Paroxysmal Supraventricular Tachycardia
Conditions
Keywords
PSVT
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.
Interventions
DRUGEtripamil NS
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.
Sponsors
IQVIA Biotech
Milestone Pharmaceuticals Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
A participant was eligible for study participation if they met all of the following criteria: 1. Had been diagnosed with PSVT by a medical professional, and reported having at least one previous episode of PSVT. For clarity, PSVT referred to episodic Supraventricular Tachycardia (SVT) that included the atrioventricular (AV) node as a critical part of reentrant circuit. 2. Was at least 18 years of age; 3. Signed NODE-303 written informed consent 4. Women of childbearing potential had to be willing to use at least 1 form of contraception during the trial, and had to be willing to discontinue from the study should they have become or planned to become pregnant. Postmenopausal females were 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
Exclusion criteria
A participant was excluded from the study if they met any of the following criteria: 1. Participants with only a history of atrial arrhythmia that did not involve the atrioventricular (AV) node as part of the tachycardia circuit (e.g. atrial fibrillation, atrial flutter, intra-atrial tachycardia) were not eligible. Participants with a history of these tachycardias who were also diagnosed with PSVT were eligible. 2. History of allergic reaction to verapamil 3. Current therapy with digoxin, or any Class I or III antiarrhythmic drug. Participants could be eligible if these drugs were stopped at least five half-lives before the administration of etripamil NS. The only exception was amiodarone which had to 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 participant, or impede the participant'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. Was 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 Acute Coronary Syndrome (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: 1. \<60mL/min/1.73m2 for participants \<60 years of age; 2. \<40mL/min/1.73m2 for participants ≥60 and \<70 years of age 3. \<35mL/min/1.73m2 for participants ≥70 years of age
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events for Self-administered Etripamil NS Outside of the Clinical Setting. | From Baseline until a maximum of 4 episodes of perceived PSVT are treated with study drug, up to a maximum duration of 40 months. | Number of participants with any adverse events experienced from baseline up to the final study visit including the treatment of up to 4 perceived PSVT episodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Conversion | Time to conversion up to 60 minutes after etripamil administration. | Kaplan-Meier estimates of time to conversion up to 60 minutes after etripamil administration for adjudicated conversion of confirmed episodes of PSVT to SR (Sinus Rhythm) reported at Follow-up Visit 1. |
Countries
Argentina, Brazil, Canada, Colombia, United States
Participant flow
Recruitment details
To enroll participants in the study, a diagnosis of PSVT by a medical professional and history of at least one previous episode of PSVT were required. The first participant was enrolled on September 23, 2019 and the last participant was enrolled on October 27, 2022.
Pre-assignment details
Participants had to meet all inclusion criteria and none of the exclusion criteria to be enrolled in the study. At baseline, the participants received the CMS, the study drug, and instructions on what to do when they started to feel the symptoms of PSVT.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants self-administered etripamil NS 70 mg and after the implementation of protocol amendment 2.1, the participants had the option to administer a second dose of etripamil 70 mg 10 minutes later, if PSVT symptoms persisted.
Considering this is an event-driven study, not all participants experienced a PSVT and could administered the study drug before the study was completed. This arm/group includes all participants that were enrolled in the study. | 1,116 |
| Total | 1,116 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ablation | 97 |
| Overall Study | Adverse Event | 25 |
| Overall Study | Death | 11 |
| Overall Study | Lost to Follow-up | 39 |
| Overall Study | Missing | 5 |
| Overall Study | Overall trial ended | 603 |
| Overall Study | Participant felt the drug did not work | 8 |
| Overall Study | Participant no longer meets the inclusion/exclusion criteria | 38 |
| Overall Study | Participant non-compliance / Protocol violation(s) | 25 |
| Overall Study | Participant tolerability | 5 |
| Overall Study | Participant wanted to try other therapy or treatment | 34 |
| Overall Study | Participant withdrawn due to COVID-19 situation | 4 |
| Overall Study | Physician Decision | 50 |
| Overall Study | Pregnancy | 3 |
| Overall Study | Withdrawal of consent | 66 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous Age at first diagnosis of PSVT | 48.3 years STANDARD_DEVIATION 16.2 |
| Age, Continuous Age at informed consent signed | 54.3 years STANDARD_DEVIATION 14 |
| Age, Customized Age at informed consent signed 18 to < 60 years | 695 Participants |
| Age, Customized Age at informed consent signed 60 to < 70 years | 263 Participants |
| Age, Customized Age at informed consent signed ≥ 70 years | 158 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 396 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 696 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 24 Participants |
| Height | 167.2 cm STANDARD_DEVIATION 9.4 |
| Number of participant-reported emergency department visits since diagnosis | 3.5 emergency department visits STANDARD_DEVIATION 6.3 |
| Number of participant-reported PSVT episodes in the past year | 8.6 episodes STANDARD_DEVIATION 16.5 |
| Number of participant-reported urgent care visits since diagnosis | 5.0 urgent care visits STANDARD_DEVIATION 11.2 |
| Number of participant-reported visits to doctor's office since diagnosis | 5.0 visits to doctor's office STANDARD_DEVIATION 10.2 |
| Number of participant-reported visits to the arrhythmia clinic / day hospital since diagnosis | 5.0 visits to the arrhythmia clinic/day hosp STANDARD_DEVIATION 13.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 8 Participants |
| Race (NIH/OMB) Asian | 30 Participants |
| Race (NIH/OMB) Black or African American | 57 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 106 Participants |
| Race (NIH/OMB) White | 913 Participants |
| Sex: Female, Male Female | 762 Participants |
| Sex: Female, Male Male | 354 Participants |
| Time since first PSVT diagnosis | 6.2 years STANDARD_DEVIATION 8.9 |
| Weight | 82.3 Kg STANDARD_DEVIATION 21.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 503 | 7 / 613 |
| other Total, other adverse events | 237 / 503 | 32 / 613 |
| serious Total, serious adverse events | 34 / 503 | 22 / 613 |
Outcome results
Primary
Number of Participants With Adverse Events for Self-administered Etripamil NS Outside of the Clinical Setting.
Number of participants with any adverse events experienced from baseline up to the final study visit including the treatment of up to 4 perceived PSVT episodes.
Time frame: From Baseline until a maximum of 4 episodes of perceived PSVT are treated with study drug, up to a maximum duration of 40 months.
Population: The Safety Population includes all participants who self-administered any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Etripamil | Number of Participants With Adverse Events for Self-administered Etripamil NS Outside of the Clinical Setting. | 324 Participants |
Secondary
Time to Conversion
Kaplan-Meier estimates of time to conversion up to 60 minutes after etripamil administration for adjudicated conversion of confirmed episodes of PSVT to SR (Sinus Rhythm) reported at Follow-up Visit 1.
Time frame: Time to conversion up to 60 minutes after etripamil administration.
Population: The Efficacy Population includes participants who received study drug for an event confirmed as PSVT by the Sponsor's medical review of the ECG CMS data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Etripamil | Time to Conversion | 17.7 minutes |