeated. Enrollment at the Qualification Visit in the NODE-302 study may proceed without these 
safety results, but if there is an exclusionary safety laboratory result, upon availability of these results, the patient will be 
asked to return to the site and be withdrawn from the NODE-302 study.  
11. Hematology, chemistry, and urine samples will be collected only at the first Follow-up Visit for which the patient took 
the study drug. 
12. Hematology, chemistry, and urine safety tests will be performed only if the patient took the study drug. 
13. For females of childbearing potential only. Urine pregnancy test required at the Qualification Visit and at the Follow-up 
Visit(s). Serum pregnancy tests will be performed by the central laboratory any time blood samples are sent to the central 
laboratory.   
14. The study kit will include the study drug (etripamil NS), a CMS, a study identification card, patient’s study instructions, 
and other study-related material. 
15. After the initial study kit is dispensed, patients that decide to continue in the study will receive a new study kit including 
new study drug (up to a maximum of 11 doses of etripamil NS 70 mg in the NODE-302 study) after each episode of 
PSVT. Patients may retain the study identification card (if unused, otherwise it will be replaced). The patient will be 
provided with a new diary (TSQM and relief of symptoms numeric scoring scales). The CMS safety report for the treated 
episode of PSVT must be reviewed before an additional drug kit is dispensed.  
16. The interpretation of the CMS ECG will be provided by the cardiac monitoring core laboratory to the site. The 
operational aspects are described in the MoOP. These reports will be sent to the site and the Medical Monitor. 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.  
17. During the Treatment Period(s), 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 etripamil NS 70 mg intranasally as instructed. If symptoms of an episode of PSVT have not resolved 
within 20 minutes after study drug administration, patients should seek appropriate medical care. In all cases, the 
presence of an episode of PSVT and termination will be reported to the Investigator by the cardiac monitoring core 
laboratory as well as potential arrhythmia or conduction issues identified on the 5-hour recording. 
18. The CMS recording during an episode of PSVT should continue for at least 5 hours regardless of treatment outcome. 
19. For the Treatment Period in the NODE-301 study. 
20. Including used study drug and CMS. The CMS will be checked to ensure that all data was downloaded and transmitted to 
the core laboratory prior to being given back to the patient. 
21. Including used or unused study drug and CMS and study identification card. 
AE = adverse event; CMS = Cardiac Monitoring System; CMS safety report = analysis of the ECG tracing by a core 
laboratory for cardiac safety; ECG = electrocardiogram; IRT = Interactive Response Technology; MoOP = Manual of 
Operations and Procedures; NS = nasal spray; PSVT = paroxysmal supraventricular tachycardia; TSQM = Treatment 
Satisfaction Questionnaire for Medication; VM = Vagal Maneuver. 


Milestone Pharmaceuticals Inc. 
Clinical Study Protocol MSP-2017-1158 
Confidential & Proprietary 
 
Version 2.0, 18 October 2018 
61 
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) 
An on-site urine pregnancy test will be performed at the Qualification Visit and at the Follow-up 
Visit(s). A serum pregnancy test will be performed by the central laboratory any time blood 
samples are sent to the central laboratory. 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Multi-Centre, Open-Label, Safety Study of Etripamil Nasal Spray in Spontaneous 
Episodes of Paroxysmal Supraventricular Tachycardia 
 
Investigational Product: 
MSP-2017 (etripamil) 
Protocol Number: 
MSP-2017-1158 (NODE-302) 
Phase: 
3 
Original Protocol: 
18 May 2018 V1 
Amendment 1 
18 October 2018 V2 
Statistical Analysis Plan Version: 
1.0 
Statistical Analysis Plan Date: 
27 Aug 2021  
 
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. 
 


Francis Plat
Digitally signed by Francis Plat 
Date: 2021.08.27 14:56:50 -04'00'
Douglas Wight
Digitally signed by Douglas Wight 
Date: 2021.08.27 15:08:07 -04'00'
Milestone Pharmaceuticals Inc. 
MSP-2017-1158 NODE-302 
STUDY TITLE: 
CONFIDENTIAL 
Vl.O 
SIGNATURE PAGE 
Statistical Analysis Plan 
27 Aug 2021 
Multi-Centre, Open-Label, Safety Study of Etripamil Nasal Spray in Spontaneous Episodes of 
Paroxysmal Supraventricular Tachycardia 
Prepared by 
Li Yang, MS 
Statistical Analyst 
Medpace, Inc. 
Approved by 
Signature 
Mwlz,~ 
Mark Simmons, PhD 
Biostatistician 
Medpace, Inc. 
Douglas Wight, MSc 
Vice-President, Drug Development 
Milestone Pharmaceuticals lnc. 
Francis Plat, MD 
CMO 
Milestone Pharmaceuticals Inc. 
Page 2 of 24 
Date 


