Clinical trial NCT04072835
Conditions: Paroxysmal Supraventricular Tachycardia
Keywords: PSVT
Sponsor: Milestone Pharmaceuticals Inc.
Start date: 2019-09-23; Completion date: 2023-01-26
Enrollment: 1116 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
NODE-303 was a multi-center, open label study to evaluate the safety of etripamil NS in participants with Paroxysmal Supraventricular Tachycardia (PSVT). Participants were provided with an ambulatory Cardiac Monitoring System (CMS) to help document PSVT episodes. The CMS was self-applied by the participant, when they felt the onset of PSVT symptoms. Participants self-administered etripamil NS if vagal maneuver was ineffective. After an episode of PSVT where study drug was administered, the participant returned to the investigative site and had the option to continue in NODE-303 and manage up to three subsequent episodes of PSVT with etripamil NS for a maximum of four episodes.

Detailed description:
NODE-303 was a multi-center, open label study to evaluate the safety of etripamil NS in participants with PSVT. Participants were provided with an ambulatory CMS to help document PSVT episodes. The CMS was self-applied by the participant, when they felt the onset of PSVT symptoms. Participants self-administered etripamil NS 70 mg if vagal maneuver (VM) was ineffective. Approximately 2 years after study initiation, a protocol amendment was implemented to allow participants to administer a second dose of etripamil 70 mg 10 minutes after the first dose, if PSVT symptoms persisted. After an episode of PSVT where study drug was administered, the participant returned to the investigative site and had the option to continue in NODE-303 and manage up to three subsequent episodes of PSVT with etripamil NS for a maximum of four episodes.

The study included:

A Screening Visit during which the Investigator verified that the participant met the eligibility criteria of the NODE-303 study, obtained the signed informed consent, took blood and urine for laboratory evaluations, and conducted other screening procedures. The informed consent for NODE-303 was applicable for the initial and all subsequent PSVT episodes. A Baseline Visit during which the site confirmed eligibility, concomitant medications, trained the participant on study procedures, and gave the participant study drug, participant reported outcome (PRO) materials, and the CMS materials. A Treatment Period during which the participant completed the monthly PRO survey, self-identified symptoms of PSVT, used the CMS during 60 minutes, performed a VM, and self-administered etripamil NS if the symptoms did not resolve after the VM. Participants could be contacted during this period for reminders and training on what to do during a PSVT episode. Participants also completed a per episode survey after any PSVT episode they experience. During the Treatment Period, Follow-up Visits occurred at the study site up to 14 days after each episode of PSVT treated with etripamil NS, and during which the Investigator evaluated the results of the last usage of etripamil NS and reassessed participant's eligibility to continue in the study based on study inclusion and exclusion criteria. Participants who were eligible to continue in the study received additional study medication.

A Final Study Visit occurred when a participant discontinued or withdrew from the study, or when the overall study was completed, or the participant had completed the maximum number of doses. NODE-303 continued until enough documented self-administrations of etripamil NS were included in the safety database to meet regulatory requirements for the etripamil NS development program. The common study end date (CSED) for the entire study depended on the rate of accrual of the primary endpoint, unique participants with an episode. When the criteria for concluding the study were met, the Sponsor announced the CSED for the entire study and sites were informed in advance to schedule all final participant visits prior to the CSED.

Arms: arm 1: Participants self-administered etripamil NS 70 mg. After implementation of protocol amendment 2.1 (16 March 2021), participants had the option to administer a second dose of etripamil 70 mg 10 minutes after the first dose, if PSVT symptoms persisted arm 2: Participants not treated with etripamil NS for a PSVT episode.
Interventions: intervention 1: Etripamil NS
Intervention descriptions: intervention 1: Participants were provided with an ambulatory Cardiac Monitoring System (CMS) to help document PSVT episodes. The CMS was self-applied by the participant, when PSVT symptoms begin. Participants self-administered etripamil NS if vagal maneuver was ineffective. After implementation of protocol amendment 2.1, participants had the option to administer a second dose of etripamil 70 mg 10 minutes after the first dose, if symptoms persisted. After an episode of PSVT where drug was administered, the participant returned to the investigative site for a study visit and was given the option to continue in NODE-303 and manage up to three subsequent episodes of PSVT with etripamil NS for a maximum of four episodes.

Protocol documents:
Prot_002.pdf: 
Milestone Pharmaceuticals 
Confidential 
Clinical Study Protocol 
NODE-303 
16 Mar 2021 
Version: 2.1, Rev. to Amend No. 1 
MP Project #:  MSP-2017-1174 
Page 1 of 68 
The NODE-303 Trial 
Multi-Centre, Multi-National, Open Label, Safety Study of Etripamil 
Nasal Spray for Patients with Paroxysmal Supraventricular Tachycardia 
Investigational Product: Etripamil (MSP-2017) 
Protocol Number: NODE-303 
Version #2.1, Revision to Amendment No. 1, 16MAR2021 
Version #2.0, Amendment No. 1, 15FEB2021 
Version #1.0, 21JUN2019 
Sponsor:  Milestone Pharmaceuticals Inc. 
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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Confidential 
Clinical Study Protocol  
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STUDY PROTOCOL 
 
COMPOUND 
NAME/NUMBER: 
 
Etripamil (MSP-2017) 
PROTOCOL NUMBER: 
 
NODE-303  
US IND NUMBER: 
 
IND #114386 
EUDRACT NUMBER: 
 
2019-001857-13 
DEVELOPMENT PHASE: 
 
Phase 3 
PROTOCOL TITLE: 
Multi-Centre, Multi-National, Open Label, Safety Study of 
Etripamil Nasal Spray for Patients with Paroxysmal 
Supraventricular Tachycardia 
 
PROTOCOL VERSION: 
 
Version 2.1  
PROTOCOL DATE: 
 
16 March 2021 
CONTRACT RESEARCH 
ORGANIZATION: 
IQVIA Biotech 
1700 Perimeter Park Drive 
Morrisville, NC 27560, United States 
 
This study will be performed in compliance with Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. 
 
 


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Confidential 
Clinical Study Protocol  
NODE-303 
16 Mar 2021 
Version: 2.1, Rev. to Amend No. 1 
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APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
NODE-303  
PROTOCOL VERSION: 
2.1, 16MAR2021 
PROTOCOL TITLE: 
Multi-Centre, Multi-National, Open Label, Safety Study of Etripamil 
Nasal Spray for Patients with Paroxysmal Supraventricular 
Tachycardia
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study. 
 
 Francis Plat, MD 
Chief Medical Officer 
Milestone Pharmaceuticals Inc. 
 
 
 
 
Date 
Doug Wight 
VP Drug Development 
Milestone Pharmaceuticals Inc. 
 
 
 
      Date 
_______________________________________________________     ________________________ 
Guy Rousseau
Senior VP Regulatory Affairs
Milestone Pharmaceuticals Inc. 
 
 
 
      Date 
 


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Version: 2.1, Rev. to Amend No. 1 
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Study Contact and Details 
 
SERIOUS ADVERSE EVENT 
REPORTING 
 
Via Electronic Data Capture system.  If not possible, then by 
email/fax to Safety-inbox.biotech@iqvia.com, or phone call to 
1-866-761-1274 (toll-free) or 919-313-1412 (toll) 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
 
Francis Plat, MD 
Chief Medical Officer, Milestone Pharmaceuticals 
E-mail: fplat@milestonepharma.com 
Telephone: +1-514-336-0444, ext. 225 
 
SPONSORED BY: 
Milestone Pharmaceuticals Inc. 
1111 Dr. Frederik-Philips Blvd., Suite 420 
Saint-Laurent, QC H4M 2X6, Canada 
Telephone: +1-514-336-0444 
 
CONTRACT RESEARCH 
ORGANIZATION: 
 
 
IQVIA Biotech 
1700 Perimeter Park Drive 
Morrisville, NC 27560, United States  
SPONSOR MEDICAL 
EXPERT: 
 
Nydia Cottely, MD 
Telephone: +33-6-16680269 
E-mail: ncottely@milestonepharma.com 
 
Silvia Shardonofsky, MD 
Telephone: +1-514-336-0444, ext. 235 
E-mail: sshardonofsky@milestonepharma.com 
 
INVESTIGATORS: 
 
 
A current list of clinical investigators will be maintained in the 
Trial Master File (TMF) 
 
 
 


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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 my governing Regulatory Authority (FDA, 
EMA, Regional/Country Authority) Regulations, Institutional Review Board/Ethic Committee 
Regulations and International Council for Harmonization Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
 
 
______________________________________________ 
Site Name/City/Country 
 
 


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1. SYNOPSIS 
PRODUCT 
NAME/NUMBER 
Etripamil (MSP-2017) 
PROTOCOL 
NUMBER 
NODE-303 
DEVELOPMENT 
PHASE 
Phase 3 
PROTOCOL TITLE Multi-Centre, Multi-National, Open Label, Safety Study of Etripamil Nasal 
Spray for Patients with Paroxysmal Supraventricular Tachycardia 
INDICATION 
Paroxysmal Supraventricular Tachycardia (PSVT) 
OBJECTIVES 
Primary: 
1. The primary objective is to evaluate the safety of self-administered 
etripamil nasal spray (NS) outside of the clinical setting 
Secondary Objectives: 
1. To evaluate the efficacy of self-administered etripamil NS outside 
of the clinical setting, and  
2. To evaluate the impact of etripamil NS on PSVT disease burden, and 
3.  To evaluate the safety and efficacy of etripamil NS when used for 
multiple PSVT episodes 
 
STUDY POPULATION 
The study will enroll up to 3000 patients with a documented history of 
PSVT. 
STUDY ENTRY 
CRITERIA 
Inclusion Criteria: 
A patient will be eligible for study participation if they meet all of the 
following criteria: 
1) Has been diagnosed with PSVT by a medical professional, and reports 
having at least one previous episode of PSVT.  For clarity, PSVT refers 
to episodic SVT that includes the AV node as a critical part of reentrant 
circuit.  See Section 6.4 for details on diagnostic criteria.   
2) Is at least 18 years of age.  
3) Signed NODE-303 written informed consent. 
4) Women of child-bearing potential must be willing to use at least 1 
form of contraception during the trial and must be willing to 
discontinue from the study should they become or plan to become 
pregnant. Postmenopausal females are defined as having amenorrhea 
for at least 12 months prior to Screening without an alternative medical 
cause. 


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5) Willing and able to comply with study procedures. 
Exclusion criteria:  
A patient will be excluded from the study if they meet any of the following 
criteria: 
1) Patients with only a history of atrial arrhythmia that does not involve the 
atrioventricular (AV) node as part of the tachycardia circuit (e.g. atrial 
fibrillation, atrial flutter, intra-atrial tachycardia) are not eligible.  
Patients with a history of these tachycardias who are also diagnosed with 
PSVT are eligible. 
2) History of allergic reaction to verapamil.  
3) Current therapy with digoxin, or any Class I or III antiarrhythmic drug. 
Patients may be eligible if these drugs are stopped at least five half-lives 
before the administration of etripamil NS. The only exception is oral 
amiodarone which must be stopped 30 days before enrollment.  
4) History or evidence of ventricular pre-excitation, e.g., delta waves, 
Wolff-Parkinson-White syndrome.  
5) History or evidence of a second- or third-degree AV block.  
6) History or evidence of severe ventricular arrhythmia (e.g., torsades de 
pointes, ventricular fibrillation, or sustained ventricular tachycardia). 
7) Symptoms of congestive heart failure New York Heart Association 
Class II to IV. 
8) SBP < 90 mmHg at Screening, Baseline or any Follow-up Visit. 
9) Severe symptoms of hypotension experienced during PSVT episodes. 
10) Significant physical or psychiatric condition including alcoholism or 
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. 
11) History of syncope due to an arrhythmic etiology at any time, or history 
in last 5 years of unexplained syncope. 
12) Is pregnant or breastfeeding. 
13) Previously enrolled in a clinical trial for etripamil and received study 
drug or participation in any clinical trial for other investigational 
products or medical devices within 30 days of Screening. 
14) History of ACS or stroke within 6 months of Screening. 
15) Evidence of renal dysfunction as determined by an estimated glomerular 
filtration rate assessed at the Screening Visit as follows:  
a) <60mL/min/1.73m2 for patients <60 years of age; 


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b) <40mL/min/1.73m2 for patients ≥60 and <70 years of age 
c) <35mL/min/1.73m2 for patients ≥70 years of age 
STUDY DESIGN 
NODE-303 is a multi-center, open label (OL) study to evaluate the safety 
of etripamil NS in patients with PSVT. Patients will be provided with an 
ambulatory Cardiac Monitoring System (CMS) to help document PSVT 
episodes. The CMS will be self-applied by the patient when they feel the 
onset of PSVT symptoms. Patients will self-administer etripamil NS if the 
vagal maneuver (VM) is ineffective.  After an episode of perceived PSVT 
for which etripamil NS is administered, the patient will return to the 
investigative site and have the option to continue in NODE-303 and manage 
subsequent episodes of PSVT with etripamil NS. 
The study will include: 
A Screening Visit during which the Investigator will verify that the patient 
meets the eligibility criteria of the NODE-303 study, will obtain the signed 
informed consent, take blood and urine for laboratory evaluations, and 
conduct other screening procedures. The informed consent for NODE-303 
will be applicable for the total duration of participation in the study, to 
include the treatment of up to 4 perceived PSVT episodes.  
A Baseline Visit during which the site will confirm eligibility, concomitant 
medications, train the patient on study procedures, and give the patient study 
drug, patient reported outcome (PRO) materials, and the CMS materials. 
A Treatment Period during which the patient will complete the monthly 
PRO survey, self-identify symptoms of PSVT, use the CMS, perform a VM, 
and self-administer etripamil NS if the symptoms do not resolve during or 
after the VM.  Patients may be contacted during this period for reminders 
and training on what to do during a PSVT episode.  Patients will also 
complete a per episode survey after any PSVT episode they experience. 
During the Treatment Period, Follow-up Visits  will occur at the study site 
up to 14 days after a perceived episode of PSVT which is treated with 
etripamil NS, and during which the Investigator will evaluate the results of 
the last usage of etripamil NS and reassess patient’s eligibility to continue 
in the study based on study inclusion  and exclusion criteria. Patients who 
are eligible to continue in the study will receive two additional kits 
containing study medication. 
A Final Study Visit that will occur when a patient discontinues or withdraws 
from the study, or when the overall study is completed, or the patient has 
completed the maximum number of 4 treated perceived PSVT episodes. 
NODE-303 will continue until enough documented self-administrations of 
etripamil NS are included in the safety database to meet regulatory 
requirements for the etripamil NS development program. The common 
study end date (CSED) for the entire study will depend on the rate of accrual 
of the primary endpoint, unique patients with an episode.  


