Efficacy and Safety of Etripamil for the Termination of Spontaneous PSVT. NODE-301

NODE-301 is a multi-centre, randomized, double-blind, placebo-controlled study to evaluate
the efficacy and safety of a nasal spray of etripamil, a new calcium channel blocker, in
patients who experience an episode of paroxysmal ventricular tachycardia (PSVT).

The study includes a Screening Visit during which prospective study patients suffering
episodes of PSVT will sign the informed consent form. All patients will receive a test dose
of etripamil nasal spray 70 mg to evaluate the tolerability of etripamil under medical
supervision including continuous ECG. A patient will be randomized only if the test dose is
well tolerated.

All the randomized patients will be trained to recognize the symptoms of PSVT, perform a
vagal maneuver, and self-administer the nasal spray study drug to terminate the episode of
PSVT. The patient will place an ambulatory cardiac monitoring system (CMS) on the chest at
the onset of symptoms to record at least 5 hours of continuous ECG and document the
tachycardia and its termination. A Final Study Visit will occur at the study site within 7
days after the episode to evaluate the clinical effects of the study drug and to review the
report of the CMS data.

Follow-up Visits will occur approximately monthly from the time of randomization and will be
conducted in person at the site or by telephone.

Inclusion Criteria:

1. Male or female patients at least 18 years of age

2. Electrographically documented history of PSVT (e.g., ECG obtained during an episode of
PSVT, Holter monitoring, or loop recorder, etc.)

3. History of sustained episodes of PSVT (i.e., typically lasting approximately 20
minutes or longer)

4. Females of childbearing potential must agree to use an approved highly effective form
of contraception from the time of signed informed consent until 30 days after the last
administration of study drug and should have a negative serum pregnancy test result at
the Screening Visit, a negative urine pregnancy test at the Test Dose Randomization
Visit and must use an approved form of contraception between the 2 visits. Approved
forms of contraception include hormonal intrauterine devices, hormonal contraceptives
(oral birth control pills, Depo-Provera®, patch, or other injectables) together with
supplementary double-barrier methods, such as condoms or diaphragms with spermicidal
gel or foam.

The following categories define females who are NOT considered to be of childbearing
potential:

- Premenopausal females with 1 of the following:

1. Documented hysterectomy,

2. Documented bilateral salpingectomy, or

3. Documented bilateral oophorectomy, or

- Postmenopausal females, defined as having amenorrhea for at least 12 months
without an alternative medical cause;

5. Males, except those who are surgically sterile, must use an approved highly effective
form of contraception during the 3 days after any study drug administration; and

6. Signed written informed consent.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from participation in the
study:

1. Systolic blood pressure <90 mmHg after a 5-minute rest in sitting position at the
Screening Visit or before the test dose. In patients treated with a chronic
prophylactic drug for PSVT (e.g., beta-blockers, verapamil, and diltiazem), the drug
may be stopped for at least the equivalent of 5 half-lives and patients may be
rescreened once

2. History of severe symptoms of hypotension, especially syncope, during episodes of PSVT

3. History of atrial arrhythmia that does not involve the AV node as part of the
tachycardia circuit (e.g., atrial fibrillation, atrial flutter, intra-atrial
tachycardia)

4. History of allergic reaction to verapamil

5. Current therapy with digoxin or any Class I or III antiarrhythmic drug, except if
these drugs are stopped at least the equivalent of 5 half-lives before the Test Dose
Randomization Visit

6. Current therapy with amiodarone, or have taken amiodarone within 30 days prior to the
Test Dose Randomization Visit

7. Evidence of ventricular pre-excitation (e.g., delta waves, short PR interval <100
msec, Wolff-Parkinson-White syndrome) on the ECG performed at the Screening Visit or
before the test dose administration

8. Evidence of a second- or third-degree AV block on the ECG performed at the Screening
Visit or before the test dose administration

9. History or evidence of severe ventricular arrhythmia (e.g., torsades de pointes,
ventricular fibrillation, or sustained ventricular tachycardia)

10. Current congestive heart failure defined by the New York Heart Association Class II to
IV

11. Stroke in the last 6 months

12. Evidence of hepatic dysfunction defined as alanine aminotransferase or aspartate
aminotransferase >3 × the upper limit of normal (ULN) or total bilirubin >2 × ULN at
the Screening Visit, unless due to Gilbert syndrome;

13. Evidence of renal dysfunction as determined by an estimated glomerular filtration rate
assessed at the Screening Visit as follows:

1. <60 mL/min/1.73 m2 for patients <60 years of age;

2. <40 mL/min/1.73 m2 for patients ≥60 and <70 years of age; or

3. <35 mL/min/1.73 m2 for patients ≥70 years of age;

14. Evidence or history of any significant physical or psychiatric condition including
drug abuse, which, in the opinion of the Investigator, could jeopardize the safety of
patients, or affect their participation in the study. Additionally, the Investigator
has the ability to exclude a patient if for any reason the Investigator judges the
patient is not a good candidate for the study or will not be able to follow study
procedures

15. Current participation in any investigational drug or device study or the use of any
investigational drug or device within 30 days of the Screening Visit.

Before randomization, all patients will receive a test dose of etripamil NS 70 mg to
evaluate tolerability and to train patients for the procedures. A failure of the test dose
is considered if patients meet any of the following criteria occurring after administration
of the etripamil NS 70 mg test dose:

1. Any symptoms consistent with clinically severe hypotension such as pre-syncope,
medically significant lightheadedness, syncope, nausea, or vomiting;

2. For patients with a pre-test dose Systolic Blood Pressure above 100 mmHg:

1. Decrease in SBP ≥40 mmHg after test dose; or

2. Post-test dose SBP <80 mmHg;

3. For patients with a pre-test dose SBP between 90 mmHg and 100 mmHg (inclusive):

a) Post-test dose SBP <75 mmHg;

4. Third-degree AV block, Mobitz II second-degree AV block, or Wenckebach with
bradycardia ≤40 bpm;

5. New, significant sinus bradycardia Heart Rate ≤40 bpm or sinus pauses (≤3 seconds), if
considered by the Investigator to put the patient's safety at risk if either were to
occur while not under medical supervision;

6. Any significant ventricular arrhythmia (premature ventricular beats and couplets [>6
premature ventricular contractions per 45 seconds ECG] are considered significant);
and

7. Atrial fibrillation (event lasting longer than 30 seconds).

Patients who fail the test dose will proceed in the study as follows:

- If the Investigator identifies a possible reversible cause of the initial test dose
failure (e.g., concomitant medication such as beta-blocker), a re-challenge with a new
test dose of etripamil NS 70 mg will be possible after elimination of the reversible
cause (e.g., withdrawal of concomitant therapy with the appropriate washout period).
Patients may be randomized if they pass the second test dose and the cause of the test
dose failure is eliminated for the duration of the study; or

- If the Investigator cannot identify a reversible cause of the initial test dose
failure, or if the potential cause cannot be modified (e.g., necessary
antihypertensive drug to control blood pressure), patients will not be randomized and
will complete a Final Study Visit. Patients who fail the test dose will be part of the
Test Dose Population, including all patients who received at least 1 test dose of
etripamil NS 70 mg