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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 
2.2 
Study Design .............................................................................................................. 6 
2.2.1 
Treatment Regimen and Dosage ......................................................................... 7 
2.2.2 
Drug Randomization ........................................................................................... 7 
3. 
EFFICACY ASSESSMENTS ................................................................................... 8 
3.1 
Primary Efficacy Endpoint ........................................................................................ 8 
3.2 
Adjudication Process ................................................................................................. 8 
4. 
SAFETY ASSESSMENTS ....................................................................................... 9 
4.1 
Adverse Events .......................................................................................................... 9 
4.2 
Serious Adverse Event ............................................................................................... 9 
4.3 
Pregnancy Reporting ............................................................................................... 10 
4.4 
Clinical Laboratory Evaluations .............................................................................. 10 
4.5 
Vital Signs ............................................................................................................... 10 
4.6 
Electrocardiograms .................................................................................................. 10 
4.7 
Physical Examinations ............................................................................................. 10 
5. 
STATISTICAL METHODOLOGY ........................................................................ 11 
5.1 
Procedures for Handling Missing Data.................................................................... 11 
5.2 
Definition of Censoring Data................................................................................... 11 
5.3 
Statistical Methods................................................................................................... 11 
5.4 
Analysis Populations ............................................................................................... 12 
5.4.1 
Efficacy Population ........................................................................................... 12 
5.4.2 
Safety Population .............................................................................................. 12 
5.5 
Subject Disposition .................................................................................................. 12 
5.6 
Protocol Deviation ................................................................................................... 12 
5.7 
Demographic and Baseline Characteristics ............................................................. 12 
5.8 
Prior/Concomitant Medications ............................................................................... 12 
5.9 
Study Drug Administration ..................................................................................... 13 
5.10 
Analysis of Efficacy ................................................................................................ 13 
5.10.1 Primary Efficacy Analysis ................................................................................ 13 
5.10.2 Secondary efficacy analyses ............................................................................. 14 
5.11 
Analysis of Safety .................................................................................................... 15 


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5.11.1 Adverse Events ................................................................................................. 15 
5.11.2 Clinical Laboratory Tests .................................................................................. 16 
5.11.3 Vital Signs ......................................................................................................... 17 
5.11.4 Electrocardiograms and Cardiac Monitoring System recordings ..................... 17 
5.11.5 Physical Examination ........................................................................................ 18 
6. 
INTERIM ANALYSIS ............................................................................................ 18 
7. 
SAMPLE SIZE DETERMINATION ...................................................................... 18 
8. 
CHANGE FROM PROTOCOL .............................................................................. 18 
9. 
PROGRAMMING SPECIFICATIONS .................................................................. 18 
APPENDIX A:  SCHEDULE OF PROCEDURES ............................................................. 19 
APPENDIX B:  TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION ........................................................................................................ 21 
APPENDIX C: CLINICAL LABORATORY ANALYTES ............................................... 24 
 
 


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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 
CMS  
Cardiac Monitoring System 
DBP  
Diastolic Blood Pressure 
DSMC 
Data Safety Monitoring Committee  
ECG  
Electrocardiogram 
EEAC 
ECG Events Adjudication Committee 
EP 
Electrophysiology 
HR 
Heart Rate 
LLN  
Lower Limit of Normal 
MedDRA  
Medical Dictionary for Regulatory Activities 
NS 
Nasal Spray  
PSVT  
Paroxysmal Supraventricular Tachycardia 
PT 
Preferred Term 
PVCs 
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-302 study (protocol number MSP-2017-1158). 
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 evaluate the safety of etripamil nasal spray (NS) 70 mg 
when self-administered by patients with an episode of PSVT in an outpatient setting (i.e., without 
medical supervision). 
2.1.2 
Secondary Objectives 
The secondary objective of this study is to evaluate the safety and efficacy of etripamil NS 70 mg 
for the treatment of multiple episodes of PSVT. 
 