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When the criteria for concluding the study have been met, the Sponsor will 
announce the common study end date (CSED) for the entire study and sites 
will be informed in advance to schedule all final patient visits prior to the 
CSED. 
Safety Monitoring will be conducted from the time of consent throughout 
study participation. New Adverse Events (AEs) will be collected at every 
study visit. At the time of the final study visit, any AEs which are ongoing 
will be followed for up to 30 days. Serious Adverse Events (SAEs) will be 
captured and reported regardless of when they occur.  All SAEs should be 
followed until satisfactory resolution, even after database lock.  
Screening Visit:  
See Section 9.1.1 for a full list of Screening Visit procedures. 
Clinical sites will: 
• Obtain Informed Consent. 
• Evaluate the patient’s medical status and concomitant medications. 
• Confirm the diagnosis of PSVT based on a clinician’s diagnosis and 
a patient report of at least one episode of PSVT.  See Section 6.4 for 
details on diagnostic criteria.   
• Perform a 12-lead safety ECG and upload it. Site personnel will 
review ECG for safety concerns and eligibility. 
• Take blood and urine for clinical laboratory evaluations. 
• Assessment of patient’s eligibility for NODE-303 according to the 
inclusion/exclusion criteria; patients who have signed the ICF and 
are deemed non-eligible for the study will be considered screen 
failures. 
Baseline Visit: 
See Section 9.1.2 for a full list of Baseline Visit procedures.  As detailed in 
that section, it is permitted to conduct the Screening and Baseline Visit 
procedures on the same day, using a local laboratory to conduct preliminary 
clinical safety evaluations. 
Clinical sites will: 
• Review concomitant medication information. 
• Confirm patient eligibility. 
• Train the patient on study procedures and give them study materials. 
• Have the patient execute their first patient reported outcome 
measurements. 


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Each qualified patient will be given a study kit which will include two kits 
of etripamil NS, a CMS kit, a study identification card, and study training 
and informational material.  
Treatment Period: 
See Section 9.1.3 for a full list of Treatment Period procedures. 
The patients will be instructed to perform the following steps after they have 
identified symptoms they consider to be consistent with PSVT: 
• Apply and activate the CMS to record cardiac activity.  
• Perform a VM. If the VM is successful in relieving symptoms, the 
patient will not self-administer study drug and will remove the CMS 
and the patient will remain in the study for a subsequent episode.  
• If symptoms do not resolve after completion of the VM, self-
administer etripamil NS as instructed, and wear the CMS for at least 
1 hour after administration. 
• After the episode has resolved, patients will complete the relevant 
per episode survey. If the patient took etripamil NS for the episode, 
they will contact the site for a Follow-up Visit.   
If the symptoms of PSVT have not resolved within 30 minutes after the 
initial study drug administration, the patient should seek appropriate 
medical care as needed. If the patient goes to a medical facility for PSVT 
treatment, they must give the study identification card included in the study 
kit to the on-site medical personnel. This study identification card will 
contain a brief description of the study, a description of study drug, and the 
Investigator (study physician) contact information.   
Patients will also complete the monthly PRO measures during the Treatment 
Period.  Sites should follow up with patients failing to complete the PRO. 
Follow-up Visits: 
See Section 9.1.4 for a full list of Follow-up Visit procedures. 
During the Treatment Period, patients who take study drug for an episode 
will be instructed to return to the site within 14 days after the episode for 
the following assessments by the Investigator or designee: 
• Obtain Patient Informed Consent again in the event its contents were 
modified since initial consent was obtained. 
• Evaluation of the patient’s medical status.  
• Collect used and unused study drug. 
• Recording of any adverse events (AEs).  
• Review of available CMS data (See Section 9.3.2.4 for more details 
on the CMS). 


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• Evaluate any additional medical intervention the patient received for 
PSVT episodes during the Treatment Period including any 
concomitant medications. 
• Assess patient’s eligibility to continue in study NODE-303 for 
treatment of subsequent episodes of PSVT with etripamil NS, and 
provide two new study drug kits. 
• Provide any additional CMS materials and patient training or 
retraining required. 
• Follow-up Visit assessments should be completed for the first three 
treated perceived PSVT episodes. Once the patient has had the 
fourth treated perceived PSVT episode, complete a Final Study 
Visit, not a fourth Follow-up Visit. 
Final Study Visit: 
See Section 9.1.5 for a full list of Final Study Visit Procedures. 
Upon completion of the overall study (Common Study End Date), 
discontinuation or withdrawal of a patient, or after receiving study treatment 
for the fourth perceived PSVT episode the site should have the patient return 
for the Final Study Visit procedures below. 
• Evaluation of the patient’s medical status.  
• Recording of any adverse events (AEs).  
• Review of available CMS data (See Section 9.3.2.4 for more details 
on the CMS). 
• Evaluate any additional medical intervention the patient received for 
PSVT episodes during the Treatment Period including any 
concomitant medications. 
• Collect CMS.   
• Collect used and unused study drug.  
• Complete patient’s End of Study form in the eCRF. 
INVESTIGATIONAL 
PRODUCT 
The formulation of etripamil will consist of MSP-2017 (etripamil), water, 
acetic acid, disodium ethylene-diamine-tetra-acetic acid (EDTA), and 
sulfuric acid. The investigational product for self-administration will be in 
prefilled and packaged Aptar Pharma Nasal Spray Bidose System devices, 
each containing etripamil NS 70 mg (i.e., 200 µL).  
REFERENCE 
PRODUCT 
There is no reference product in this study. 


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TREATMENT 
REGIMEN 
The treatment regimen of etripamil to be evaluated is an initial dose of 
etripamil NS 70 mg (one spray of 100 µL in each nostril), to be followed by 
a second dose (one spray of 100 µL in each nostril) 10 minutes later (not to 
exceed 15 minutes) if the patient continues to experience PSVT symptoms. 
Patients who are symptom-free within 10 minutes after the first dose do not 
repeat the dose.  
PRINCIPAL 
INVESTIGATOR 
Francis Plat, MD 
PLANNED STUDY 
SITES 
This study will be conducted at up to 400 sites globally. 
CRITERIA FOR 
EVALUATION 
Efficacy Variables: 
The primary objective of this study is to evaluate the safety of self-
administered etripamil NS. Efficacy variables will be collected as secondary 
or exploratory analyses. 
The secondary efficacy endpoints will include: 
• Frequency of additional medical intervention to treat PSVT, as 
measured by emergency department (ED) visits, hospital admissions, 
and concomitant medication use. 
• Improvement in patient quality of life, as measured by the BIPQ, CAQ, 
SF-36 questionnaire and other surveys.   
• Patient satisfaction with treatment, as measured by the Treatment 
Satisfaction Questionnaire for Medication (TSQM-9) and other 
questions. 
• Termination of PSVT episodes within 1 hour of the start of study drug 
administration or initiation of CMS recording. 
The exploratory endpoints will include: 
• Frequency of PSVT episodes, and use of etripamil NS for those 
episodes, as captured by the PRO. 
• Characteristics of patient PSVT episodes, as measured by the data 
collected by the CMS. 
Safety Variables: 
Safety variables will include clinical adverse events (AEs), vital signs, and 
arrhythmias and conduction disorders detected on surface ECG or CMS 
recordings.  
 


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STATISTICAL 
METHODS 
Analysis populations: 
All patients who are enrolled will be included in the Overall Population.  
Patients who receive any amount of study drug will be included in the Safety 
Population. Patients who receive at least two sprays of study drug for an 
episode determined to be PSVT will be included in the Efficacy Population. 
Efficacy analyses: 
The efficacy analyses will be performed on the Efficacy Population.  
Comparative analyses may be conducted on data available from patients in 
Safety Population. 
Efficacy endpoint analyses will include summaries, both over time and as 
comparisons between the Efficacy Population and the Safety Populations 
for the endpoints of; medical interventions, patient quality of life, treatment 
satisfaction, and PSVT episode characteristics. Continuous efficacy data 
will be presented with n, minimum, maximum, median, mean, and standard 
deviation, whereas discrete efficacy data will be summarized with 
frequency counts and percentages.   
Safety analyses: 
Safety analyses will be performed on the Safety Population.  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. 
Additional analyses will be described in detail in the Statistical Analysis 
Plan (SAP). 
 
SAMPLE SIZE 
DETERMINATION 
There is no statistical hypothesis in this uncontrolled OL safety study. 
NODE-303 will continue until the end of the development program, i.e., 
when enough patients with documented self-administrations (1000 to 1500 
across all studies) of etripamil NS are included in the safety database. 
It is anticipated that as many as 3000 patients may need to be enrolled in 
NODE 303 in order to accrue a sufficient number of patients with perceived 
PSVT episodes in the Safety Population within 24 months. 


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STUDY AND 
TREATMENT 
DURATION 
Patients may continue in the study until they receive treatment for a 
maximum of 4 perceived PSVT episodes at which time they will complete 
the study and be eligible for participation in an early access program in line 
with local country regulations. The duration of treatment will depend on the 
frequency of a patient’s PSVT episodes. 
After each episode of perceived PSVT is treated with the study drug, eligible 
consenting patients will have the opportunity to continue in NODE-303 and 
self-manage up to a maximum of four perceived episodes of PSVT with 
etripamil NS. The patient may receive two new treatment kits after every 
episode treated with etripamil NS provided that no adverse effect nor any 
eligibility criteria would preclude another administration of etripamil NS.   
NODE-303 will continue until the end of the development program, i.e., 
when enough documented self-administrations of etripamil NS are 
included in the safety database. 


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2. TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................6 
2. 
TABLE OF CONTENTS .........................................................................................15 
2.1 
List of Tables.....................................................................................................19 
2.2 
List of Figures ...................................................................................................19 
3. 
LIST OF ABBREVIATIONS ..................................................................................20 
4. 
INTRODUCTION ....................................................................................................22 
4.1 
Background .......................................................................................................22 
4.2 
Clinical Experience ...........................................................................................22 
4.2.1 Phase 1 PK Study ..................................................................................22 
4.2.2 Phase 2 Study ........................................................................................23 
4.2.3 NODE-301 Phase 3 Efficacy and Safety Study ....................................26 
4.2.4 NODE-302 Phase 3 Open Label Extension Study ................................27 
4.2.5 NODE-301 Part 2, the RAPID study .....................................................28 
4.3 
Rationale for the Study......................................................................................28 
4.4 
Summary of Potential Risks and Benefits .........................................................29 
5. 
OBJECTIVES ...........................................................................................................29 
5.1 
Primary Objective .............................................................................................29 
5.2 
Secondary Objectives ........................................................................................29 
6. 
STUDY DESIGN ......................................................................................................29 
6.1 
Overall Study Design and Plan .........................................................................29 
6.1.1 Screening Visit (Within 30 days of Baseline) .......................................30 
6.1.2 Baseline Visit ........................................................................................30 
6.1.3 Treatment Period ...................................................................................30 
6.1.4 Follow-Up Visits (up to 14 days after an episode) ................................31 
6.1.5 Final Study Visits ..................................................................................32 
6.2 
Discussion of Study Design ..............................................................................32 
6.3 
Rationale for Dosing .........................................................................................32 
6.4 
Inclusion/Exclusion ...........................................................................................33 
7. 
Study POPULATION ...............................................................................................34 
7.1 
Selection of Study Population and Diagnosis ...................................................34 
7.2 
Study Entry Criteria ..........................................................................................34 
7.2.1 Inclusion Criteria ...................................................................................34 
7.2.2 Exclusion Criteria ..................................................................................35 
7.3 
Patient Discontinuation/Withdrawal .................................................................35 


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8. 
TREATMENTS ........................................................................................................36 
8.1 
Identification of Investigational Product ...........................................................36 
8.2 
Labeling and Packaging ....................................................................................36 
8.2.1 Labeling .................................................................................................36 
8.2.2 Packaging ..............................................................................................37 
8.3 
Treatments Administered ..................................................................................37 
8.4 
Additional Medical Intervention .......................................................................37 
8.5 
Drug Storage and Accountability ......................................................................37 
8.6 
Treatment Compliance ......................................................................................38 
8.7 
Prior and Concomitant Therapies......................................................................38 
9. 
STUDY PROCEDURES ..........................................................................................39 
9.1 
Study Periods, Visits, and Procedures...............................................................39 
9.1.1 Screening Visit (Days -30 to -1) ............................................................39 
9.1.2 Baseline Visit ........................................................................................40 
9.1.3 Treatment Period (Until patient withdrawal, completion, or discontinuation)
 40 
9.1.4 Follow-up Visit (up to 14 days after an episode) ..................................42 
9.1.5 Final Study Visit ....................................................................................43 
9.1.6 Conduct of NODE-303 Study during COVID-19 pandemic ................44 
9.2 
Study Duration ..................................................................................................44 
9.2.1 Common Study End Date (CSED) ........................................................44 
9.3 
Assessments ......................................................................................................44 
9.3.1 Efficacy .................................................................................................44 
9.3.1.1 
Patient Reported Outcomes – PRO System ..............................44 
9.3.1.2 
Additional Medical Intervention Required ...............................45 
9.3.1.3 
Characteristics of patient PSVT episodes .................................45 
9.3.2 Safety .....................................................................................................46 
9.3.2.1 
Adverse Events..........................................................................46 
9.3.2.2 
Clinical Laboratory Safety Assessments ...................................46 
9.3.2.3 
Clinical Examinations ...............................................................46 
9.3.2.4 
Cardiac Monitoring System (CMS) ..........................................47 
10. ADVERSE EVENTS ................................................................................................48 
10.1 Definitions .........................................................................................................48 
10.1.1 Adverse Events ......................................................................................48 
10.1.2 Adverse Drug Reaction .........................................................................48 
10.1.3 Unexpected Adverse Event/Adverse Drug Reaction ............................49 
10.1.4 Serious Adverse Events/Drug Reaction ................................................49 


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10.1.5 Treatment-Emergent Adverse Events ...................................................49 
10.2 Management of Adverse Events .......................................................................49 
10.2.1 Collection of Adverse Events ................................................................50 
10.2.2 Evaluation of Adverse Events ...............................................................50 
10.2.2.1 Severity of Adverse Events .......................................................50 
10.2.2.2 Seriousness ................................................................................50 
10.2.2.3 Action(s) Taken .........................................................................50 
10.2.2.4 Outcome at the Time of Last Observation ................................50 
10.2.2.5 Adverse Event Relationship to the Study Drug ........................51 
10.2.3 Documentation ......................................................................................52 
10.2.4 Follow-up of Adverse Events ................................................................52 
10.2.5 SAE Reporting ......................................................................................52 
10.2.5.1 Serious Adverse Events.............................................................52 
10.2.5.2 Adverse Drug Reactions ...........................................................53 
10.2.5.3 Nonserious Adverse Events ......................................................53 
10.3 Special Considerations ......................................................................................53 
10.3.1 Adverse Events of Special Interest ........................................................53 
10.3.2 Pregnancy ..............................................................................................54 
10.3.3 Overdose ................................................................................................54 
11. Study Committees .....................................................................................................55 
12. STATISTICS .............................................................................................................55 
12.1 Study Endpoints ................................................................................................55 
12.1.1 Primary Endpoint ..................................................................................55 
12.1.2 Secondary Efficacy Endpoints ..............................................................55 
12.1.3 Safety Endpoints ....................................................................................56 
12.2 Sample Size Determination ...............................................................................56 
12.3 Analysis Populations .........................................................................................56 
12.4 Statistical Analyses ...........................................................................................56 
12.4.1 Study Patients and Demographics .........................................................56 
12.4.1.1 Disposition and Withdrawals ....................................................56 
12.4.1.2 Protocol Deviations ...................................................................56 
12.4.1.3 Demographics and Other Baseline Characteristics ...................57 
12.4.2 Exposure and Compliance .....................................................................57 
12.4.3 Handling of Missing Data .....................................................................57 
12.4.4 Efficacy Analyses ..................................................................................57 
12.4.4.1 Secondary Efficacy Analyses ....................................................57 
12.4.4.2 Exploratory Efficacy Analyses .................................................57 


