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

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ClinicalTrials.gov Identifier: NCT03464019
Recruitment Status : Recruiting
First Posted : March 13, 2018
Last Update Posted : August 30, 2019
Sponsor:
Collaborator:
Medpace, Inc.
Information provided by (Responsible Party):
Milestone Pharmaceuticals Inc.

Brief Summary:
The primary objective of this study is to determine whether etripamil nasal spray (NS) 70 mg is superior to placebo at terminating episodes of PSVT in an outpatient setting.

Condition or disease Intervention/treatment Phase
Paroxysmal Supraventricular Tachycardia Drug: Etripamil Drug: Placebo Device: Aptar Pharma Nasal Spray Phase 3

Detailed Description:

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 will comprise of 2 parts, Part 1 and Part 2. Part 1 will consist of patients that will be dosed with the double-blind study drug or have discontinued the study before the adjudication of the 150th positively adjudicated PSVT episode. The data from patients in Part 1 will be cleaned and locked, on a per-patient basis, and will be included in pivotal analyses. Pivotal analyses will include safety; and primary, secondary, and exploratory efficacy analyses for Part 1 only. Patients in Part 1 will be unblinded after data is locked.

Part 2 will consist of patients that will not be included in Part 1, i.e., Part 2 will consist of patients who were not dosed with the double-blind study drug or have not discontinued the study before the adjudication of the 150th positively adjudicated PSVT episode. The data from patients in Part 2 will be combined with that from Part 1 and will be included in exploratory analyses. Exploratory analyses will include safety; and primary, secondary, and exploratory efficacy analyses for Parts 1 and 2 combined. Patients in Part 2 will be unblinded at the end of the study. Part 2 will end when one of the following criteria is met:

  • 75% of patients in Part 2 have completed the study (Final Study Visit), or
  • Approximately 9 months after the date of the adjudication of the 150th positively adjudicated PSVT episode.

Based on the results of the pivotal analyses from Part 1, the planned statistical analysis and conduct of Part 2 may be amended. However, in no case will the Part 2 dataset be integrated with the Part 1 pivotal dataset for primary efficacy or primary safety analyses.

The study will include a Screening Visit, a Test Dose Randomization Visit, Follow-up Visits, a Treatment Period, and a Final Study Visit.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia. The NODE-301 Trial.
Actual Study Start Date : June 18, 2018
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020

Arm Intervention/treatment
Experimental: Etripamil

The dose of etripamil to be evaluated in NODE-301 is 70 mg. Patients will receive a total of 200 μL of etripamil Nasal Spray 70 via the Aptar Pharma Nasal Spray Bidose System.The devices will be prefilled and packaged into child-resistant boxes and instructions for its use will be provided in the study drug box.

The same formulation will be used for the Test Dose Randomization Visit and for the Treatment Period.

Drug: Etripamil
Etripamil will be administered via the Aptar Pharma Nasal Spray Bidose System.

Device: Aptar Pharma Nasal Spray
Study drug and placebo will be administered via the Aptar Pharma Nasal Spray.

Placebo Comparator: Placebo
Patients will receive a total of 200 μL of placebo via the Aptar Pharma Nasal Spray Bidose System.The devices will be prefilled and packaged into child-resistant boxes and instructions for its use will be provided in the study drug box.
Drug: Placebo
Placebo will be administered via the Aptar Pharma Nasal Spray Bidose System.

Device: Aptar Pharma Nasal Spray
Study drug and placebo will be administered via the Aptar Pharma Nasal Spray.




Primary Outcome Measures :
  1. The time to conversion of an episode of PSVT to sinus rhythm (SR) after study drug administration. [ Time Frame: 10 months ]
    The primary efficacy endpoint is defined as an adjudicated termination of a positively adjudicated episode of PSVT (AV nodal reentrant tachycardia or AV reentrant tachycardia determination if possible) and conversion to sinus rhythm (SR) for at least 30 seconds.


Secondary Outcome Measures :
  1. Relief of specific symptoms (i.e., heart palpitations, rapid pulse feeling, chest pain, anxiety, shortness of breath, dizziness, and fainting) potentially associated with an episode of PSVT. [ Time Frame: 10 months ]
  2. Rating of Treatment Satisfaction Questionnaire for Medication (TSQM). [ Time Frame: 10 months ]

Other Outcome Measures:
  1. The number of positively adjudicated episodes of PSVT terminated by a vagal maneuver (VM). [ Time Frame: 10 months ]
  2. The percentage of patients requiring additional medical intervention to terminate an episode of PSVT. [ Time Frame: 10 months ]
  3. The repeat of key efficacy endpoints in various subgroups of interest (e.g., concomitant medications). [ Time Frame: 10 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female patients at least 18 years of age;
  2. Electrographically documented history of PSVT (e.g., electrocardiogram [ECG] obtained during an episode of PSVT, Holter monitoring, loop recorder, etc). If patient had a prior ablation for PSVT, patient must have documented ECG evidence of PSVT post-ablation;
  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. Females who are pregnant or lactating;
  15. Evidence or history of any significant physical or psychiatric condition including drug abuse, which, in the opinion of the Investigator, could jeopardize the safety of patients, or affect their participation in the study. Additionally, the Investigator has the ability to exclude a patient if for any reason the Investigator judges the patient is not a good candidate for the study or will not be able to follow study procedures;
  16. 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 new significant ventricular arrhythmia (premature ventricular beats and couplets [>6 premature ventricular contractions per 45 seconds ECG] are considered significant); and
  7. Atrial fibrillation or atrial flutter (event lasting longer than 30 seconds).

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

  • If the Investigator identifies a possible reversible cause of the initial test dose failure (e.g., concomitant medication such as beta-blocker), a re-challenge with a new test dose of etripamil NS 70 mg will be possible after elimination of the reversible cause (e.g., withdrawal of concomitant therapy with the appropriate washout period). Patients may be randomized if they pass the second test dose and the cause of the test dose failure is eliminated for the duration of the study; or
  • If the Investigator cannot identify a reversible cause of the initial test dose failure, or if the potential cause cannot be modified (e.g., necessary antihypertensive drug to control blood pressure), patients will not be randomized and will complete a Final Study Visit. Patients who fail the test dose will be part of the Test Dose Only Population, including all patients who received at least 1 test dose of etripamil NS 70 mg

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03464019


Contacts
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Contact: Douglas Wight +1-514-336-0444 ext 226 dwight@milestonepharma.com
Contact: Francis Plat 1-514-336-0444 ext 225 fplat@milestonepharma.com

  Show 70 Study Locations
Sponsors and Collaborators
Milestone Pharmaceuticals Inc.
Medpace, Inc.

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Responsible Party: Milestone Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03464019     History of Changes
Other Study ID Numbers: MSP-2017-1138
First Posted: March 13, 2018    Key Record Dates
Last Update Posted: August 30, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Milestone Pharmaceuticals Inc.:
Paroxysmal supraventricular tachycardia
cardiac monitoring
atrioventricular nodal reentrant tachycardia
atrioventricular reciprocating tachycardia
calcium channel blocker
conversion rate
Additional relevant MeSH terms:
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Tachycardia
Tachycardia, Supraventricular
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Cardiac Conduction System Disease
Pathologic Processes