2.2 
Study Design  
The NODE-302 study is an extension of the NODE-301 Part 1 efficacy study. NODE-302 is a 
multi-centre, open-label study designed to evaluate the safety of etripamil NS 70 mg when self-
administered by patients for spontaneous episodes of PSVT in an outpatient setting. All patients 
randomized in the NODE-301 Part 1 study and who meet the inclusion and exclusion criteria of 
the NODE-302 study are eligible for the NODE-302 study. 
After each episode of PSVT, patients will have the option to continue in the NODE-302 study 
and manage subsequent episodes of PSVT with etripamil NS 70 mg if they do not meet any 
withdrawal criteria. 
Each episode of PSVT 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. 
This study will be conducted at the same sites as the NODE-301 Part 1 study. 
The study will include the following:  
Qualification Visit  


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The Qualification Visit may coincide with the NODE-301 Part 1 Final Study Visit, or it may be 
conducted at a future time. During the Qualification Visit, the Investigator will review the 
patient’s recent medical status and verify the patient’s eligibility for the NODE-302 study. 
Treatment Period(s) 
Following the Qualification Visit, eligible patients will enter the Treatment Period(s). During the 
Treatment Period(s), patients will perform a sequence of steps, including etripamil NS 70 mg 
self-administration when patients identify symptoms of an episode of PSVT. Each patient will 
have the option to manage up to a maximum of 11 episodes of perceived PSVT with etripamil 
NS 70 mg in the NODE-302 study. However, each patient will receive only 1 study kit including 
1 dose of study drug at a time, and a new study kit will be dispensed at the Follow-up Visit. 
Follow-up Visit(s) 
Every time the patient self-administers study drug (up to a maximum of 11 doses of etripamil NS 
70 mg in the NODE-302 study), the patient will be instructed to return to the site within 7 days 
after study drug administration for a complete assessment by the Investigator and will receive 
another study kit including 1 dose of study drug, if the patient does not meet any withdrawal 
criteria. 
Final Study Visit 
A complete assessment will be performed by the Investigator. 
Early Termination Visit 
The Early Termination Visit will occur under the following circumstances: the patient withdraws 
from the study after taking etripamil NS 70 mg and had a Follow-up Visit, or the patient 
withdraws from the study and did not take etripamil NS 70 mg. In these cases, the patient should 
come to the site to return the study kit and the Investigator should close the case with Interactive 
Response Technology. 
2.2.1 
Treatment Regimen and Dosage  
The dose of etripamil to be evaluated in NODE-302 is 70 mg.  
All patients will receive a total of 200 μL of etripamil NS 70 mg (i.e., 100 μL in each nostril via 
the Aptar Pharma Nasal Spray Bidose System) each time they self-administer study drug. 
2.2.2 
Drug Randomization 
There is no statistical hypothesis in this uncontrolled open-label safety study. Based on the 
anticipated randomization of 500 patients in the NODE-301 Part 1 study, it is estimated that 300 
to 500 patients will be eligible for the NODE-302 study. 


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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. 
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 
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 Data and Safety Monitoring Committee (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: 
x The presence of PSVT (AVNRT or AVRT determination if possible); 
Note: Non-PSVT episodes, including, but not limited to, sinus tachycardia, atrial 
tachycardia, atrial fibrillation, and atrial flutter will not be included in the Efficacy analyses 
for PSVT episodes.  Patients who do not have any PSVT episode in the study will not be 
included in the Efficacy Population. 
x Termination of PSVT due to VM if PSVT was present; and  
x Termination of PSVT to SR for at least 30 seconds after study drug administration if PSVT 
was present.  
The Adjudication Committee will also adjudicate the time of 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). 
Further details are provided in the NODE-302 study Adjudication Committee Charter. 