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12.4.5 Safety and Tolerability Analyses ..........................................................58 
12.4.5.1 Adverse Events..........................................................................58 
12.4.5.2 Clinical Laboratory Evaluations ...............................................58 
12.4.5.3 Vital Signs .................................................................................58 
12.4.5.4 Physical Examination Findings .................................................58 
12.4.6 Interim Analyses ....................................................................................58 
13. Investigator Requirements and Quality Control ...................................................59 
13.1 Ethical Conduct of the Study ............................................................................59 
13.2 Institutional Review Board/Independent Ethics Committee .............................59 
13.3 Informed Consent ..............................................................................................59 
13.4 Study Monitoring Requirements .......................................................................60 
13.5 Data Collection..................................................................................................60 
13.6 Disclosure of Data .............................................................................................60 
13.7 Retention of Records .........................................................................................61 
13.8 Audits and Inspections ......................................................................................61 
13.9 Publication Policy .............................................................................................61 
13.10 Financial Disclosure ..........................................................................................61 
14. Study Administrative Information ..........................................................................62 
14.1 Protocol Amendments .......................................................................................62 
14.2 Protocol Authors ...............................................................................................62 
15. Final Clinical Study Report .....................................................................................62 
16. REFERENCES .........................................................................................................63 
17. ATTACHMENTS .....................................................................................................64 
17.1 Schedule of Assessments ..................................................................................64 
APPENDICES ..................................................................................................................66 
A. 
Address List ......................................................................................................67 
B. 
Regulations and Good Clinical Practice Guidelines .........................................68 
1. 
Regulations ............................................................................................68 
2. 
Good Clinical Practice Guidelines ........................................................68 


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LIST OF TABLES AND FIGURES 
 
2.1 
List of Tables 
Table 1. 
Summary of Induced, Sustained Paroxysmal Supraventricular Tachycardia to Sinus 
Rhythm Conversion Within 15 Minutes After Study Drug Administration .......24 
Table 2. 
Schedule of Procedures .......................................................................................64 
 
2.2 
List of Figures 
Figure 1. 
Kaplan-Meier Plot of Conversion 15 Minutes After Study Drug Administration 
 
 .............................................................................................................................25 
Figure 2. 
Mean Change in Systolic Blood Pressure (mmHg) Over Time ..........................26 
Figure 3. 
NODE-303 Study Design....................................................................................32 
 


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3. LIST OF ABBREVIATIONS 
 
 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AV 
Atrioventricular 
AVNRT 
Atrioventricular nodal reentry tachycardia 
AVRT 
Atrioventricular reentrant tachycardia 
BDS 
Aptar Pharma Nasal Spray Bidose System 
BIPQ 
Brief Illness Perception Questionnaire 
CAQ 
Cardiac Anxiety Questionnaire 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CMS 
Cardiac monitoring system 
CRA 
Clinical research associate 
CRO 
Clinical research organization 
CSED 
Common study end date 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
ED 
Emergency department 
EDTA 
Disodium ethylene-diamine-tetra-acetic acid 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
ENT 
Ears nose throat 
EP / EPL 
Electrophysiology / Lab 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good manufacturing practice 
HR 
Heart rate 
IB 
Investigator’s brochure 


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ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IN 
Intranasal 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IV 
Intravenous 
MFD 
Maximum feasible dose 
NA 
Not available / Not applicable 
NS 
Nasal spray 
OL 
Open label 
PK 
Pharmacokinetic 
PRO 
Patient reported outcome 
PSVT 
Paroxysmal supraventricular tachycardia 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SAP 
Statistical analysis plan 
SC 
Steering committee 
SD 
Standard deviation 
SF-36 
Short form (36) health survey 
SOC 
System organ class 
SR 
Sinus rhythm (normal) 
TSQM-9 
Treatment satisfaction questionnaire for medication 
USB 
Universal serial bus 
VM 
Vagal maneuver 
 


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4. INTRODUCTION 
4.1 
Background  
Etripamil (also referred to as MSP-2017 in study documents), an L-type calcium channel 
antagonist and short-acting verapamil analog, is being developed by Milestone Pharmaceuticals 
Inc. (hereinafter Milestone) for the treatment of paroxysmal supraventricular tachycardia (PSVT), 
hereinafter used in reference to both the disorder and its associated tachyarrhythmia. A relatively 
common disorder, PSVT is characterized by episodes of tachyarrhythmia typically with a heart 
rate (HR) over 100 bpm and a QRS duration of <120 msec.1 Etripamil is directed towards the 
2 most common subtypes of PSVT, atrioventricular (AV) nodal reentrant tachycardia (AVNRT) 
and AV reentrant tachycardia (AVRT), together accounting for approximately 90% of PSVT 
cases.1 In both conditions, a pharmaceutical agent capable of transiently prolonging AV 
conduction time can result in arrhythmia termination and restoration of normal sinus rhythm (SR). 
Historically, intravenous (IV) verapamil has been used as an effective agent for treatment of acute 
episodes of PSVT.2 However, it has been replaced in recent years by IV adenosine, which is 
equally effective in terminating acute episodes of PSVT.3 Adenosine has the advantage of having 
a very short half-life, as it is rapidly metabolized during the time required to terminate an episode 
of PSVT.4 However, the short half-life of adenosine renders it ineffective when given via routes 
of administration other than IV. As both of these medications require the establishment of IV 
access, they are not appropriate for a patient self-administration paradigm in an outpatient setting. 
4.2 
Clinical Experience 
4.2.1 Phase 1 PK Study 
A Phase 1 study (MSP-2017-1096) evaluated the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of etripamil, with the aim of determining the maximum tolerated dose or 
maximum feasible dose (MFD) of 2 different formulations administered via the intranasal (IN) 
route in 30 healthy, adult male subjects. All etripamil doses were generally well tolerated, and 
there was no difference in the safety profile and PK between the 2 etripamil formulations (MSP-
2017A and MSP-2017B). The study of formulation A was stopped at 60 mg, and formulation B 
was studied at 105 mg and 140 mg. Pharmacokinetic analyses demonstrated rapid absorption and 
elimination following IN administration of etripamil (across the dose range tested), and a dose 
proportional systemic exposure (area under the curve and maximum plasma concentration for 
MSP-2017 and its inactive metabolite [MSP-2030]) following administration of up to 140 mg of 
MSP-2017. The 140 mg dose was the MFD because neither the concentration (350 mg/mL) nor 
the volume (200 µL) of solution administered in each nostril could be increased.  
MSP-2017-1205 (NODE-102) study was a randomized, double-blind, placebo-controlled, single 
dose, 4-way crossover, single dose Phase I study to assess the PK, PD, and safety and tolerability 
of etripamil NS at three dose levels and placebo in healthy Japanese and non-Japanese adults. The 
primary objective was to assess the safety and tolerability of etripamil in healthy Japanese and 
non-Japanese volunteers. The secondary objectives were to assess the PK and PD of etripamil in 
healthy Japanese and non-Japanese volunteers and the exploratory objectives were to assess the 
PK and PD of etripamil in healthy male and female volunteers. 
A maximum of 24 participants, 12 Japanese and 12 non-Japanese, were planned and enrolled in 
the study and 23 completed the study (1 Japanese subject discontinued prematurely due to the 


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


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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 
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 


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for the 7 patients who converted within 15 minutes was more widely dispersed in the placebo 
group compared with the etripamil groups. 
Figure 1 shows the distribution of time to conversion for each patient reported as a Kaplan-Meier 
plot. Patients who did not convert within 15 minutes after study drug administration were censored 
at 15 minutes. 
Figure 1. 
Kaplan-Meier Plot of Conversion 15 Minutes After Study Drug 
Administration 
 
Note: Patients who did not convert within 15 minutes after study drug administration were censored at time 15. 
Source: Clinical Study Report MSP-2017-1109 
At least 1 adverse event (AE) considered related to the study drug, according to the Investigator 
assessment, was reported in 17 (85.0%) patients in the etripamil NS 35 mg group, 
18 (78.3%) patients in the 70 mg group, 15 (75.0%) patients in the 105 mg group, 
20 (95.2%) patients in the 140 mg group, and 4 (20.0%) patients in the placebo group. The 
incidence of AEs was not dose dependent.  
Most AEs were mild (44.2%) or moderate (24.0%) across all treatment groups. A total of 3 severe 
AEs were considered possibly related to etripamil; 1 patient who received etripamil NS 35 mg 
experienced facial flushing, shortness of breath, and chest discomfort; and 2 patients who received 
etripamil NS 105 mg had nausea and vomiting (1 patient) and a serious AE (SAE) of cough 
(1 patient). There were no AEs that led to study discontinuation or death. 
Adverse events that occurred with an incidence of >10% in any etripamil group and ≤10% in the 
placebo group were nasal discomfort, nasal congestion, oropharyngeal pain, rhinorrhea, cough, 
dysgeusia, increased lacrimation, vomiting, and nausea.  
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. 


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The mean systolic blood pressure (SBP) was decreased from the baseline measurements (before 
PSVT induction) to measurements done in PSVT before study drug administration (time 0). 
A decrease of 7 mmHg was statistically significant in the placebo group only (Figure 2). 
Compared with baseline, SBP measurements taken from 2 minutes to 16 minutes post-study drug 
administration demonstrated no decrease in mean SBP in the placebo and the etripamil NS 35 mg 
group, a minor change of 2 mmHg at 4 minutes post-dose in the etripamil NS 70 mg group, and 
decreases of 17 mmHg (p<0.05 versus baseline) 6 minutes post-dose in the etripamil NS 105 mg 
group, and 20 mmHg at 6 minutes and 8 minutes post-dose (p<0.05 versus baseline) in the 
etripamil NS 140 mg group. 
There was no decrease in mean SBP compared to baseline from 16 to 30 minutes post-study drug 
administration when all patients were back in normal SR. 
Figure 2. 
Mean Change in Systolic Blood Pressure (mmHg) Over Time 
 
Note: Baseline is defined as the average of the 20 and 10 minutes pre-dose measurements. Time 0 is defined as the average of the 
measurement during PSVT between 0 and 5 minutes before study drug administration. 
Source: Clinical Study Report MSP-2017-1109 
4.2.3 NODE-301 Phase 3 Efficacy and Safety Study 
NODE-301 (MSP-2017-1138), was a Randomized, Double-Blind, Placebo-Controlled Phase 3 
safety and efficacy study of etripamil NS in patients with PSVT receiving the drug in an at-home 
setting.  The study was conducted in the United States and Canada.  Patients first received etripamil 
NS at the clinical site while in normal sinus rhythm during a Test Dose Visit.  Patients who showed 
an acceptable safety and tolerability profile in the Test Dose Visit were randomized in a 2:1 ratio 
to receive either etripamil NS or matching placebo.  They returned home and waited for a PSVT 
episode to occur, at which time they may have taken etripamil NS or placebo.  Each episode was 
documented by an ambulatory Cardiac Monitoring System (CMS) that was placed on the chest by 
the patient or caregiver when symptoms began and recorded at least 5 hours of continuous 
electrocardiogram (ECG).  After taking etripamil NS or placebo for the treatment of one PSVT 


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episode, a patient completed the NODE-301 study and was eligible for the open label extension 
study NODE-302. 
In NODE-301 Part 1, 419 out of 431 subjects (97%) who received the test dose were randomized 
into the study. 198 subjects self-administered the study drug for a perceived episode of PSVT of 
which 156 subjects (79%) had positively adjudicated PSVT episodes; 107 (68.6%) subjects 
received etripamil and 49 (31.4%) subjects received placebo. Etripamil (70 mg) did not achieve 
its primary endpoint of time to conversion of PSVT to sinus rhythm compared to placebo over the 
5-hour period following study drug administration. The hazard ratio (95% CI) at 5 hours was 1.086 
(0.726, 1.623); P value 0.12 in favor of etripamil. The median time to conversion was 25 minutes 
[95% CI: 16, 43] for etripamil vs. 50 minutes [95% CI: 31,101] for placebo. A post hoc efficacy 
analysis of the NODE-301 Part 1 study demonstrated that within 30 minutes after drug 
administration, etripamil was highly effective, with a sinus rhythm conversion rate of 54% of 
etripamil subjects vs. 35% of placebo subjects, i.e., approximately a 19% absolute difference. 
These results are consistent with the rapid onset of action of etripamil and the PK/PD profile of 
the drug and are similar to those observed in Phase 2 (NODE-1). Overall, the prolonged 5-hour 
efficacy observation period likely confounded the results of the primary analysis of the Phase 3 
clinical trial. 
A total of 431 subjects have received a test dose of etripamil 70 mg NS while in sinus rhythm and 
198 subjects received study drug (138 etripamil 70 mg; 60 placebo) during a perceived episode of 
PSVT. There were no new or clinically relevant safety findings seen in NODE-301 Part 1 study. 
A total of 308 subjects have had at least one adverse event (AE). The maximum severity was mild 
(49.8%) or moderate (17.6%). The most commonly reported TEAEs occurring after study drug 
administration were nasal discomfort, nasal congestion, rhinorrhea, throat irritation and 
lacrimation. Severe TEAEs included throat irritation, drug hypersensitivity, rhinorrhea, epistaxis 
and hypotension, each reported in one subject. Fourteen serious adverse events were reported and 
were assessed by the Investigator as not related to the study treatment. 
Of note, two subjects experienced syncope 168 and 68 days after the test dose of etripamil. One 
subject reported “near-syncope” prior to etripamil administration. Therefore, none of these events 
was related to the drug administration. 
4.2.4 NODE-302 Phase 3 Open Label Extension Study 
NODE-302 (MSP-2017-1158) was an open label extension study for NODE-301.  This study is 
now closed and enrolled PSVT patients who had previously completed NODE-301, and followed 
them for multiple at-home administrations of 70 mg etripamil NS. Each episode was documented 
by an ambulatory CMS.  As of the cut-off date (10 December 2020), 105 subjects have received 
at least one dose of etripamil 70 mg NS. This study is currently in the reporting phase.  
There have been no new or clinically relevant safety findings seen in the MSP-2017-1158 study. 
A total of 57 (54.3%) subjects have had at least one AE. The maximum severity of treatment 
emergent adverse events (TEAEs) for most subjects was mild (44.8%) or moderate (7.6%). Severe 
AEs were reported in 2 (1.9%) subjects (rhinorrhea in 1 subject, and two episodes of epistaxis in 
1 subject). These severe AEs were assessed as definitely related to the study treatment by the 
Investigator.  
Eleven SAEs were reported in 9 (8.6%) subjects including 5 episodes of supraventricular 
tachycardia (3 moderate episodes in 1 subject), a mild and a moderate episode in 1 each subject, 


