Paroxysmal Supraventricular Tachycardia (PSVT)
Conditions
Brief summary
The primary objective of this study is to demonstrate the superiority of at least 1 dose of intranasal (IN) MSP-2017 (Etripamil) over placebo in terminating PSVT induced in an electrophysiology (EP) laboratory.
Detailed description
This is a multi-center, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the effects of 4 different doses of MSP-2017 (Etripamil) in subjects with paroxysmal supraventricular tachycardia. It includes an up to 21-day Screening Period, a 1-day Treatment Visit, and either a Follow-up Visit or Early Termination Visit occurring 12 hours to 5 days after the Treatment Visit. Subjects will be randomized to yield at least 100 evaluable subjects distributed into 5 groups of at least 20 subjects each.
Interventions
DRUGEtripamil
intranasal administration via 4 prefilled Aptar Pharma Unit-Dose Spray devices
DRUGPlacebo
intranasal administration via 4 prefilled Aptar Pharma Unit-Dose Spray devices
Sponsors
Medpace, Inc.
Milestone Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
If, during the double-blind study, PSVT could not be induced, the mechanism of PSVT was neither atrioventricular (AV) reentrant tachycardia (AVRT) nor AV nodal reentrant tachycardia (AVNRT), or it was not possible to sustain an episode of PSVT for 5 minutes in a subject who previously provided written informed consent for substudy participation, the subject was eligible to participate in the optional open-label substudy.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, aged 18 years and older at Screening * Has a history of PSVT * Is scheduled for an electrophysiology study and catheter ablation * Has provided written informed consent * Agrees to use a medically accepted form of contraception or abstinence to prevent pregnancy. Males must agree to use an acceptable form of contraception or abstinence from the time of study drug administration through the Follow-up Visit. Females must agree to use an acceptable form of contraception or abstinence from Screening until 30 days following study drug administration. Post-menopausal female subjects must be amenorrheic for ≥ 12 months prior to Screening or ≥ 6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) prior to Screening, if they do not wish to use an acceptable form of contraception or abstinence. Acceptable forms of contraception include: A condom and an intrauterine device; A condom and hormonal contraception; A condom and a diaphragm; Sterilization of the subject or the subject's partner(s) (sterilization procedure must have been performed 3 or more months prior); Hysterectomy of the subject or the subject's partner(s) * If a female of childbearing potential: Has a negative serum pregnancy test result at Screening (Screening must occur ≥7 days prior to randomization \[ie, on or before Day -7\]) and at the Treatment Visit (pre-PSVT induction); Has had a menstrual period within 28 days of the Treatment Visit.
Exclusion criteria
* Has a history of serious allergic reaction to verapamil (especially when administered intravenously) including rash, itching or swelling (especially of the face, tongue, or throat), severe dizziness, or trouble breathing * Is currently participating in another drug or device study, or has received an investigational drug or device within 30 days of Screening * Has evidence of clinically significant cardiovascular, endocrine, gastrointestinal, hematologic, hepatic, immunologic, neurologic, oncologic, pulmonary, psychiatric, or renal disease or any other condition which, in the opinion of the Investigator, would jeopardize the safety of the subject or impact the validity of study results * Is a female who is breast feeding, pregnant, or planning to become pregnant during the study period * Has evidence of any clinically significant acute or chronic condition of the nasal cavity (e.g., rhinitis or deviated septum) which could interfere with IN administration of the study drug in either or both nasal cavities * Has any of the following at screening or at the Treatment Visit: Systolic blood pressure \<100 mmHg, Diastolic blood pressure \<50 mmHg * Has evidence of hepatic impairment, defined as: Alanine aminotransferase or aspartate aminotransferase levels that are greater than or equal to 3× upper limit of normal (ULN) or Bilirubin levels that are greater than or equal to 2× ULN, unless due to Gilbert's syndrome * Has evidence of renal impairment, defined as an estimated glomerular filtration rate \<30 mL/min (Modification of Diet in Renal Disease method) * Has taken digoxin, verapamil, diltiazem, or any Class I, II (e.g., beta blockers), or III antiarrhythmic drug less than the equivalent of 5 half-lives of this drug prior to the Treatment Visit * Has taken amiodarone within 30 days of the Treatment Visit * Has taken drugs of abuse which, in the opinion of the Investigator, would impact the validity of study results * Has had myocardial infarction, percutaneous coronary intervention, cerebrovascular accident, transient ischemic attack, unstable angina, or acute decompensation of heart failure within 6 months of Screening * Has a history or evidence of second- or third-degree atrioventricular block * Has an implanted device (e.g., pacemaker, or implantable cardioverter defibrillator) that precludes study participation in the opinion of the Investigator and Study Medical Monitor * Has a history or evidence of preexcitation syndrome (e.g., Wolff-Parkinson- White syndrome, short PR, etc.) * Has evidence of a QT interval (Bazett's correction) (QTcB) \>455 milliseconds at Screening or at the Treatment Visit * Has a history or evidence of familial long QT syndrome, torsades de pointes, ventricular fibrillation, sustained ventricular tachycardia, Brugada syndrome, or sudden cardiac death * Has evidence of recurrent or chronic atrial tachycardia, atrial flutter, or atrial fibrillation; that could interfere with the current investigation; or * Has a history or evidence of congestive heart failure (except New York Heart Association Class I) or pulmonary edema In addition, randomized subjects who meet any of the following criteria at the Treatment Visit (Day 1) prior to study drug administration, will be excluded from participation in the study: * PSVT cannot be induced or the mechanism of PSVT is neither Atrioventricular reentrant tachycardia (AVRT) nor Atrioventricular nodal reentry tachycardia (AVNRT) * It is not possible to sustain an episode of PSVT for 5 minutes * The subject requires a continuous sedative (e.g., propofol), continuous analgesic, or inhaled anesthetic at any point until time 30. Minimally necessary dose(s) of benzodiazepine(s) (e.g., midazolam) and/or narcotic(s) (e.g., fentanyl) (given via single or multiple administration\[s\]) may be used at the Investigator's discretion. The identity(-ies) and actual administered dose(s) of any benzodiazepine(s) and/or narcotic(s) should be recorded in the study documentation. Local anesthetic(s) may be used at the Investigator's discretion; any use should be recorded in the study documentation * The subject has undergone prior ablation, and the subject's atrioventricular node function is abnormal in the opinion of the Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration | Within 15 minutes of study drug administration | The primary efficacy endpoint was the rate of successful PSVT conversion to sinus rhythm lasting at least 30 seconds within 15 minutes of study drug administration after a minimum of 5 minutes in sustained PSVT. |
Countries
Canada, United States
Participant flow
Recruitment details
Adults aged 18 years and older with Paroxysmal supraventricular tachycardia (PSVT) who met the study inclusion/exclusion criteria. Study was initiated on March 27, 2015 and completed on December 8, 2016 and was performed in electro-physiology clinics in the USA and Canada.