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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 Treatment Period(s), safety variables will be recorded. 
The EEAC report data will include 
1) The occurrence of  atrial fibrillation, atrial flutter, or atrial tachycardia lasting longer than 
30 seconds. 
2) Non-sustained/unsustained ventricular tachycardia defined as equal or greater than 3 wide 
consecutive beats originating in the ventricles at a rate of >100bpm, terminating 
spontaneously.  
3) Sustained Ventricular Tachycardia >30 sec or requiring termination due to hemodynamic 
compromise in <30 sec  
4) Reoccurence of PSVT defined as a new onset of PSVT after initial conversion to sinus 
rhythm for at least 30 seconds 
5) Any sinus rate equal or less than 40 bpm 
6) Type I AV block lasting greater than 30 seconds. 
7) Any occurrence of Type II or Type III AV block (including AV dissociation or the presence 
of more than 2 non-conducted P waves in a row). 
8) Any pause equal or greater than 3 seconds.  
9) 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.  
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: 
x Death, 
x A life-threatening AE, 


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x An event that requires hospitalization or prolongation of existing hospitalizations, 
x A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, 
x A congenital anomaly/birth defect, or 
x 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 Qualification Visit, the first Follow-up Visit for which the patient took the 
etripamil NS 70 mg, and at the Final Study Visit if the patient took etripamil NS 70 mg. Urine 
pregnancy tests will be performed on female patients of childbearing potential at the Qualification 
Visit and at the Follow up Visit(s). Serum pregnancy tests will be performed by the central 
laboratory any time blood samples are sent to the central laboratory. See Appendix B for a list of 
clinical laboratory analytes. 
4.5 
Vital Signs 
Vital signs (i.e., blood pressure and HR) will be obtained at the Qualification Visit, at Follow up 
Visit(s), and at the Final Study Visit. Vital signs will be obtained after at least a 5-minute rest in a 
seated position. 
4.6 
Electrocardiograms 
A 12-lead ECG will be performed at the Qualification Visit. 
Safety variables will include clinical arrhythmias and conduction disorders detected on surface 
ECG or CMS recordings.  
CMS recordings: 
During the Treatment Period, arrhythmias, recurrence of episodes of PSVT, and conduction 
disorders will be reported from the CMS recording 
  
4.7 
Physical Examinations 
A physical examination (including height and weight) will be performed at the Qualification Visit 
and the Final Study Visit. 


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5. 
STATISTICAL METHODOLOGY 
5.1 
Procedures for Handling Missing Data  
All observed data will be used in the analyses and unless otherwise specified, missing data will 
not be imputed besides the partial date missing. 
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 and all analyses of time to 
conversion. 
For adjudicated episodes of PSVT, the EEAC will indicate at what time-point a patient episode 
should be censored. Patients who convert to another arrhythmia will be censored at the time of 
that conversion.  Patients who receive medical intervention, or who do not convert within the 5 
hour observation period will be censored at the end of the observation period.   
For patients without an adjudicated episode (i.e. patients presenting another type of tachycardia 
or no tachycardia at all), the EEAC will determine the time to termination of this non-qualifying 
tachycardia and the episode will be censored at  end of the observation period. 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.  
5.3 
Statistical Methods 


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Summary tabulations will be presented that will display descriptive statistics. 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.  
5.4 
Analysis Populations 
5.4.1 
Efficacy Population 
The Efficacy Population will include all patients who use etripamil NS 70 mg to treat a 
positively adjudicated episode of PSVT.  
5.4.2 
Safety Population 
The Safety Population will include all patients who take etripamil NS 70 mg. 
5.5 
Subject Disposition 
The numbers and percentages of subjects will be provided for subject disposition and for each 
study population.  
For subjects who discontinue from the study, the primary reason for discontinuation will be listed 
and summarized. 
5.6 
Protocol Deviation 
A listing of all protocol deviations will be provided. 
5.7 
Demographic and Baseline Characteristics 
Summary statistics will be provided for demographic characteristics (e.g., age, gender, race, and 
ethnicity) and for baseline disease variables (e.g., weight, height, body mass index). A listing of 
all demographic data will be provided. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
21.0). A listing of all medical history will be provided. 
5.8 
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 
first etripamil NS 70 mg administration. Concomitant medications include medications that start 
any time and are taken at any time after the start date and time of first etripamil NS 70 mg 
administration until the end of the follow-up period. Medications missing both start and stop 