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bradycardia in 1 subject, syncope in 1 subject, ataxia in 1 subject, troponin increased in 1 subject, 
diverticular perforation in 1 subject and pancreatitis in 1 subject. All these SAEs were assessed by 
the Investigator as not related to the study treatment. The most commonly reported TEAEs to date 
(regardless of relationship to study drug) were nasal discomfort, nasal congestion, and rhinorrhea.  
Of note, two subjects reported an episode of syncope 49 and 126 days from the last etripamil 
administration. None of them were considered related to etripamil by the Investigator. 
4.2.5 NODE-301 Part 2, the RAPID study  
NODE-301 is a multicenter, randomized, double-blind, placebo-controlled, efficacy, and safety 
study of etripamil NS 70 mg for the termination of spontaneous episodes of PSVT. This study 
consists of 2 parts:  
• NODE-301 Part 1 consisted of subjects that were dosed with the double-blind study drug 
or had discontinued the study before the adjudication of the 150th positively adjudicated 
PSVT episode.  
• NODE-301 Part 2 (the RAPID Study, ongoing) consists of subjects randomized into Part 
1 who were not dosed with the double-blind study drug or had not discontinued the study 
before the adjudication of the 150th positively adjudicated PSVT episode, and new subjects 
enrolled into the study following the completion of Part 1.  
Based on the results of Part 1, subjects in Part 2 of NODE-301 (RAPID) will be randomized to a 
dosing regimen that will permit a second 70 mg dose if symptoms still persist at 10 minutes after 
the first dose. The primary efficacy endpoint is defined as time to an adjudicated termination of a 
positively adjudicated episode of PSVT and conversion to sinus rhythm for at least 30 seconds 
within 30 minutes of start of study drug dosing. 
4.3 
Rationale for the Study 
The primary objective of this study is to characterize the safety of etripamil NS for the patient-
administered treatment of acute episodes of PSVT outside of the clinical setting. The secondary 
objectives of the study are to further evaluate the efficacy of etripamil NS for the patient-
administered treatment of acute episodes of PSVT outside of the clinical setting, to evaluate the 
impact of etripamil NS on PSVT disease burden (as measured by CMS, PROs, and healthcare 
utilization data) and to evaluate the safety and efficacy of etripamil NS when used for multiple 
PSVT episodes.  The study is designed to capture safety data when using etripamil NS in a real-
world setting.   
Etripamil NS addresses an unmet medical need since there are currently no short-acting products 
available for patient self-administered treatment of 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 PSVT would give patients the option to safely terminate acute episodes of PSVT 
without the need for a hospital visit. An episodic treatment option may 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 


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the opportunity to consider episodic management with etripamil NS as a viable alternative 
treatment option. This large study will further characterize the benefit to risk assessment. 
4.4 
Summary of Potential Risks and Benefits 
The potential risks of study participation include those associated with exposure to etripamil NS. 
The assessment includes the risks of medical evaluation, including venipuncture. Adverse events 
(AEs) associated with etripamil NS include nasal irritation, nasal discomfort, and throat irritation.  
Potential adverse events which have been rare or not observed in studies to date include other 
cardiac arrhythmias, or AEs associated with drops in blood pressure (dizziness, headache).   
The primary benefit of this study is that patients may be able to safely and rapidly terminate acute 
episodes of PSVT without the need for a hospital visit to receive IV medication.  Patients may also 
be able to discontinue chronic prophylactic therapies they are taking for PSVT.  Patients who are 
waiting for, ineligible, or unwilling to undergo ablation procedures may have an option for at-
home treatment of their PSVT episodes. 
A summary of the pharmaceutical properties and known potential risks of etripamil NS is provided 
in the current version of the Investigator’s Brochure (IB).  
5. OBJECTIVES 
5.1 
Primary Objective 
The primary objective is to evaluate the safety of self-administered etripamil NS outside of the 
clinical setting. 
5.2 
Secondary Objectives 
The secondary objectives are;  
1. To evaluate the efficacy of self-administered etripamil NS outside of the clinical setting, 
and 
2. To evaluate the impact of etripamil NS on PVST disease burden, and 
3. To evaluate the safety and efficacy of etripamil NS when used for multiple PSVT episodes. 
6. STUDY DESIGN 
6.1 
Overall Study Design and Plan 
NODE-303 is a multi-center, open label (OL) study to evaluate the safety of etripamil NS in 
patients with PSVT. Patients will be provided with an ambulatory Cardiac Monitoring System 
(CMS) to help document PSVT episodes. The CMS will be self-applied by the patient, when they 
feel the onset of PSVT symptoms.  Patients will then self-administer the dose regimen of etripamil 
NS if vagal maneuver (VM) is ineffective. After each episode of perceived PSVT for which 
etripamil NS was administered, the patient will return to the investigative site, and have the option 
to continue in NODE-303 and manage subsequent episodes of PSVT with etripamil NS. 
The Study is divided into four parts: A Screening Visit, a Baseline Visit, a Treatment Period (with 
up to 3 Follow-up Visits), and a Final Study Visit.   


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6.1.1 Screening Visit (Within 30 days of Baseline) 
See Section 9.1.1 for a full description of study procedures during the Screening Visit. 
Prospective study patients will be required to sign an informed consent form before the 
commencement of any study-related assessments or procedures.  
If a screened patient meets at least 1 exclusion criterion, the patient will be considered a screening 
failure. Re-screening may be allowed after consultation between the Investigator and Medical 
Monitor, or should the inclusion/exclusion change. 
During the Screening Visit the Investigator or designee will obtain the signed informed consent, 
will verify that the patient meets the eligibility criteria of the NODE-303 study, take blood and 
urine for laboratory evaluations, and conduct other screening procedures. The informed consent 
for NODE-303 will be applicable for the total duration of participation in the study including up 
to 4 treated perceived PSVT episodes. 
The Screening Visit may occur up to 30 days prior to the Baseline Visit to allow time for safety 
laboratory parameters, review of the safety ECG, and any washout of background medications.  
Screening ends when the patient completes a Baseline Visit and is dispensed study drug or is 
determined to be a Screen failure. 
6.1.2 Baseline Visit 
See Section 9.1.2 for a full description of procedures to conduct during the Baseline Visit. 
The Baseline Visit will occur after screening procedures are completed, and clinical laboratory 
evaluations are available.  As detailed in Section 9.1.2, it is permitted to conduct the Screening 
and Baseline Visits on the same day, using a local laboratory to conduct preliminary clinical 
laboratory evaluations.  The site will confirm patient eligibility, record any changes to concomitant 
medications, train the patient on study procedures (drug administration, PRO, CMS), and give the 
patient study drug, PRO materials, and the CMS materials.  Patients will complete their first PRO 
measure on-site at the Baseline Visit.  The site will provide the patient with training and any other 
study materials.   
6.1.3 Treatment Period  
Full details on the procedures a patient and site perform can be found in Section 9.1.3.   
The Treatment Period refers to the duration of the study after a patient has completed their Baseline 
Visit and been given study drug and sent home until they discontinue from the study, complete the 
study, or the overall study is completed.  During the Treatment Period, when a patient has a 
perceived episode AND takes study drug, they will return to the clinic for a Follow-up Visit and 
return their used and unused nasal spray devices.  If the patient does not take study drug for a 
perceived PSVT episode, they may continue in the Treatment Period if they have sufficient CMS 
materials to record another episode (See Section 9.3.2.4 for CMS details).  Patients may continue 
in the study until they have treated a total of 4 perceived PSVT episodes. After the fourth treated 
episode patients will complete a Final Study Visit and may be eligible for participation in an early 
drug access program in line with local regulations. 


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Patients 
During the Treatment Period, patients will complete a monthly survey regarding their quality of 
life and PSVT. Patients will receive reminders via the PRO platform regarding study participation 
and how to use etripamil NS and the CMS. Site phone contacts for patients not completing the 
PRO questionnaires regularly will also be made.  During the Treatment Period, the patient should 
self-identify symptoms of PSVT.  When an episode occurs, they will apply the CMS, then perform 
a VM, and self-administer etripamil NS if the symptoms do not resolve during or after the VM. 
Patients will complete the TSMQ-9 questionnaire (if they administer etripamil NS) and other 
specified questions related to an episode within 24 hours after each episode resolves.   
If the symptoms of PSVT have not resolved within 30 minutes after initial study drug 
administration, the patient may seek appropriate medical care as needed. If the patient goes to a 
medical facility for PSVT treatment, they must give the study identification card included in the 
study kit to the on-site medical personnel. This study identification card will contain a brief 
description of the study, a description of study drug, and the Investigator (study physician) contact 
information.  
Sites 
During the Treatment Period sites will follow up via phone with patients who have failed to 
complete two consecutive monthly electronic surveys.  During this follow-up phone call, sites 
should remind patients to complete their monthly PRO, and to schedule a Follow-up Visit if they 
have a perceived episode and take study drug.  Sites will be notified of patients who fail to 
complete their electronic PRO as required. They should also contact patients who have had a 
perceived episode as identified by the PRO system to schedule any required Follow-up Visits or 
provision of new CMS materials.   
Details on the use of CMS can be found in Section 9.3.2.4.  Details on the patient reported outcome 
can be found in Section 9.3.1.1. 
6.1.4 Follow-Up Visits (up to 14 days after an episode) 
A full description of the procedures to be conducted during a Follow-up Visit is provided in Section 
9.1.4. 
After a patient experiences a perceived PSVT episode AND takes study drug, they should return 
to the clinic for a Follow-up Visit. During this visit, the Investigator will evaluate the results of the 
last usage of etripamil NS and will decide whether the patient can continue in the study and receive 
two additional study drug kits.   
To continue in the study patients will: 
1. Continue to meet the inclusion/exclusion criteria of the most current protocol version 
2. Have completed the latest version of the Informed consent form (ICF) 
3. Express a willingness and desire to continue in the study 
4. Have treated less than 4 perceived PSVT episodes with etripamil NS in this study 
If the patient continues in the Treatment Period, the site will provide any required retraining and 
dispense two additional study drug kits, and any CMS materials required.  Patients who have 


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treated 4 perceived PSVT episodes with etripamil NS in this study may be eligible for the early 
drug access program as per local regulations. 
6.1.5 Final Study Visits  
See Section 9.1.5 for a full description of procedures during a Final Study Visit.   
Final Study Visits will occur when a patient discontinues or withdraws from the study, completes 
the study (reaches the maximum number of treated perceived PSVT episodes in the study), or 
when the overall study is completed.  These visits have similar procedures to a Follow-up Visit, 
except no new study drug is dispensed.   
6.2 
Discussion of Study Design 
Comparative double-blind efficacy and safety data on self-administered etripamil NS in patients 
with PSVT is being collected in the ongoing Phase 3 study NODE-301 and uncontrolled safety 
and efficacy is being collected in the open-label extension study NODE-302. To further 
characterize the safety of etripamil NS, a larger number of patients need to be studied outside the 
clinical setting.  The NODE-303 design is appropriate to provide a measurement of etripamil NS 
safety in a use setting which closely mimics a real-world setting.   
The study design is depicted in Figure 3. 
Figure 3. 
NODE-303 Study Design 
 
6.3 
Rationale for Dosing 
The choice of the dose level of etripamil NS (70 mg) was made according to the data obtained in 
Phase 1 and Phase 2 studies.  The selected dose is also being studied in the ongoing Phase 3 
program, Studies NODE-301 and NODE-302. 
In the Phase 1 study, etripamil 140 mg was determined to be the MFD with the current formulation 
based on the maximal concentration of etripamil and the required volume of administration (up to 
220 µL of the solution) in each nostril. The 4 highest doses tested in Phase 1 (30, 60, 105, and 
140 mg) produced an increase in the PR interval of the ECG that was consistent with the necessary 
PD effect required to convert reentry tachycardia involving the AV node to SR (see Section 4.2). 
Four doses (35, 70, 105, and 140 mg) were tested in the NODE-1 Phase 2 study. The 3 highest 
doses (70, 105, and 140 mg) were statistically significantly superior compared with placebo for 
terminating induced PSVT in the EPL within 15 minutes of dosing; in addition, the time to 


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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 4.2.2). 
A drop in SBP versus baseline was observed with the 105 and 140 mg doses between 4 and 
10 minutes after etripamil administration, with mean reductions of 11.4% (105 mg), and 15.6% 
(140 mg) mmHg. These decreases were generally asymptomatic and quickly resolved.  Mean SBP 
did not drop following administration of etripamil 35 and 70 mg. 
Etripamil NS 70 mg satisfies the need to balance benefit and risk. The required delivery dose 
(70 mg) is well tolerated; efficacy (measured in PSVT termination rate) is at the plateau of the 
dose response curve; and the AE profile is acceptable, with no post-dose reductions observed in 
SBP. 
The protocol Version 2.0, Amendment No. 1 introduces a new etripamil NS dose regimen to the 
study protocol. The treatment regimen of etripamil to be evaluated is an initial dose of etripamil 
NS 70 mg (one spray of 100 µL in each nostril), to be followed by a second dose (one spray of 
100 µL in each nostril) 10 minutes later (not to exceed 15 minutes) if the patient continues to 
experience PSVT symptoms. Patients who are symptom-free within 10 minutes after the first dose 
do not repeat the dose.  
In study MSP-2017-1096, two 30 mg doses given 10 minutes apart demonstrated that drug 
exposure and PR interval increased and remained elevated for a longer period as compared to the 
single 30 mg dose. Based on these clinical data, combined with the post hoc analysis of the NODE-
301 Part 1, a new dosing regimen was adopted for the RAPID study (NODE-301 Part 2) that allows 
subjects to receive a second dose of etripamil NS 70 mg 10 minutes after the first dose if the 
symptoms of PSVT persist (i.e., a total of 140 mg etripamil NS only to subjects who do not respond 
to etripamil NS 70 mg at 10 minutes post dose). This new dosing regimen aims to increase 
etripamil exposure and its overall PD effect. In addition, the split-dose regimen reduces the volume 
of spray administered at one time in the nostrils, compared to what would be required to administer 
a higher dose of drug in a single administration (a lower spray volume is associated with greater 
bioavailability). Therefore, it is legitimate to study the same dose regimen in this large open label 
study. 
6.4 
Inclusion/Exclusion  
To enroll in the study a patient should be diagnosed with PSVT by a medical professional, and 
report having had at least one previous episode of PSVT.  For clarity, PSVT refers to episodic SVT 
that includes the AV node as a critical part of the reentrant circuit. 
Documentation of patient’s PSVT should be similar to what would be generated in a real-world 
setting.  The study does not require that AV nodal involvement be confirmed by 
electrocardiographic study, and suspected AV nodal dependent SVT is sufficient for inclusion. 
Suspected AV nodal dependency on an electrocardiographic recording is based on the following 
criteria: regular rhythm, heart rate above 100 bpm, narrow QRS complex, and possibly retrograde 
P waves. Appropriate documentation to support enrollment of a patient in NODE-303 would 
include; 
• Electrocardiographic documentation such as: 
o 12-lead ECG 


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o Holter study 
o Ambulatory monitor, including mobile or wearable devices 
o Electrophysiology study 
• Confirmation of arrhythmia conversion after adenosine or CCB administration 
• Documentation (report, hospital or ED discharge summary, or physicians’ notes) 
confirming a history of PSVT from an electrophysiologist, cardiologist, or emergency 
physician who had obtained electrocardiographic evidence of PSVT in the past 
• Documentation from other medical personnel should be discussed with the medical 
monitor 
Patients who have had an ablation should have evidence (electrocardiographic and repeated clear 
symptoms) of PSVT occurring after the ablation in order to be enrolled in NODE-303. 
Patients who plan to have an ablation may be enrolled in the study if they are expected to have at 
least one PSVT episode prior to the planned ablation.  It is not required that patients agree to 
participate in the study for the maximum 4 episodes in order to be enrolled, only 1 episode is 
required.   
Patients to be enrolled in the study should generally experience symptomatic PSVT episodes which 
last more than 5 minutes. Patients with asymptomatic PSVT, or with short duration of episodes 
are unlikely to benefit from etripamil and should not be enrolled in the study. Note that an actual 
tracing showing PSVT for longer than 5 minutes is not required for inclusion in the study. 
7. STUDY POPULATION 
7.1 
Selection of Study Population and Diagnosis 
The Study will enroll up to approximately 3000 patients in order to obtain up to 1500 patients (in 
overall development program) with a perceived PSVT episode within 24 months of study 
enrollment. Patients will be diagnosed with PSVT by a medical professional and will have reported 
having at least one previous episode of PSVT prior to study screening.  
7.2 
Study Entry Criteria 
7.2.1 Inclusion Criteria 
A patient will be eligible for study participation if they meet all of the following criteria: 
1) Has been diagnosed with PSVT by a medical professional and reports having at least one 
previous episode of PSVT.  For clarity, PSVT refers to episodic SVT that includes the AV 
node as a critical part of reentrant circuit.  See Section 6.4 for details on diagnostic criteria. 
2) Is at least 18 years of age. 
3) Signed NODE-303 written informed consent. 
4) Women of child-bearing potential must be willing to use at least 1 form of contraception 
during the trial and must be willing to discontinue from the study should they become or plan 
to become pregnant.  Postmenopausal females are defined as having amenorrhea for at least 
12 months prior to Screening without an alternative medical cause. 
5) Willing and able to comply with study procedures. 