Participants by arm
| Arm | Count |
|---|---|
| Etripamil_140 mg 1 dose of Etripamil via 4 prefilled Aptar Pharma Unit-Dose Nasal Spray devices. | 21 |
| Etripamil_105 mg 1 dose of Etripamil via 4 prefilled Aptar Pharma Unit-Dose Nasal Spray devices. | 20 |
| Etripamil_70 mg 1 dose of Etripamil via 4 prefilled Aptar Pharma Unit-Dose Nasal Spray devices. | 23 |
| Etripamil_35 mg 1 dose of Etripamil via 4 prefilled Aptar Pharma Unit-Dose Nasal Spray devices. | 20 |
| Placebo 1 dose of Placebo via 4 prefilled Aptar Pharma Unit-Dose Nasal Spray devices. | 20 |
| Open- Label Etripamil 70 mg 1 dose of Etripamil via 4 prefilled Aptar Pharma Unit-Dose Nasal Spray devices. | 9 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Atrial Tachycardia induced not PSVT | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Blood pressure <100 after sedation | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Failed PSVT with mechanism of AVNRT | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Failure to induce PSVT | 6 | 10 | 5 | 13 | 8 | 0 |
| Overall Study | Lab result not available in time | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Patient on antiarrhythmic medication | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Patient was given Propofol | 0 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Patient with Atrial Tachycardia | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 0 | 1 | 2 | 0 |
| Overall Study | PSVT < 5 minutes | 5 | 6 | 6 | 6 | 5 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Open- Label Etripamil 70 mg | Placebo | Etripamil_140 mg | Etripamil_35 mg | Etripamil_105 mg | Etripamil_70 mg |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 0 Participants | 2 Participants | 7 Participants | 1 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 96 Participants | 9 Participants | 18 Participants | 14 Participants | 19 Participants | 17 Participants | 19 Participants |
| Race/Ethnicity, Customized ASIAN | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 14 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized OTHER | 7 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized WHITE | 91 Participants | 7 Participants | 18 Participants | 17 Participants | 17 Participants | 14 Participants | 18 Participants |
| Region of Enrollment Canada | 26 participants | 0 participants | 4 participants | 4 participants | 7 participants | 7 participants | 4 participants |
| Region of Enrollment United States | 78 participants | 9 participants | 16 participants | 17 participants | 13 participants | 13 participants | 19 participants |
| Sex: Female, Male Female | 65 Participants | 6 Participants | 10 Participants | 13 Participants | 14 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Male | 48 Participants | 3 Participants | 10 Participants | 8 Participants | 6 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 20 | 0 / 23 | 0 / 20 | 0 / 20 | 0 / 9 |
| other Total, other adverse events | 20 / 21 | 14 / 20 | 18 / 23 | 17 / 20 | 4 / 20 | 7 / 9 |
| serious Total, serious adverse events | 0 / 21 | 3 / 20 | 0 / 23 | 0 / 20 | 1 / 20 | 0 / 9 |
Outcome results
Primary
The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration
The primary efficacy endpoint was the rate of successful PSVT conversion to sinus rhythm lasting at least 30 seconds within 15 minutes of study drug administration after a minimum of 5 minutes in sustained PSVT.
Time frame: Within 15 minutes of study drug administration
Population: The efficacy analysis was based on the Evaluable Population which included all randomized subjects who were induced and sustained Supraventricular tachycardia (SVT) for 5 minutes, received the study drug, and completed the assessment of conversion to sinus rhythm.~The Open- Label Etripamil 70 mg group was not part of the Evaluable Population, as the subjects did not meet the criteria of having sustained Supraventricular tachycardia (SVT) for 5 minutes.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Etripamil_140 mg | The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration | 20 Participants |
| Etripamil_ 105 mg | The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration | 15 Participants |
| Etripamil_70 mg | The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration | 20 Participants |
| Etripamil_35 mg | The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration | 13 Participants |
| Placebo | The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration | 7 Participants |
Comparison: Statistical analysis was performed with the Fisher's exact test to compare the conversion rate between the MSP-2017 groups and the placebo group.p-value: <0.05Fisher Exact