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dates or having a start date prior to the start of etripamil NS 70 mg administration 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.  
A listing of all medications including the reported term, preferred term, ATC class, start and stop 
dates, and other relevant data will be provided. 
5.9 
Study Drug Exposure 
Summary statistics will be provided for: 
x The number of patients who experience 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 episodes;  
x Number of patients who experience 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 positively adjudicated 
PSVT episodes;  
x Number of patients who took a half dose for an episode and percent of episodes a half 
dose was taken for;  
x Average duration on study;  
x Average duration from patient enrollment until first, second, and third episode on the 
study; and  
x The estimated number of episodes per year ((365 / Days on Study) * # Episodes)) for all 
enrolled patients and for patients in the Safety Population.   
x The estimated number of positively adjudicated episodes per year for all enrolled patients 
and for patients in the Efficacy Population. 
A listing of all patients taking half doses will be provided.   
5.10 
Analysis of Efficacy 
The primary efficacy analyses will be performed on the Efficacy Population for each patient’s 
first positively adjudicated PSVT episode treated with etripamil NS 70 mg.  [For example; if a 
patient has two non-PSVT episodes, followed by a third episode which is PSVT, the third 
episode will be used for the primary efficacy analysis]  
The primary efficacy variable is the time to conversion of an episode of PSVT to SR (for at least 
30 seconds) after etripamil NS 70 mg administration. 
5.10.1 
Primary Efficacy Analysis 
Patients who did not convert after 5 hours following etripamil NS 70 mg administration or who 
converted following medical assistance will be censored as described under section 5.2.  
The Kaplan-Meier estimates of time to conversion will be calculated and reported as a Kaplan-
Meier plot. The Kaplan-Meier estimate and confidence intervals of the time at which 25%, 50%, 
and 75% of an episode of PSVT conversions occur will be calculated. 
Sample SAS code: 


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**************************************************************************  
Note: STATUS = censored status (1 = censored, 0 = event occurred) 
*************************************************************************;  
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; 
5.10.2 
Secondary efficacy analyses 
Individual TSQM-9 questionnaire results (n, mean, median, minimum, maximum, standard 
deviation) will be summarized by the first treated episode.  
Treatment satisfaction will be analyzed by summarized the score of TSQM-9 for effectiveness, 
convenience, and global satisfaction domain. 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 
Overall 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. 
Descriptive statistics of the numbers of episodes of PSVT converted by performing a VM will be 
reported.  
Descriptive statistics of the numbers of positively adjudicated episodes of PSVT converted by 
performing a VM will be reported.  
Descriptive statistics of the number of patients that required healthcare intervention to terminate 
an episode of PSVT will be reported. 


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5.10.3 
Exploratory Efficacy analyses 
To further evaluate the efficacy of etripamil NS 70 mg, the following exploratory analyses will 
be conducted; 
x The effect of first treatment episode, including whether the outcome of the first treatment 
episode can predict the outcome of future treatment episodes, will be explored via; 
o A logistic regression comparing response on a second episode by response observed 
during a patient’s first episode. 
o Analysis via ANOVA mode of the proportion of episodes a patient responds to 
treatment compared to total episodes experienced. 
o The primary efficacy analysis will be repeated for patients second positively 
adjudicated PSVT episode. 
o The primary efficacy analysis will be repeated for patients third positively 
adjudicated PSVT episode. 
 
x The primary efficacy will be repeated for all PSVT episodes in the study [Patients with 
multiple events will be counted multiple times] 
x The number and percentage of patients who sought medication intervention for an episode 
will be presented for patients first, second, third, and fourth or more episodes.  This analysis 
will be conducted in the Efficacy Population, and the Safety Population.   
x The primary efficacy analysis will be repeated, but with patients who receive medical 
intervention being censored at the time of conversion to SR after medical intervention. 
x The primary efficacy analysis will be repeated for patients >70 years of age, or >60 and 
<70 years of age on a concomitant medication of beta blocker or calcium channel blockers. 
5.11 
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.  
5.11.1 
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: 
x Any AE, 
x Treatment Emergent Adverse Events (TEAEs); defined as AEs with a start date occurring 
0 to 24 hours after each study dose, 
x TEAEs by maximum severity, 