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7.2.2 Exclusion Criteria 
A patient will be excluded from the study if they meet any of the following criteria: 
1) Patients with only a history of atrial arrhythmia that does not involve the atrioventricular (AV) 
node as part of the tachycardia circuit (e.g., atrial fibrillation, atrial flutter, intra-atrial 
tachycardia) are not eligible. Patients with a history of these tachycardias who are also 
diagnosed with PSVT are eligible. 
2) History of allergic reaction to verapamil.  
3) Current therapy with digoxin, or any Class I or III antiarrhythmic drug. Patients may be eligible 
if these drugs are stopped at least five half-lives before the administration of etripamil NS. The 
only exception is oral amiodarone which must be stopped 30 days before enrollment. 
4) History or evidence of ventricular pre-excitation, e.g., delta waves, Wolff-Parkinson-White 
syndrome. 
5) History or evidence of a second- or third-degree AV block.  
6) History or evidence of severe ventricular arrhythmia (e.g., torsades de pointes, ventricular 
fibrillation, or sustained ventricular tachycardia). 
7) Symptoms of congestive heart failure New York Heart Association Class II to IV. 
8) SBP < 90 mmHg at Screening, Baseline or any Follow-up Visit. 
9) Severe symptoms of hypotension experienced during PSVT episodes. 
10) Significant physical or psychiatric condition including alcoholism or 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. 
11) History of syncope due to an arrhythmic etiology at any time, or history in last 5 years of 
unexplained syncope. 
12) Is pregnant or breastfeeding. 
13) Previously enrolled in a clinical trial for etripamil and received study drug or participation in 
any clinical trial for other investigational products or medical devices within 30 days of 
Screening. 
14) History of ACS or stroke within 6 months of Screening. 
15) Evidence of renal dysfunction as determined by an estimated glomerular filtration rate assessed 
at the Screening Visit as follows:  
a) <60mL/min/1.73m2 for patients <60 years of age 
b) <40mL/min/1.73m2 for patients ≥60 and <70 years of age 
c) <35mL/min/1.73m2 for patients ≥70 years of age. 
7.3 
Patient Discontinuation/Withdrawal 
All patients will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 


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attempt to keep patients in the study; however, patients must be withdrawn from the study if they 
withdraw consent to participate.  
After a patient self-administers a dose of etripamil NS to treat the fourth perceived PSVT episode 
in this study, they should return for a Final Study Visit within 14 days of the episode, not a Follow-
up Visit, and they may be eligible for the early drug access program as per the local guidelines. 
Investigators must attempt to contact patients who fail to attend scheduled visits to verify 
continued participation in the study, or if the patient is withdrawing from the study.  If a patient 
withdraws, the reason for withdrawal should be determined, and if an AE was the cause of 
withdrawal, the AE must be documented, reported, and followed as described in Section 10.2. 
Milestone reserves the right to request the withdrawal of a patient because of protocol violations 
or other reasons. 
The investigator also has the right to withdraw patients from the study or discontinue study drug 
treatment at any time for apparent lack of therapeutic effect, or drug treatment that is intolerable 
or otherwise unacceptable to the patient, for intolerable or unacceptable AEs, intercurrent illness, 
noncompliance with study procedures, administrative reasons, or in the investigator’s opinion, to 
protect the patient’s best interest.   
If a patient is withdrawn or discontinues treatment, the reason and the date of discontinuation will 
be recorded on the appropriate electronic case report form (eCRF). Whenever possible and 
reasonable, the evaluations that were to be conducted at a Final Study Visit should be performed 
at the time a patient withdraws from the study. Common reasons expected to lead to 
discontinuation for patients in this study include; 
• Patient goes on to receive ablation therapy.  See Section 8.7 for more information regarding 
ablations 
• Patient does not want to continue to additional Treatment Periods 
8. TREATMENTS 
8.1 
Identification of Investigational Product 
The formulation of etripamil is for IN administration and will consist of MSP-2017 (etripamil), 
water, acetic acid, disodium ethylene-diamine-tetra-acetic acid (EDTA), and sulfuric acid.  
8.2 
Labeling and Packaging 
Clinical labeling and packaging of the study drug will be performed by Catalent. 
8.2.1 Labeling 
Study drug will be labeled according to the requirements of local law and legislation, as well as 
current Good Manufacturing Practice (GMP) and International Council for Harmonization (ICH) 
Good Clinical Practice (GCP) guidelines. In compliance with these regulations and guidelines, the 
label may include information such as the study protocol number, administration sequence, lot 
number, storage conditions, expiry date, Sponsor identification, or appropriate cautionary 
language for investigative material. Proof labels, detailing actual label text, will be available in the 
study files. 


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8.2.2 Packaging 
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 identified with a kit identifier.  Each 
kit will contain one 70 mg nasal spray device, patients will receive two kits. The kit identifiers for 
each patient will be recorded in the Cenduit clinical supply tracking system for the study. 
8.3 
Treatments Administered 
The treatment regimen of etripamil is an initial dose of etripamil NS 70 mg (one spray of 100 µL 
in each nostril), to be followed by a second dose (one spray of 100 µL in each nostril) 10 minutes 
later (not to exceed 15 minutes) if the patient continues to experience PSVT symptoms. Patients 
who are symptom-free within 10 minutes after the first dose do not repeat the dose.  
The devices will be prefilled and packaged.  Instructions for its use will be provided to the patient. 
Prior to administration, patients should be seated with their head in an upright position. Patients 
will be instructed to hold their breath and avoid inhaling during study drug administration (a 
caregiver may help the patient with this procedure). For 10 minutes after each drug administration, 
patients are to remain in a seated position with their head upright, breathe normally, and refrain 
from blowing their nose. 
If the BDS does not deploy, it will be considered a missed dose.  If only one spray, per dosing 
session, of the BDS is administered for any reason, it will be considered a partial dose. Missed and 
partial doses will be recorded in the eCRF. 
8.4 
Additional Medical Intervention 
During an episode, if the symptoms of PSVT have not resolved within 30 minutes after initial 
study drug administration, the patient may seek appropriate medical care as needed. If the patient 
goes to a medical facility for PSVT treatment, they must give the study identification card included 
in the study kit to the on-site medical personnel. This study identification card will contain a brief 
description of the study, a description of study drug, and the Investigator (study physician) contact 
information. 
Sites will enter all concomitant medications taken and concomitant procedures conducted during 
any medical facility visit in the EDC. 
8.5 
Drug Storage and Accountability 
Study drug will be stored at the clinical site at ambient room temperature (15°C to 30°C [59°F to 
86°F]) and will be protected from light in a secure area with access limited to authorized personnel. 
During the study, the patient will be instructed to keep and return used and unused BDS devices 
to the site at each Follow-up Visit for 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 drug accountability during their Final Study 
Visit. 
Records will be maintained at each clinical site indicating the receipt and dispensation of all study 
drug supplies. The responsible pharmacist or designee at the investigational site must keep an 
accurate inventory of study drug shipments received and the amount of study drug used or not used 
by each patient. A full reconciliation of drug inventory will be performed at the end of the study, 
and the results of the inventory will be recorded in the drug accountability log. 


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The final accountability of study drug (both used and unused kits) will be performed by the Clinical 
Research Associate (CRA) at the sites. The sites will be allowed to destroy study drug after CRA 
accountability.  If sites are not able to destroy drug, they should return drug for destruction. The 
details about drug return are outlined in the Pharmacy Manual provided to the sites. If no study 
drug remains at a site, this will be indicated in the drug accountability log. 
8.6 
Treatment Compliance 
All doses of the study drug will be administered by the patient in an at-home setting.  Patients will 
report whether they took study drug, and at what date and time they took study drug.     
Dosing details will be recorded in the patient’s eCRF. 
8.7 
Prior and Concomitant Therapies 
All concomitant medications and treatments used within 30 days of the Screening Visit (including 
over-the-counter medications and herbal supplements) until the Final Study Visit will be recorded 
in the source document and on the appropriate eCRF. 
Current therapy with digoxin, or any Class I or III antiarrhythmic drug is not allowed during the 
study. Patients may be eligible to participate if these drugs are stopped at least five half-lives before 
the study drug is dispensed. The only exception is oral amiodarone which must be stopped 30 days 
before study drug is dispensed. The 30-day maximum duration between Screening and Baseline 
Visits allows patients to wash-out amiodarone.   
Class I or III Antiarrhythmic drugs used on an acute basis (e.g., lidocaine) for a procedure or 
treatment will NOT require a patient be withdrawn from the study.  These patients will be 
instructed not to take etripamil NS for at least 5 half-lives of the concomitant antiarrhythmic drug, 
unless the drug is amiodarone.  Amiodarone use during the study is prohibited.   
The use of any drugs of abuse which, in the opinion of the Investigator, would impact the validity 
of the study results is prohibited. 
Ablation: Patients who plan to have an ablation for the treatment of their PSVT are eligible to 
enroll in the study so long as they are deemed highly likely to have a PSVT event prior to the 
ablation   Enrolled patients who are scheduled to receive an ablation procedure for the treatment 
of PSVT in a time frame which makes it unlikely they will have an at-home episode of PSVT 
treated with etripamil NS, should withdraw from the study and complete a final Follow-up Visit 
prior to the ablation procedure.  Patients who have previously had an ablation for the treatment of 
PSVT that is determined to be unsuccessful are eligible to enroll in the study if they experience 
PSVT 
episodes 
after 
the 
ablation 
is 
completed 
and 
should 
have 
evidence 
(electrocardiographic and repeated clear symptoms) of PSVT occurring after the ablation. 
If a patient starts or plans to start any prohibited medication or treatment, they should withdraw 
from the study and complete a Final Study Visit. 


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9. STUDY PROCEDURES 
Prospective study patients will be asked to sign the informed consent form (ICF) before the 
commencement of any study-related assessments or procedures, including the cessation of 
prohibited concomitant therapy. Patients who have previously consented will be asked to sign a 
new ICF in the event that its contents have been updated, at the time of their next scheduled study 
visit. 
For a summary of assessments and procedures throughout the study, refer to the schedule of 
assessments (Section 17.1). 
9.1 
Study Periods, Visits, and Procedures 
9.1.1 Screening Visit (Days -30 to -1) 
Prospective study patients will be asked to sign the informed consent form before the 
commencement of any study-related assessments or procedures.  
If a patient meets at least 1 exclusion criterion, the patient will be considered a screening failure. 
Re-screening may be allowed after consultation between the Investigator and Medical Monitor, or 
should the inclusion/exclusion change. 
The Screening Visit will include at least one visit to the clinic, during which the Investigator or 
designee will verify that the patient meets the eligibility criteria of the NODE-303 study, will 
obtain the signed informed consent, and conduct screening procedures. The informed consent for 
NODE-303 will be applicable for the duration of the study period; ICF should be signed again at 
the following scheduled study visit in the event its contents are updated during the study.   
The Screening Visit may occur up to 30 days prior to Baseline to allow time for safety laboratory 
parameters, review of the safety ECG, and any washout of background medications.  Screening 
ends when the patient is dispensed study drug or screen fails. 
The following procedures will be performed at Screening: 
1. Obtain written informed consent. 
2. Assign a patient number via IRT system. 
3. Review inclusion/exclusion criteria.   
4. Record demographics and detailed medical history, including review of medications taken 
within 30 days before Screening.  
5. Record concomitant medications.  Patients on prohibited therapies may participate in the study 
if these drugs are stopped at least five half-lives before study drug is dispensed. The only 
exception is oral amiodarone which must be stopped 30 days before study drug is dispensed. 
6. Perform a complete physical examination (excluding breast and genitourinary examination) 
with review of body systems (See Section 9.3.2.3.3 for systems). 
7. Record vital signs (blood pressure, heart rate) after the patient has been in a seated position for 
at least 5 minutes. 
8. Measure height and weight. 
9. Collect blood and urine samples for clinical laboratory tests (hematology, serum chemistry, 
pregnancy test, and urinalysis); see Section 9.3.2.2.1 for a complete list of required laboratory 
tests. 


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10. Conduct a 12-lead ECG reading, upload results to the archive. A previous 12-lead ECG (taken 
within 1 month prior to the Screening Visit) of sufficient quality to fully assess patient safety 
and eligibility may be used by the site as long as there has been no significant change in the 
patient’s underlying condition or general health (such as having an ablation, or other cardiac 
event).  Previous ECGs should also be uploaded to the archive. 
11. Receive results of clinical laboratory tests, review the ECG, and confirm patient eligibility. 
9.1.2 Baseline Visit 
The Baseline Visit will occur after screening procedures are completed.  
To ensure the safety of trial participants in NODE-303, and to reduce the risks associated with the 
COVID-19 pandemic by reducing the number of visits the patient is required to make to the 
investigative site, it is permitted that all Screening Visit procedures and Baseline Visit procedures 
be conducted on the same day.  In this case, duplicate Screening Visit blood and urine samples 
will be collected, one set will be sent to the central laboratory, and the second set will be analyzed 
by a local laboratory. If there are no exclusionary results from the local laboratory, the patient will 
be permitted to continue with the Baseline Visit procedures.  If the patient successfully completes 
all Screening and Baseline Visit procedures, and is preliminarily enrolled (pending receipt of 
results from the central laboratory), they will be dispensed study medication and all study 
materials, but instructed not to use the study medication until they are informed by the investigative 
site that the results have been received from the central laboratory, there are no exclusionary results 
and the patient has been successfully enrolled.  The official date of enrollment of the patient into 
the study will be the date the site receives the results from the central laboratory. If there are 
exclusionary results from the central laboratory, the patient will return to the site, be withdrawn 
from the study and complete a Final Study Visit. 
The local laboratory will not be certified for use in the study, and the local laboratory results will 
not be entered into the study database but will be retained in the patient’s site study file. 
The following procedures will be performed at the Baseline Visit: 
1. Charge the patient’s CMS Device prior to the visit. 
2. Confirm patient remains eligible for the study. 
3. Record any changes in concomitant medications. 
4. Train patients on how to use the PRO (See Section 9.3.1.1 for full details on the PRO), the 
CMS, and the etripamil nasal spray device,  
5. Provide patient with patient instructions and other materials. 
6. Have the patient complete a baseline PRO survey while on-site, but may complete the validated 
scales (BIPQ, CAQ, SF-36) up to 48 hours after the Baseline Visit. 
7. Determine how much CMS material a patient is likely to need (patients with frequent short 
episodes for which they may not use etripamil NS may require additional materials).   
8. Once all other Screening and Baseline procedures are complete, dispense two study drug kits 
and CMS materials.  
9.1.3 Treatment Period (Until patient withdrawal, completion, or discontinuation) 
The Treatment Period refers to the duration of the study after a patient has been given study drug 
and sent home until they have a perceived episode, discontinue from the study, or the overall study 
is completed.  After a patient has a perceived episode AND takes study drug, they should return to 


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the clinic for a Follow-up Visit (see Section 9.1.4 below).  If the patient does not take study drug 
for a perceived PSVT episode, they may continue in the Treatment Period.  Patients may continue 
in the study until they have treated a total of 4 perceived PSVT episodes with etripamil NS, after 
which they will complete the study and may be eligible for the early drug access program as per 
local guidelines. 
During the Treatment Period, patients will complete a monthly survey regarding their quality of 
life and PSVT. Patients may receive reminders regarding study participation and how to use 
etripamil NS and the CMS during the Treatment Period. During this period, the patient should self-
identify symptoms of PSVT.  When an episode occurs, they will perform a VM, and self-
administer etripamil NS if the symptoms do not resolve during or after the VM.  Patients will 
complete the TSMQ-9 questionnaire (if they administer etripamil NS) and other specified 
questions related to an episode within 24 hours after each episode resolves. 
If the symptoms of PSVT have not resolved within 30 minutes after initial study drug 
administration, the patient may seek appropriate medical care as needed. If the patient goes to a 
medical facility for PSVT treatment, they must give the study identification card included in the 
study kit to the on-site medical personnel. This study identification card will contain a brief 
description of the study, a description of study drug, and the Investigator (study physician) contact 
information.  
Full details on the CMS can be found in Section 9.3.2.4.  Details on the patient reported outcome 
system can be found in Section 9.3.1.1. 
The following procedures will be performed by the Site during a Treatment Period: 
1. Follow up via phone with patients who have failed to complete two consecutive monthly 
surveys. 
2. Contact patients who have had a perceived episode as identified by the patient reported 
outcome system and schedule a Follow-up Visit if they took study drug.   
3. If a patient runs out of CMS materials but has not taken study drug, provide additional materials 
to the patient. 
The following procedures will be performed by the patient during a Treatment Period: 
1. Patients will complete the monthly PRO survey throughout the Treatment Period. 
2. When a patient self-identifies that a PSVT episode is occurring they should; 
a. If possible, log in to the PRO system for step by step guidance on procedures. 
b. Apply the CMS.   
c. Perform a VM.  If symptoms resolve after this VM, patients should NOT take drug.  
They should remove the CMS Device from its connection, and switch it off, complete 
the other episode survey questions on the PRO, and continue in the Treatment Period. 
If symptoms do not resolve, they should proceed with the procedures below. 
d. Self-administer etripamil NS.   
e. Mark the time etripamil NS was taken by pressing on the CMS Device as trained by 
site staff. 


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f. If symptoms persist after 10 minutes have passed since taking etripamil NS, the patient 
should self-administer a second dose of etripamil NS. If symptoms persist 30 minutes 
after the initial administration the patient may seek additional medical care as needed.   
g. Keep the CMS Device on for at least 1 hour after taking etripamil NS. 
3. After a PSVT episode occurs during which study drug was taken, the patient should; 
a. As soon as possible after an episode has resolved, complete the TSQM-9 questionnaire 
and other episode survey questions on the PRO. 
b. After wearing the CMS for at least 1 hour following the initial administration of the 
drug, they should switch off the CMS Device and remove the CMS from the chest and 
the device from the connecting electrodes.   
c. Contact their clinical site to schedule a Follow-up Visit. 
d. Keep the empty etripamil nasal spray device(s) and bring them together with any 
unused etripamil NS to the Follow-up Visit. 
e. Bring the CMS Device with them to the Follow-up Visit. 
f. If a patient requires additional CMS system materials (patches or training materials), 
they should contact the site to get the needed materials. 
9.1.4 Follow-up Visit (up to 14 days after an episode) 
After a patient experiences a perceived PSVT episode AND takes study drug, they should return 
to the clinic for a Follow-up Visit.  If the patient has a perceived episode but did not take study 
drug, they do not need to schedule a Follow-up Visit.  During this visit, the Investigator will 
evaluate the results of the last usage of etripamil NS, along with the CMS data, and will decide 
whether the patient can continue in the study.   
To continue in the study patients should; 
1. Meet the inclusion/exclusion criteria of the most current protocol version 
2. Have completed the latest version of the Informed consent form (ICF) 
3. Express a willingness and desire to continue in the study 
4. Have treated less than 4 perceived episodes of PSVT with etripamil NS in this study.   
If the patient treated their fourth perceived PSVT episode in this study, complete a Final Study 
Visit instead of a Follow-up Visit.  If it is determined that a patient should not continue in the study 
for any reason, the site should conduct a Final Study Visit (Section 9.1.5) instead of a Follow-up 
Visit. 
The following procedures will be performed at a Follow-up Visit: 
1. Immediately log in to the CMS online portal. Upload the CMS data. This starts the 
processing of Holter data by the CMS lab.  The data should be processed, and an initial 
safety report returned to the site within 1.5 hours from data upload.   
2. Review inclusion/exclusion criteria to make sure the patient remains eligible for the study. 
3. Record concomitant medications.   
4. Record vital signs (blood pressure, heart rate) after the patient has been in a seated position 
for at least 5 minutes.   
5. Record weight. 


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6. Collect the used and unused nasal spray devices from the patient.  If the patient does not 
have the drug devices, confirm they took the drug and record the lost devices in the eCRF. 
7. Review the CMS data;  
a. For quality and adherence to the protocol, and  
b. To determine whether there are any safety or eligibility concerns that merit 
withdrawing the patient from the study, and  
c. To determine whether any AEs are present   
If CMS data is not processed and returned within 1.5 hours from data upload, and no other 
safety concerns exist, the site may keep the patient in the study and dispense two additional 
drug kits. When the initial CMS safety report becomes available, sites will review it for 
any safety issues to determine if the patient needs to be called back for withdrawal and a 
Final Study Visit. 
8. Review the PRO data for quality and adherence, evaluate any additional medical 
intervention (including vagal maneuvers) the patient received for PSVT episodes during 
the Treatment Period.  Make sure the patient is completing the PRO for any PSVT episodes 
that occur, regardless of whether or not they took etripamil NS. 
9. Collect any adverse event data during the Treatment Period, and the accurate onset date 
and time. 
10. Provide any additional training on study procedures or devices. 
11. If the patient remains eligible to continue in the study, two study drug kits and any required 
CMS materials (or training materials) may be dispensed.   
9.1.5 Final Study Visit  
Upon completion of the overall study (Common Study End Date), treating 4 perceived PSVT 
episodes with etripamil NS in this study, discontinuation or withdrawal of a patient, the site should 
have the patient return for the Final Study Visit procedures below. 
1. Record concomitant medications.   
2. Record vital signs (blood pressure, heart rate) after the patient has been in a seated position 
for at least 5 minutes. 
3. Record weight. 
4. Collect the used and unused nasal spray devices from the patient.  If the patient does not 
have the devices, confirm they took the drug and record the lost devices in the eCRF. 
5. Review the CMS data to determine whether any AEs are present. 
6. Review the PRO data for quality and adherence, evaluate any additional medical 
intervention the patient received for PSVT episodes during the Treatment Period. Close 
out the patient in the PRO system and collect any electronic device provided to the patient. 
7. Collect any adverse event data during the Treatment Period, and the accurate onset date 
and time. 
8. Collect the CMS.  
9. Collect any reason for discontinuation and complete the patient’s End of Study form in the 
eCRF. 


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9.1.6 Conduct of NODE-303 Study during COVID-19 pandemic 
To ensure the safety of trial participants in NODE-303, new processes or modification of listed 
processes may be put in place to reduce the risks associated with the COVID-19 pandemic.  These 
potential changes include, but are not limited to, the use of tele-medicine to conduct study visit 
procedures, conduct of study procedures outside of the clinical site (i.e., at a patient’s home) by 
site personnel or by trained but non-study personnel, and the distribution of investigational 
products by alternative secure delivery methods. In the event alternative processes are 
implemented, the process and the reason for the implementation for the contingency measure will 
be documented by the sponsor and clinical investigators. 
9.2 
Study Duration 
Patients may continue in the study until they treat 4 perceived PSVT episodes with etripamil NS, 
at which time they will complete the study and may be eligible for the early drug access program 
in line with local country regulations. The duration of treatment will depend on the frequency of a 
patient’s PSVT episodes. 
After each episode of perceived PSVT is treated with the study drug, eligible consenting patients 
will have the opportunity to continue in NODE-303 and self-manage subsequent episodes of PSVT 
with etripamil NS. The patient can come back to receive two additional treatment kits after every 
episode treated with etripamil NS provided that no adverse effect nor any eligibility criteria would 
preclude another administration of etripamil NS.   
9.2.1 Common Study End Date (CSED) 
NODE-303 will continue until the end of the development program, i.e., when enough documented 
self-administrations of etripamil NS are included in the safety database as determined by Sponsor.  
The CSED will depend on the rate of accrual of the primary endpoint, unique patients with an 
episode. When the sponsor announced the CSED, sites will be notified, and should schedule all 
current patients to return to the site as soon as possible for a Final Study Visit. The CSED 
announcement will contain additional information on study closeout timelines.    
Patients who have a perceived episode and take study drug during this period should return for 
their Final Study Visit within 14 days of when the episode occurred and have any ongoing AEs 
monitored for resolution for at least 30 days after the last dose of study drug administration.  
9.3 
Assessments 
9.3.1 Efficacy 
9.3.1.1 Patient Reported Outcomes – PRO System 
At the Baseline Visit, patients will be provided with a phone application which provides a variety 
of study assessments and information throughout the course of the study. The PRO system will 
work regardless of device connectivity at the time of use, as data will be uploaded the next time a 
patient is connected. If a patient does not have a smartphone or device, they may be given a device 
if available. The PRO system will include the following;   
• A general walk-through of procedures to follow during an episode, designed for use during 
a PSVT episode. 


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• A baseline survey which captures information about a patients PSVT, and administers 
validated scales, the BIPQ, CAQ, and SF-36.  Patients should complete the baseline survey 
on-site, and may complete the validated scales within 2 days of the Baseline Visit. 
• A per episode survey which includes questions regarding each specific PSVT episode the 
patient experiences including information on drug administration, symptoms, the episode 
itself, and medical interventions required. When a patient takes etripamil NS, it will 
administer the TSQM-9. 
• A monthly PRO survey will be administered, including items related to the patient’s PSVT, 
quality of life, and the impact of PSVT on their activities. Validated scales BIPQ, CAQ, 
and SF-36 will be administered every 6 months.   
9.3.1.1.1 Monthly Survey – Brief Illness Perception Questionnaire (BIPQ), Cardiac 
Anxiety Questionnaire (CAQ), Short Form (36) Health Survey (SF-36) and other 
questions 
Each month patients will be asked to complete the Monthly Survey which pertains to their PSVT 
specific symptoms and the underlying course of their disease over the last month. At Baseline and 
every 6 months, patients will be asked to complete the BIPQ, CAQ, and SF-36. 
The BIPQ is a 9-item patient reported measure of cognitive and emotional representations of 
illness.  Questions focus on aspects of personal attributions and control of the course of the disease. 
The CAQ is an 18-item patient reported measure with three subscales designed to assess cardiac 
specific anxiety.  Individual items are summed and divided by 18 to obtain a CAQ scale.   
The SF-36 is a 36-item patient reported survey of general patient health and quality of life.  It 
consists of eight scaled scores, which are weighted sums of the questions in their section.  The 
lower the score, the more disability.   
9.3.1.1.2 Per Episode Survey - Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) and other questions 
After each episode, patients will be asked to complete a per-episode survey regarding the episode, 
drug administration, symptoms, and medical interventions. If the patient takes etripamil NS for the 
episode, they will also be administered the TSQM-9. 
The TSQM-9 is a 9-item patient reported questionnaire on four key dimensions of treatment 
satisfaction.   
9.3.1.2 Additional Medical Intervention Required 
The degree to which patients require medical intervention for PSVT episodes will be assessed by 
collecting information on emergency department visits, hospital admissions, discontinuations to 
receive ablation, and concomitant medication use. This information will be collected both by the 
PRO device, and by site personnel through the course of the study. 
9.3.1.3 Characteristics of patient PSVT episodes 
The characteristics of a patient’s PSVT episode will initially be assessed by the investigator, and 
finally determined by a medical central reviewer based upon data from the CMS and other 
available information on an episode. Section 9.3.2.4 outlines what data will be assessed. 