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x Drug-related TEAEs, 
x Drug-related TEAEs by maximum severity, 
x Serious Adverse Events (SAEs), 
x Drug-related Serious Adverse Events, 
x AEs leading to Death, 
x AEs leading to study drug discontinuation, 
x Drug-related AEs leading to study drug discontinuation, 
x AEs with a start date occurring 0 to 48 hours after each drug self-administration. 
x AEs with a start date occurring 0 to 7 days after each drug self-administration. 
x TEAEs occurring after a patient first dose 
x TEAEs occurring after a patient second dose 
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 etripamil NS 70 mg based on the available date entries.  
Events with partial onset times which occur on the same day as 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 Treatment Emergent AEs. AEs will be summarized overall.  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 AE, as well as the most extreme relationship of the AE to 
etripamil NS 70 mg 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 etripamil NS 70 mg, severe AEs, SAEs, and AEs leading to etripamil NS 70 mg 
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 etripamil NS 70 mg discontinuation will be provided. The number of days between 
treatment drug dose and when the AE occurred will be presented (i.e., relative study day), as will 
duration of the AE. 
5.11.2 
Clinical Laboratory Tests 
Clinical laboratory results (mean, median, minimum, maximum, standard deviation) will be 
summarized. The change and percentage change from the qualification visit to follow-up visit 
and final study visit will be summarized. Incidence of laboratory (<LLN and >ULN) will be 
summarized. Listings of all clinical laboratory tests will be provided. 


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5.11.3 
Vital Signs  
Vital signs results (n, mean, median, minimum, maximum, standard deviation) will be 
summarized. The changes and percentage of change (n, mean, median, minimum, maximum, 
standard deviation) in HR, SBP, and DBP will be summarized. 
5.11.4 
Electrocardiograms and Cardiac Monitoring System recordings 
Electrocardiograms results will be summarized.  
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 Safety Population.   
For episodes after a patient is enrolled, 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 Safety Population when the 
CMS data is collected but etripamil NS 70 mg was not taken (successful vagal maneuver, or 
other reason for not taking etripamil NS 70 mg).  These data will also be reported in the Safety 
population by treatment for CMS data which is collected after administration of  etripamil NS 70 
mg. 
 
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 non-sustained/insustained ventricular tachycardia defined as equal or 
greater than 3 wide consecutive beats originating in the ventricles at a rate of > 100 bpm, 
terminating spontaneously. 
3) N (%) of subjects with Sustained Ventricular Tachycardia e> 30 sec or requirring 
termination due to hemodynamic compromise in < 30 sec 
4) N(%) of subjects with recurrence of PSVT, defined as a new onset of PSVT after initial 
conversion to SR for at least 30 sec. 
 
4) N (%) of subjects with any sinus rate equal or less than 40 bpm 
5) N(%) of subjects with  Type I AV block lasting > 30 seconds 
6) 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). 
7) N (%) of subjects with any pause equal or greater than 3 seconds. 


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5.11.5 
Physical Examination 
Physical examination data at each evaluation will be listed.  
6. 
INTERIM ANALYSIS 
No interim analysis has been planned. 
7. 
SAMPLE SIZE DETERMINATION 
There is no statistical hypothesis in this uncontrolled open-label safety study. Based on the 
anticipated randomization of 500 patients in the NODE-301 Part 1 study, it is estimated that 300 
to 500 patients will be eligible for the NODE-302 study. The final number of episodes of PSVT 
in the NODE-302 study will depend on the frequency and timing of episodes of PSVT during the 
study.  
8. 
CHANGE FROM PROTOCOL 
No Change from Protocol is recorded. 
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 
Qualification 
Visit1 
Treatment 
Period(s)2 
Follow-up 
Visit(s)3 
Final Study 
Visit4 
Early Termination 
Visit5 
Informed consent 
X 
 
 
 
 
Eligibility 
X6 
 
X 
 
 
Review post-dose AEs from 
NODE-301 Part 1 study 
X 
 
 
 
 
Contact the Telephone 
Coach 
 
X7 
 
 
 
Recent medical status 
X8 
 
X 
X 
 
Concomitant medications 
X 
 
X 
X 
 
Physical examination9 
X 
 
 
X 
 
Vital signs (blood pressure 
and heart rate) 
X 
 
X 
X 
 
Hematology, chemistry, and 
urinalysis 
X10 
 
X11 
X12 
 
Pregnancy test13 
X 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
AEs 
 
X 
X 
X 
 
Dispense study kit14 
X 
 
X15 
 
 
Review CMS safety report16 
X 
 
X 
X 
 
Administer study drug and 
record time of dosing 
 
X17 
 
 
 
Review/have patient 
complete patient diary 
entries of scoring scales 
 
X 
X 
X 
 
Identify PSVT episode 
 
X 
 
 
 
Apply and start CMS 
 
X18 
 
 
 
Perform VM 
 
X 
 
 
 
Evaluate medical 
intervention during the 
Treatment Period(s) 
X19 
 
X 
X 
 
Collect study kit 
 
 
X20 
X21 
X21 
Identify reason(s) for study 
completion or withdrawal 
 
 
 