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Based on these assessments, analyses will be conducted on the number of episodes a patient 
experiences, the frequency of those episodes over time, the number terminated by VM, type of 
PSVT (including not a true PSVT event), duration of PSVT, time to conversion post etripamil NS 
administration, and the proportion of patients who convert at 3, 5, 10, 15, 20, 30 and 60 minutes 
after etripamil NS administration. 
9.3.2 Safety 
Safety assessments will include the evaluation of AEs; vital sign measurements; CMS recordings, 
and physical examination findings. 
9.3.2.1 Adverse Events 
The definitions and management of and special considerations for AEs are provided in Section 10. 
9.3.2.2 Clinical Laboratory Safety Assessments 
9.3.2.2.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time point specified in the 
schedule of assessments (Section 17.1). 
Hematology 
Hemoglobin, hematocrit, red blood cell count, red blood cell indices, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, platelet count (or estimate), and white blood cell count, 
including differential 
Serum Chemistry 
Albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, creatinine, glucose, sodium, potassium, chloride, bicarbonate, 
lactate dehydrogenase, and uric acid 
Urinalysis 
pH, specific gravity, blood, glucose, protein, and ketones 
Pregnancy Test 
For women of childbearing potential only. A blood test will be 
performed at Screening and as required throughout the study to confirm 
any suspected pregnancy 
Urine Drug Screen 
Amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, and tetrahydrocannabinol 
Blood and urine samples for hematology, serum chemistry, and urinalysis will be sent to a central 
laboratory for analyses. 
9.3.2.3 Clinical Examinations 
9.3.2.3.1 Vital Signs 
Vital signs will include blood pressure, heart rate, and weight. Blood pressure and heart rate will 
be measured after the patient has been in a sitting position for 5 minutes.  
9.3.2.3.2 12 Lead Safety ECG 
A 12 lead Safety ECG will be conducted at Screening to confirm that patient meets 
inclusion/exclusion criteria.  A previous 12-lead ECG (taken within 1 month prior to the Screening 
Visit) of sufficient quality to fully assess patient safety and eligibility may be used by the site as 
long as there has been no significant change in the patient’s underlying condition or general health 
(such as having an ablation, or other cardiac event).  Previous ECGs should also be uploaded to 


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the archive.  Data from the ECG will be collected at the site and reviewed by site personnel for 
potential concomitant disorders which would exclude the patient from the trial.  
12-Lead Safety ECGs will be uploaded and stored centrally in the study database throughout the 
study. 
9.3.2.3.3 Physical Examination 
A complete physical examination (excluding breast and genitourinary examination) will be 
performed at Screening.  Systems examined should include General Appearance/Constitution, 
Eyes, ENT/Mouth, Respiratory, Cardiovascular, Gastrointestinal, Muscular, Skin, Neurological, 
Endocrine, Lymph Nodes, Allergy/Immunological, and Psychiatric.   
9.3.2.4 Cardiac Monitoring System (CMS)  
A portable device will be used as the CMS for this study.  The CMS is an at-home ECG monitor 
which will be applied as soon as possible when an episode of PSVT is perceived by the patient. It 
is removed after (at least) 1 hour post initial study drug administration.   
Patients should be provided with a CMS Device, and sufficient materials to record anticipated 
perceived PSVT episodes until their next Follow-up Visit.  Patients with frequent short PSVT 
episodes for which they may not use study drug should receive extra CMS materials.  
During a perceived PSVT episode, patients will apply the CMS. After the episode they should 
switch off the CMS Device. If they took drug, they will return to the site for a Follow-up Visit.   
Immediately at the start of a Follow-up Visit, the site should log into the online web portal and 
plug the CMS Device into the docking station to upload the episode data.  This data will be 
processed by the CMS lab, and an initial .pdf formatted CMS safety report will be generated. The 
data should be processed, and an initial CMS safety report returned to the site within 1.5 hours 
from data upload. Sites should then review the CMS safety report, See Section 9.1.4 for details.   
If CMS data is not processed and returned within 1.5 hours from data upload, and no other safety 
concerns exist, the site may keep the patient in the study and dispense two additional drug kits.  
When the initial CMS safety report becomes available, sites will review it for any safety issues to 
determine if the patient needs to be called back for withdrawal and a Final Study Visit. 
Data from the episode will be reviewed centrally by a designated medical expert.  This medical 
expert will review the CMS data for several items: 
1. 
Potential safety or eligibility concerns that may impact the decision whether to continue 
treating a patient with etripamil NS. All such concerns will be communicated to the site, 
and the investigator will make the final decision based on a full evaluation of the patient 
and data. 
2. 
Potential Adverse Events. All data indicating potential AEs will be communicated to the 
site, and the investigator will make the final decision of whether a finding constitutes an AE 
based on a full evaluation of the patient and data. 
3. 
Abnormal findings from the CMS Holter recordings.  Pre-specified types of abnormal 
Holter findings will be documented by the medical central reviewer and will be entered in 
the EDC. 
4. 
Whether an episode was a true PSVT event, or something else.  This will be documented 
in the EDC. 


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5. 
The time to conversion, and time to conversion after study drug administration (when 
determinable).  This will be documented in the EDC.   
10. ADVERSE EVENTS 
10.1 Definitions 
10.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation in a 
patient administered a pharmaceutical product that does not necessarily have a causal relationship 
with the product. An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically important abnormal laboratory finding), symptom, or disease, temporally associated 
with the product, whether or not related to the product. 
During Screening the Investigator or designee will assess all findings from physical exams, vital 
signs, laboratory assessments, and Screening ECGs. Clinically significant findings will be 
recorded as medical history.  Pre-existing diseases or conditions will not be considered AEs unless 
there is an increase in the frequency or severity, or a change in the quality, of the disease or 
condition. (Worsening of a pre-existing condition is considered an AE.) 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms will be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it will be recorded as a separate AE on the eCRF. In cases requiring 
medical or surgical procedures, the underlying condition, rather than the procedure itself, will be 
recorded as an AE(s). 
Clinically significant abnormal assessments that are detected during the study or are present at 
Screening and significantly worsen will be reported as AEs or SAEs. The Investigator will exercise 
his or her medical and scientific judgment in deciding whether an abnormal assessment is clinically 
significant. Any abnormal assessments considered clinically significant by the Investigator must 
be recorded on the AE page of the eCRF.  
Events that occur in patients during Treatment Periods of the study when study drug is not 
administered are also considered AEs. 
10.1.2 Adverse Drug Reaction 
All noxious and unintended responses to a study drug related to any dose should be considered 
adverse drug reactions (ADRs). 
The phrase “responses to a study drug” means that a causal relationship between a study drug and 
an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. All AEs judged 
by either the reporting investigator or the sponsor as having a reasonable causal relationship to a 
study drug qualify as ADRs. 
All AEs for which the judgment of relationship to the study drug is “possible” or higher will be 
considered ADRs. If a relationship to the study drug is not given, then the AE must be treated as 
if the relationship to the study drug were “possible.”  


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10.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For etripamil NS, 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. 
10.1.4 Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the study 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE. Further, an overnight stay in the hospital that is only due to 
transportation, organization, or accommodation problems and without medical 
background does not need to be considered an SAE.  For clarity, hospitalizations for 
PSVT related ablations, or conversions of PSVT episodes will not be considered SAEs. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly. 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the study 
drug during pregnancy is an SAE. However, a newly diagnosed pregnancy in a patient who 
has received a study drug is not considered an SAE unless it is suspected that the study 
drug(s) interacted with a contraceptive method and led to the pregnancy.  
• Is an important medical event. 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. The occurrence of 
malignant tumors is also to be considered serious. 
10.1.5 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening occurs less than 24 hours 
after the administration of the study drug. 
10.2 Management of Adverse Events 
Adverse events will be collected from the time of signing the ICF until the patient withdraws or 
discontinues from the study.   


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10.2.1 Collection of Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the patient will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as: 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
10.2.2 Evaluation of Adverse Events 
10.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the patient. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 10.1.4. 
10.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 10.1.4.  Seriousness (not severity) serves as the guide for defining regulatory reporting 
obligations.  All AEs that do not meet any of the criteria for serious should be regarded as non-
serious AEs. 
10.2.2.3 Action(s) Taken 
Action(s) taken may consist of: 
Dose not changed 
An indication that a medication schedule was maintained. 
Drug withdrawn 
An indication that a medication schedule was modified through termination 
of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
10.2.2.4 Outcome at the Time of Last Observation 
The outcome, including Fatal, at the time of last observation will be classified per eCRF 
completion instructions.  Only select fatal as an outcome when the AE results in death. If more 
than 1 AE is possibly related to the patient’s death, the outcome of death should be indicated for 
each such AE. Although “fatal” is usually an event outcome, events such as sudden death or 
unexplained death should be reported as SAEs. 


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10.2.2.5 Adverse Event Relationship to the Study Drug 
The assessment of the relationship of an AE to study drug administration is a clinical decision 
based on all available information at the time the event is reported. 
The relationship of an AE to study drug administration is to be assessed according to the following 
definitions: 
• Not related – An event that is definitely not associated with study drug administration and is 
judged clearly due to causes other than study drug. 
• Unlikely related – An event that follows a temporal sequence from study drug administration, 
such that a relationship is not likely and could be reasonably explained by the patient’s clinical 
state or other modes of therapy administered to the patient. 
• Possibly related – An event that follows a reasonable temporal sequence from study drug 
administration, but may be due to another cause and could also be reasonably explained by the 
patient’s clinical state or other modes of therapy administered to the patient. 
• Probably related – An event that follows a reasonable temporal sequence from study drug 
administration that is not easily explained by another cause (e.g., known characteristics of the 
patient’s clinical state or other treatment), and is confirmed by improvement on stopping or 
slowing study drug administration. 
• Definitely related – An event that is clearly associated with study drug administration. 
An AE/SAE that has been assessed as "possibly related" "probably related" or "definitely related" 
will be classified as "related" for regulatory reporting purposes. An AE/SAE that has been assessed 
as "not related" or "unlikely related" will be classified as "unrelated" for regulatory reporting 
purposes.  
The following factors will also be considered: 
• The temporal sequence from study drug administration; 
o The event should occur after study drug administration. The length of time from study drug 
exposure to event will be evaluated in the clinical context of the event. 
• Underlying, concomitant, and/or intercurrent diseases; 
o Each report will be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
• Concomitant medication; 
o The other medications the patient is taking or the treatment the patient receives will be 
examined to determine whether any might be recognized to cause the event in question. 
• Known response pattern for this class of study drug; 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses; and 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 


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• The pharmacology and PK of the study drug. 
The known pharmacological properties (e.g., absorption, distribution, metabolism, and excretion) 
of the study drug will be considered. 
10.2.3 Documentation 
All AEs occurring within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 10.2.) 
• AE name or term. 
• When the AE first occurred (start date and time). 
• When the AE stopped (stop date and time or an indication of “ongoing”). 
• Severity of the AE. 
• Seriousness (e.g., hospitalization or death). 
• Actions taken. 
• Outcome. 
• Investigator opinion regarding the AE relationship to the study drug. 
10.2.4 Follow-up of Adverse Events 
Any AE will be followed (up to a maximum of 30 days after the patient’s last dose of study drug 
in the study) to a satisfactory resolution, until it becomes stable, or until it can be explained by 
another known cause(s) (i.e., concurrent condition or medication) and clinical judgment indicates 
that further evaluation is not warranted. All findings relevant to the final outcome of an AE will 
be included in the EDC. Patients who do not receive study drug during the study do not need AEs 
followed after the Final Study Visit. AEs ongoing at the time of database lock should have all 
available information entered into the database and be followed as described in this section in case 
the AE eventually meets SAE criteria. 
All SAEs should be followed until satisfactory resolution, even after database lock.  
10.2.5 SAE Reporting 
10.2.5.1 Serious Adverse Events 
SAEs will be captured from the time ICF is signed until the Final Study Visit.  
The investigator or designee must report all SAEs promptly to IQVIA Biotech safety within 
24 hours of first becoming aware of the event by selecting Serious-Yes on the AE page of the 
eCRF and entering the valid fields as indicated below.  
At the time of first notification, the investigator or designee must provide the following 
information on the AE page of the eCRF for the SAE to be considered valid: 
• Adverse event term 
• Is the event serious- Selected as Yes 
• Seriousness criteria 
• Patient’s date of birth. 
• Patient’s gender. 


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• Initial Causality (Not related, Unlikely related, Possibly related, Probably related, Definitely 
related) 
However, the AE page of the eCRF should be completed in its entirety to ensure that a complete 
SAE Report can be created by IQVIA Biotech Safety. Additional relevant information and missing 
information concerning the SAE should be provided on the AE page of the eCRF. Source 
documentation (e.g., death certificate, autopsy reports) should be provided to IQVIA Biotech 
Safety via email or fax at Safety-inbox.biotech@iqvia.com/1-866-761-1274 (toll-free) or 919-313-
1412 (toll) using Form SM584: Site Fax Cover Sheet Template, when requested. 
In the event the EDC system is not working, the SAE must be reported within 24 hours by 
completing Form SM335: Serious Adverse Event Report Template and submitting to IQVIA 
Biotech Safety via email or fax at Safety-inbox.biotech@iqvia.com/1-866-761-1274 (toll-free) or 
919-313-1412 (toll). 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/Independent Ethics Committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. The detailed reporting duties and division of responsibilities 
between Milestone and designated vendors will be provided in a separate document (see the Safety 
Management Plan). Each investigator is obligated to learn about the reporting requirements for 
investigators in his or her country. The study monitor may be able to assist with this.  
Follow-up 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. 
10.2.5.2 Adverse Drug Reactions 
Milestone will report all ADRs related to the study drug to the proper health authorities; serious 
ADRs will be reported immediately and nonserious ADRs will be reported after completion of the 
study. Suspected serious adverse drug reactions must be reported to Milestone immediately, 
regardless of the time that has elapsed since the end of the period of observation. 
10.2.5.3 Nonserious Adverse Events 
Milestone will review nonserious AEs that are recorded in the eCRF on a regular basis. 
10.3 Special Considerations 
10.3.1 Adverse Events of Special Interest 
Due to the pathophysiology of PSVT, certain arrhythmias may occur as part of the normal course 
of the disease, particularly during the onset and conversion of PSVT episodes.  CMS holter 
abnormalities should be carefully reviewed for type, duration, relation to underlying disease, and 
general clinical context when determining if an AE occurred.  Investigators should consult with 
the medical monitor if they have any questions regarding potential CMS holter abnormalities or 
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Due to the mechanism of action of etripamil, patients could be at a higher risk of certain adverse 
events of special interest. Investigators should be on the alert for these events, or for symptoms 
which indicate an event may be present. An AESI may indicate that a patient should be withdrawn 
from the study and a careful evaluation of any patients with AESI is merited.  Investigators should 
contact the medical monitor if any safety concerns arise. 
Investigators should follow the standard protocol process for AE and SAE reporting for these 
AESI. 
Below is a list of AEs which are of particular interest in this study, if they occur within 24 hours 
of etripamil NS administration.   
List of AESI in the 24 hours after etripamil NS administration; 
• Tachyarrhythmias 
• Bradyarrhythmias 
• AV Block – any degree 
• Hypotension and/or syncope 
10.3.2 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the need 
to practice at least 1 form of adequate birth control and on the importance of avoiding pregnancy 
during study participation. Women should be instructed to contact the investigator or study staff 
immediately if pregnancy occurs or is suspected. Women who plan to become pregnant should not 
enroll, or should discontinue from the study. 
Pregnancy testing will be conducted at the Screening Visit on every woman of childbearing 
potential. A woman who is found to be pregnant at the Screening Visit will be excluded from the 
study and considered to be a screening failure. 
A woman who becomes pregnant during study drug treatment or within 30 days of discontinuing 
the study drug will be immediately discontinued from study participation. The Investigator must 
report the pregnancy within 24 hours of learning of the pregnancy, on Form SM586: Pregnancy 
Report Form Template and email or fax to IQVIA Biotech Safety at Safety-
inbox.biotech@iqvia.com/1-866-761-1274 (toll-free) or 919-313-1412 (toll). The event meets the 
SAE criterion only if it results in a spontaneous abortion or a congenital anomaly.     
Final Study Visit assessments are required as soon as possible after learning of the pregnancy. The 
investigator is also responsible for following the pregnancy until delivery or termination. Follow-
up findings must be reported on the initial Form SM586: Pregnancy Report Form Template 
submitted to IQVIA Biotech Safety and forwarded to IQVIA Biotech Safety via email or fax at 
Safety-inbox.biotech@iqvia.com/1-866-761-1274 (toll-free) or 919-313-1412 (toll). The event 
meets the SAE criterion only if it results in a spontaneous abortion or a congenital anomaly. 
10.3.3 Overdose 
The maximal dose of etripamil NS should not be exceeded during the study, as study drug is 
dispensed for single use only.   
Overdose that occurs during the study will be treated and documented as an AE /SAE if it fulfills 
the criteria. If the overdose does not result in an AE, it should be reported in written form to the 
designated individual(s) who receive SAE notification. The information contained therein should 
include study site identification, reporter identification, patient identification, study drug, dose, 


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action taken (e.g., administration of antidote [if available] or supportive measures or therapy), and 
any comments. 
11. STUDY COMMITTEES 
NODE-303 will be governed by a steering committee (SC) which will periodically review the 
safety data from Study 303 and other ongoing studies. The SC will be responsible for reviewing 
safety data and providing recommendations for alterations to the NODE-303 protocol, study sites, 
metrics, conduct, inclusion and exclusion criteria, and data.  In particular they will review clinical 
and non-clinical data at the milestones identified in Section 12.4.6.  Additional details may be 
found in the SC charter.    
12. STATISTICS 
This section briefly describes the statistical methods to be used to analyze efficacy and safety. 
These methods may be revised and updated due to reasons such as regulatory requirements or need 
for further clarifications. The final analysis plan will be documented in a formal statistical analysis 
plan (SAP) that will be finalized before database lock. The SAP will include details on how 
variables will be derived, how missing data will be handled, and how data will be presented as 
well as the details on statistical methods to be used for safety and efficacy analyses. The final 
clinical study report will discuss deviations from the SAP, if any. 
12.1 Study Endpoints 
12.1.1 Primary Endpoint 
The primary objective of this study is to evaluate the safety of self-administered etripamil NS.  
Efficacy variables will be collected as secondary or exploratory analyses.  
12.1.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are: 
• Number of emergency department visits, or other medical intervention. 
• Number of hospital admissions (including inpatient and outpatient hospitalizations). 
• Characteristics of patients who receive ablation. 
• Concomitant PSVT medication usage. 
• Improvement in patient quality of life, as measured by the PRO scales.   
• Patient satisfaction with treatment, as measured by the Treatment Satisfaction 
Questionnaire for Medication (TSQM-9).  
• Mean and Median time to conversion post etripamil NS administration. 
• Proportion of patients who convert at 3, 5, 10, 15, 20, 30, and 60 minutes after etripamil 
NS administration. 
Exploratory endpoints are: 
• Frequency of PSVT episodes, and use of etripamil NS for those episodes, as captured by 
the PRO. 
• Number of PSVT episodes a patient experiences. 
• Frequency of PSVT episodes. 