X 
X 
Close case with IRT 
 
 
 
X 
X 
Obtain signed withdrawal 
form 
 
 
 
 
X 
Note: Patients will be asked to sign the NODE-302 informed consent form before commencement of any study-related 
assessments or procedures, and the signed informed consent form will be applicable for the initial and all subsequent episodes 
of PSVT. 
1. 
The Qualification Visit of this study may coincide with the NODE-301 Part 1 Final Study Visit or it may be conducted at 
a future time. Some procedures listed in the NODE-302 Schedule of Procedures Qualification Visit may refer to 
procedures conducted specifically for the NODE-301 Part 1 study. If the Qualification Visit occurs within 48 hours of the 
NODE-301 Part 1 Final Study Visit, the results from the NODE-301 Part 1 Final Study Visit procedures may be 
reviewed and used to confirm other inclusion/exclusion criteria and/or procedures in the NODE-302 Qualification Visit, 
as applicable. If the Qualification Visit occurs after 48 hours of the NODE-301 Part 1 Final Study Visit, the study 
procedures performed at the NODE-301 Part 1 Final Study Visit cannot be used and must be repeated. See the MoOP for 
further details. 


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2. 
The Treatment Period will begin immediately following the Qualification Visit. Eligible patients will perform a sequence 
of steps, including etripamil NS 70 mg self-administration when patients identify symptoms of PSVT. 
3. 
All patients who experience an episode of PSVT and self-administer etripamil NS 70 mg will be instructed to return to 
the site within 7 days after each episode. Patients may continue to use etripamil NS 70 mg up to a maximum of 11 doses 
of etripamil NS 70 mg in the NODE-302 study. If the patient used the CMS for an episode of PSVT that subsequently 
was terminated by a successful VM (i.e., the patient did not use etripamil NS 70 mg), the patient will be instructed to 
return to the site within 7 days after the episode to ensure that all data has been downloaded from the CMS. 
4. 
A Final Study Visit will occur under different circumstances. A complete assessment will be performed by the 
Investigator. 
5. 
The Investigator should make every attempt to complete an Early Termination Visit for patients that withdraw or are 
discontinued from the study. 
6. 
Confirmation of eligibility at the Qualification Visit includes confirmation of PSVT diagnosis. Acceptable source 
documents to confirm the PSVT diagnosis are provided in the MoOP. Results from the NODE-301 Part 1 Final Study 
Visit procedures may be reviewed and used to confirm other inclusion/exclusion criteria and/or procedures in the NODE-
302 Qualification Visit, as applicable. See the MoOP for further details. 
7. 
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. 
8. 
Since the NODE-301 Part 1 study.  
9. 
Include height and weight. 
10. Hematology, chemistry, and urine safety tests will be performed for all patients in the NODE-301 Part 1 Final Study 
Visit and these safety results may be used as baseline for the NODE-302 study if the NODE-302 Qualification Visit 
occurs within 48 hours of the NODE-301 Part 1 Final Study Visit. However, if the Qualification Visit occurs after 48 
hours of the NODE-301 Part 1 Final Study Visit, the hematology, chemistry, and urine tests performed at the NODE-301 
Part 1 Final Study Visit cannot be used and must be repeated. Enrollment at the Qualification Visit in the NODE-302 
study may proceed without these safety results, but if there is an exclusionary safety laboratory result, upon availability 
of these results, the patient will be asked to return to the site and be withdrawn from the NODE-302 study.  
11. Hematology, chemistry, and urine samples will be collected only at the first Follow-up Visit for which the patient took 
etripamil NS 70 mg. 
12. Hematology, chemistry, and urine safety tests will be performed only if the patient took the  etripamil NS 70 mg. 
13. For females of childbearing potential only. Urine pregnancy test required at the Qualification Visit and at the Follow-up 
Visit(s). Serum pregnancy tests will be performed by the central laboratory any time blood samples are sent to the central 
laboratory.   
14. The study kit will include the study drug (etripamil NS 70 mg), a CMS, a study identification card, patient’s study 
instructions, and other study-related material. 
15. After the initial study kit is dispensed, patients that decide to continue in the study will receive a new study kit including 
new study drug (up to a maximum of 11 doses of etripamil NS 70 mg in the NODE-302 study) after each episode of 
PSVT. Patients may retain the study identification card (if unused, otherwise it will be replaced). The patient will be 
provided with a new diary (TSQM and relief of symptoms numeric scoring scales). The CMS safety report for the treated 
episode of PSVT must be reviewed before an additional drug kit is dispensed.  
16. The interpretation of the CMS ECG will be provided by the cardiac monitoring core laboratory to the site. The 
operational aspects are described in the MoOP. These reports will be sent to the site and the Medical Monitor. 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.  
17. During the Treatment Period(s), etripamil NS 70 mg 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 etripamil NS 70 mg intranasally as instructed. If symptoms of an episode of PSVT have not resolved 
within 20 minutes after study drug administration, patients should seek appropriate medical care. In all cases, the 
presence of an episode of PSVT and termination will be reported to the Investigator by the cardiac monitoring core 
laboratory as well as potential arrhythmia or conduction issues identified on the 5-hour recording. 
18. The CMS recording during an episode of PSVT should continue for at least 5 hours regardless of treatment outcome. 
19. For the Treatment Period in the NODE-301 Part 1 study. 
20. Including used study drug and CMS. The CMS will be checked to ensure that all data was downloaded and transmitted to 
the core laboratory prior to being given back to the patient. 
21. Including used or unused study drug and CMS and study identification card. 
AE = adverse event; CMS = Cardiac Monitoring System; CMS safety report = analysis of the ECG tracing by a core 
laboratory for cardiac safety; ECG = electrocardiogram; IRT = Interactive Response Technology; MoOP = Manual of 
Operations and Procedures; NS = nasal spray; PSVT = paroxysmal supraventricular tachycardia; TSQM = Treatment 
Satisfaction Questionnaire for Medication; VM = Vagal Maneuver. 
 