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• Number of PSVT episodes terminated by VM. 
• Type of PSVT episodes, number of true PSVT episodes. 
• Duration of PSVT episodes. 
12.1.3 Safety Endpoints 
Safety endpoints include the following: 
• Incidence of AEs. 
• Vital sign measurements. 
• Physical examination findings. 
• Holter recordings from the CMS. 
12.2 Sample Size Determination 
There is no statistical hypothesis in this uncontrolled OL safety study. NODE-303 will continue 
until the end of the development program, i.e., when enough documented self-administrations of 
etripamil NS are included in the safety database. 
It is anticipated that as many as 3000 patients may need to be enrolled in order to accrue a sufficient 
number of patients in the Safety Population within 24 months. 
12.3 Analysis Populations 
The following 4 analysis populations are planned for this study:  
• Overall Population:  All patients enrolled into the study. 
• Safety Population: The Safety Population will be the primary safety analysis population 
and will include all patients who receive any amount of the study drug.  
• Efficacy Population:  The Efficacy Population will include all patients who receive at least 
1 dose of study drug for an episode determined to be PSVT. 
12.4 Statistical Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant.  
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of patients, mean, standard 
deviation (SD), median, minimum, and maximum. For categorical variables, these statistics will 
typically include the number and percentage of patients in each category. 
12.4.1 Study Patients and Demographics 
12.4.1.1 Disposition and Withdrawals 
The numbers of patients screened, entering treatment, taking study drug, completing the study, 
withdrawing from the study, and discontinuing treatment, along with reasons for discontinuation 
or withdrawal, will be tabulated. The number of patients in each analysis population will be 
reported. 
12.4.1.2 Protocol Deviations 
Major protocol deviations will be classified and documented by Milestone before database lock 
and will be discussed in the CSR.  


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12.4.1.3 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, ethnicity, weight, PSVT history, and 
height) will be summarized. Medical history and clinical laboratory tests will be listed. 
Prior and concomitant medications will be summarized by the number and percentage of patients 
taking each medication, classified using World Health Organization Drug Dictionary Anatomical 
Therapeutic Chemical classes and preferred terms. 
12.4.2 Exposure and Compliance 
Study drug administration will be summarized in terms of number of unique patients exposed to 
drug, number of partial doses administered, number of doses taken per episode, and number of 
doses taken per patient. These quantities, including the mean, SD, minimum, and maximum, and 
categorical summary of number of doses will be provided. 
12.4.3 Handling of Missing Data 
Missing data will not be imputed in the trial.  A detailed summary of missing data, or variations in 
data collection across regions or protocol versions will be included in the CSR.  
12.4.4 Efficacy Analyses 
Efficacy variables will be summarized and analyzed using the Efficacy Population unless 
otherwise specified.  Comparisons of available data from patients in the Safety population versus 
the Efficacy Population will be done. 
Additional details are provided in the Statistical Analysis Plan. 
12.4.4.1 Secondary Efficacy Analyses 
• The proportion of patients with PSVT episode related ED visits, PSVT related medical 
interventions, PSVT related hospital admissions, receiving ablations for PSVT, using 
concomitant PSVT medication, and changing use of concomitant PSVT medication will 
be reported.   
• Improvement in patient quality of life will be analyzed as the change in elements and 
overall score in the BIPQ, CAQ, SF-36, and other survey questions over time versus 
baseline. 
• Patient satisfaction will be analyzed via the TSQM-9 numeric scoring scale after dosing 
and over multiple doses. 
• Time to conversion of PSVT will be analyzed as median time from start of CMS recording 
or drug taken marker to PSVT conversion in patients with sufficient CMS data for analysis. 
• Proportions of patients with PSVT who convert at 3, 5, 10, 15, 20, 30 and 60 minutes will 
be analyzed for patients with true PSVT episodes and sufficient CMS data for analysis. 
12.4.4.2 Exploratory Efficacy Analyses 
• Summaries will be presented for characteristics of PSVT episodes such as the frequency, 
number terminated by VM, type of PSVT (including true versus not true PSVT), duration 
of PSVT. 


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12.4.5 Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 12.3).  Data from patients in the Efficacy populations may be presented for comparison of 
key endpoints.   
Safety and tolerability will be assessed through AEs, vital signs measurements, and from the CMS 
recordings.  
No formal statistical comparisons will be performed for safety endpoints. 
12.4.5.1 Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities reporting system. 
The number and percentage of patients with AEs will be displayed for each treatment group by 
SOC and preferred term. Additionally, AEs will be tabulated for each treatment group by severity 
and by relationship to the study drug. A listing of and tabulation of SAEs will be provided. 
Adverse Events will also be analyzed by their timing relative to patient episodes and relative to 
study drug administration.  AEs which occur within 24 hours of an episode (regardless of whether 
study drug is taken) will be referred to as ‘Episode Emergent’ adverse events.  AEs which occur 
within 24 hours of taking study drug will be referred to as ‘Treated Episode Emergent’ adverse 
events.   
12.4.5.2 Clinical Laboratory Evaluations 
Clinical laboratory parameters are utilized primarily as a screening and eligibility procedure.  
Parameters will be categorized as low, normal, or high according to laboratory range 
specifications. 
Laboratory values that are outside the normal range will also be flagged in the data listings, along 
with corresponding normal ranges.   
12.4.5.3 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values will be 
reported for systolic blood pressure, diastolic blood pressure, heart rate, and weight. 
12.4.5.4 Physical Examination Findings 
Physical examination data will be presented in the listings. 
12.4.6 Interim Analyses 
The study will include regular analyses of safety data in NODE-303 and the overall etripamil NS 
development program.  These analyses will be conducted at: 
• The conclusion of the NODE-301 study primary analysis.   
• When data is obtained on at least 125 patients who are greater than 70 years of age, or 
greater than 60 years of age and taking a concomitant PSVT medication across all 
studies, and  
• After every 250 unique patients treated for perceived episodes in NODE-303.  


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Based on the results of these reviews, inclusion/exclusion criteria and study procedures in NODE-
303 will be adapted to broaden or narrow the study population, or to increase/decrease the extent 
of safety data collected. 
As NODE-303 is an open-label safety study, these interim analyses will not have an effect on the 
overall statistical analysis. 
13. INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
13.1 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. 
13.2 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 or authorized CRO. 
13.3 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 or designee 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 or designee 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. If substantial changes are made to the ICF, patients should be re-consented at their next 


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study visit, unless such changes are deemed to have a major impact on potential patient safety in 
which case patients may be asked to re-consent as soon as possible.  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. 
13.4 Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP guidelines, and applicable regulatory 
requirements, and that valid data are entered into the eCRFs. 
To achieve this objective, the CRA’s duties are to aid the Investigator and, at the same time, 
Milestone in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any patient in this study, Milestone or their designee will review with the 
Investigator and site personnel the following: the study protocol, Investigator’s Brochure, eCRFs 
and procedures for their completion, informed consent process, 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. 
13.5 Data Collection 
Data for the NODE-303 study will be collected at the site and entered into the EDC for inclusion 
in the database. Data from the CMS, at-home PRO systems, and Central laboratory will be 
transmitted to the sponsor or designee and integrated into the database prior to official lock.  All 
electronic data collection systems will be designed for 21 CFR Part 11 compliance, with audit trail 
capability.   
This study will be conducted in compliance with applicable regional data privacy and data 
handling regulations and laws. 
13.6 Disclosure of Data 
Data generated by this study must be available for inspection by local regulatory authorities, 
Milestone or their designee, applicable foreign health authorities, and the IRB/IEC as appropriate. 
Patients or their legal representatives may request their medical information be given to their 
personal physician or other appropriate medical personnel responsible for their welfare. 


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Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
13.7 Retention of Records 
To enable evaluations and/or audits from regulatory authorities or Milestone, the Investigator will 
keep records, including the identity of all participating patients (sufficient information to link 
records [e.g., eCRFs and hospital records]), all original signed informed consent forms, copies of 
all eCRFs, SAE forms, source documents, and detailed records of treatment disposition. The 
records will be retained by the Investigator according to specifications in the ICH GCP guidelines, 
local law regulations, or as specified in the clinical study agreement, whichever is longer. The 
Investigator must obtain written permission from Milestone before disposing of any records, even 
if retention requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, Milestone will be 
prospectively notified. The study records must be transferred to an acceptable designee, such as 
another Investigator, another institution, or to Milestone. 
13.8 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. 
13.9 Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with Milestone before any study 
data are submitted for publication. Milestone reserves the right to deny publication rights until 
mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication is achieved. 
13.10 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. 
NODE-303 is sponsored and funded fully by Milestone Pharmaceuticals Inc.   


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14. STUDY ADMINISTRATIVE INFORMATION 
14.1 Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by CRO or the 
Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC, unless immediate implementation of the change is necessary for patient safety.  
Previous Protocol Versions: 
Version 1.0, 21 June 2019  
Version 2.0, 15 February 2021 
14.2 Protocol Authors 
NODE-303 protocol was written and finalized by Milestone Pharmaceuticals employees, with 
external scientific advice provided by the Steering Committee and other experts, consultants, and 
vendors.   
15. FINAL CLINICAL STUDY REPORT 
Milestone will retain ownership of the data generated from the study. 
The final clinical study report will be written within 1 year of completion of the clinical part of the 
study. This report will include a summary of the study results based on a statistical evaluation and 
clinical assessment of the protocol-defined endpoints. 
 


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16. 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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17. ATTACHMENTS 
17.1 Schedule of Assessments 
Table 2. 
Schedule of Procedures 
 
Screening 
Visit 
(within 30 
days of 
baseline)7 
Baseline 
Visit9 
Treatment 
Period1 
Follow-Up 
Visits 
(within 14 
days of 
treated 
episode)10 
Final 
Study 
Visit 
Informed Consent 
X 
 
 
 
 
Eligibility 
X 
X 
 
X 
 
Demographics / medical 
history 
X 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
Physical Exam 
X 
 
 
 
 
Vital signs2 
X 
 
 
X 
X 
Hematology, chemistry, 
urinalysis, urine drug screen8 
X 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
On-site Safety ECG  
X 
 
 
 
 
Patient Training 
 
X 
 
X4 
 
Dispense study kit5 
 
X 
 
X 
 
Apply and Start CMS 
 
 
X 
 
 
Perform VM 
 
 
X 
 
 
Self-administer drug11 
 
 
X 
 
 
PROs6 
 
X 
X 
 
 
TSQM-9 
 
 
X 
 
 
Patient Reminders3 
 
 
X 
 
 
Return used study drug to site 
 
 
 
X 
X 
Review CMS data 
 
 
 
X 
X 
Adverse Events 
 
X 
 
X 
X 
Collect CMS  
 
 
 
 
X 
End of Study eCRF 
Completion 
 
 
 
 
X 
 
 
 
 
 
 
 


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Table 2 
Schedule of Procedures (Continued) 
 
1 Treatment Period assessments are done by the patient in an at-home setting.   
2 Vital signs include blood pressure, heart rate, and weight.  Height to be taken at Screening Visit only. 
3 Sites will call patients who have missed two consecutive PRO surveys to retrain and engage the patient. 
4 At Follow-up Visits, sites will re-train patients who are having issues with their CMS or PRO systems. 
5 Study kit at Baseline will include CMS Device and materials, two study drug kits, study identification 
card and any paper training or PRO materials required or requested. Study kits at Follow-up will include 
two study drug kits, additional CMS materials, and any paper training or PRO materials required or 
requested. 
6 PROs are administered via Phone or Tablet application.  PROs include a) Baseline Survey to be done on 
site at Baseline; b) the BIPQ, CAQ, and SF-36 done within 48 hours of Baseline and every 6 months 
thereafter; c) a Monthly Survey done each month after Baseline; d) a Per Episode Survey done for each 
episode regardless of whether or not a patient takes drug; e) the TSQM-9 done after each episode where 
the patient takes drug. 
7 Screening and Baseline Visits can be incorporated into one visit for purposes of avoiding an extra on-
site visit in extenuating circumstances. 
8 Blood / urine samples can be analysed locally for purposes of preliminary enrolment if 
Screening/Baseline Visits are combined; samples also to be sent to Central lab. Central lab results will 
allow enrollment in study. 
9 Baseline Visit can be conducted with Screening Visit for purposes of avoiding an extra on-site visit in 
extenuating circumstances. 
10 Follow-up Visits can be conducted within up to 60 days of treated episode in extenuating 
circumstances. 
11 Patients should self-administer one dose, wait 10 minutes, and self-administer a repeat dose if PSVT 
symptoms persist.  
 
 
 
 
 


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APPENDICES 
A. Address List 
B. Regulations and Good Clinical Practice Guidelines 
 
 


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A. Address List 
Study personnel and site addresses to be kept in the Trial Master File 
 
 


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B. Regulations and Good Clinical Practice Guidelines 
1. 
Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Patients 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
Refer to the following European Directives [and applicable regulations/guidances]: 
• European Directive 2001/20/EC and related guidance documents 
• European Directive 2005/28/EC and related guidance documents 
2. 
Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/LOB/media/MEDIA482.pdf 
 

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 


Milestone Pharmaceuticals Inc.  
MSP-2017-1158 NODE-302 
CONFIDENTIAL 
V1.0 
Statistical Analysis Plan 
  
27 Aug 2021 
 
Page 23 of 24 
 
7. Extremely Satisfied 
 
 


Milestone Pharmaceuticals Inc.  
MSP-2017-1158 NODE-302 
CONFIDENTIAL 
V1.0 
Statistical Analysis Plan 
  
27 Aug 2021 
 
Page 24 of 24 
 
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.