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APPENDIX B:  TREATMENT SATISFACTION QUESTIONNAIRE FOR 
MEDICATION 
It is essential that the TSQM is administered in the native language of the respondents. 
Additionally, adequate time must be provided for completion of the TSQM (5-15 minutes). 
The text of the TSQM should be of sufficient size to allow for easy readability. Please note 
that any large type version of the TSQM must maintain the standardized content and format of 
the original instrument, and must be submitted via email to tsqm@Quintiles.com for review 
and approval. If a respondent cannot read but can respond to the TSQM questions 
independently, then staff may provide verbatim oral instructions. 
The TSQM was developed to be administered in paper format 2-3 weeks after the medication 
is used. For each item, the respondent is asked to indicate his/her level of satisfaction or 
dissatisfaction with the medication over the last two to three weeks or since the most recent 
use by placing a single check mark next to the response that most closely corresponds to his 
or her own experiences.  
 
1. How satisfied or dissatisfied are you with the ability of the medication to treat your 
condition? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
2. How satisfied or dissatisfied are you with the way the medication relieves your symptoms? 
1. Extremely Dissatisfied 
2. Very Dissatisfied 
3. Dissatisfied 
4. Somewhat Satisfied 
5. Satisfied 
6. Very Satisfied 
7. Extremely Satisfied 
3. How satisfied or dissatisfied are you with the amount of time it 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 


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4. How easy or difficult is it to use the medication in its current form? 
1. Extremely Difficult 
2. Very Difficult 
3. Difficult 
4. Somewhat Easy 
5. Easy 
6. Very Easy 
7. Extremely Easy 
5. How easy or difficult is it to plan when you will use the medication each time? 
1. Extremely Difficult 
2. Very Difficult 
3. Difficult 
4. Somewhat Easy 
5. Easy 
6. Very Easy 
7. Extremely Easy 
6. How convenient or inconvenient is it to take the medication as instructed? 
1. Extremely Inconvenient 
2. Very Inconvenient 
3. Inconvenient 
4. Somewhat Convenient 
5. Convenient 
6. Very Convenient 
7. Extremely Convenient 
7. Overall, how confident are you that taking this medication is a good thing for you? 
1. Not at All Confident 
2. A Little Confident 
3. Somewhat Confident 
4. Very Confident 
5. Extremely Confident 
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 


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7. Extremely Satisfied 
 
 


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APPENDIX C: 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) 
An on-site urine pregnancy test will be performed at the Qualification Visit and at the Follow-up Visit(s). 
A serum pregnancy test will be performed by the central laboratory any time blood samples are sent to 
the central laboratory.