The primary objective of the RAPID study is to determine whether etripamil nasal spray (NS) self-administered by patients is superior to placebo at terminating episodes of PSVT in an at-home setting.The secondary objective of this study is to…
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Brief title
Condition
- Cardiac arrhythmias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is defined as time to an adjudicated termination
of a positively adjudicated episode of PSVT and conversion to SR for at least
30 seconds within 30 minutes of start of study drug dosing.
Secondary outcome
Additional efficacy endpoints include:
• Time to conversion at time points prior to, and later than, 30 minutes;
• Time to conversion in patients with the option of repeat administration;
• The percentage of patients requiring additional medical intervention in
emergency department to terminate an episode of PSVT
• 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;
• Rating of TSQM;
• The repeat of key efficacy endpoints in various subgroups of interest (e.g.,
concomitant medications).
During the etripamil test dose period, vital signs, SBP, DBP, HR measurements,
arrhythmia, conduction disorders on the ECGs, and clinical AEs will be
recorded. These data will be reported in the Overall Safety Population.
During the Treatment Periods, safety variables will be recorded, as detailed in
Sections 6.5 and 6.7 of the protocol.
Background summary
Etripamil, 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),
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. 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. 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. However, it has been
replaced in recent years by IV adenosine, which is equally effective in
terminating acute episodes of PSVT. 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. 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.
Study objective
The primary objective of the RAPID study is to determine whether etripamil
nasal spray (NS) self-administered by patients is superior to placebo at
terminating episodes of PSVT in an at-home setting.
The secondary objective of this study is to evaluate the safety of etripamil
when self administered by patients without medical supervision.
The exploratory objectives of the study are:
• To evaluate the safety, hemodynamic, and cardiac conduction effects of a test
dose of etripamil NS,
• To evaluate the safety and efficacy of etripamil NS in various subgroups of
interest (e.g., concomitant medications), and
• To evaluate the safety and efficacy of a treatment regimen of etripamil NS
which allows a repeat dose of etripamil to terminate episodes of PSVT in an
at-home setting.
Study design
NODE-301 is a multi-centre, randomized, double-blind, placebo-controlled study
to evaluate the efficacy and safety of etripamil NS self-administered by
patients who experience an episode of PSVT in an at-home setting. Each episode
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. Each CMS will be identified by a unique number.
The study will comprise of 2 parts, Part 1 and Part 2.
• Part 1 describes the conduct of NODE-301 up to the date of the adjudication
of the 150th positively adjudicated PSVT episode (January 15th, 2020).
• Part 2 describes the conduct of NODE-301 following the completion of Part 1.
NODE-301 - Part 1
Part 1 was conducted under protocol versions 1 through 5, and has been
completed. Part 1 has the same general study design as Part 2 of the study,
with the key differences being that Part 2 includes a repeat dosing option
during the randomized treatment phaseTreatment Period, as well as during an
added open-label treatment phaseOpen-Label Treatment Period (test dose
procedures have been amended in Part 2 to assess a repeat dose of etripamil NS
70 mg).
NODE-301 - Part 2 (the RAPID Study)
RAPID (NODE-301 Part 2) will consist of:
• New patients enrolled following protocol version 6.0 (and subsequent
versions) implementation
• Patients enrolled prior to protocol version 6.0 implementation and who
werehad not dosed with the double-blind study drug, or havehad not discontinued
the study before the adjudication of the 150th positively adjudicated PSVT
episode, and in Part 1.
• Patients enrolled into the study following the completion of Part 1.
The RAPID study will test the treatment effect of etripamil (a dosing regimen
of either single dose or second dose, if symptoms persist after 10 minutes), in
a population of patients having a perceived episode of PSVT in an at-home
setting, as measured by time to conversion to sinus rhythm for at least 30
seconds.
Enrollment into RAPID will continue until the adjudication of the 180th
positively adjudicated PSVT episode in Part 2 patients treated with
double-blind study drug during the Randomized Treatment period required for the
study*s pivotal analysis.
Intervention
Before randomization in the RAPID study, all patients will receive a test dose
of an etripamil NS dosing regimen (an initial dose of etripamil NS 70 mg
followed by a second dose of etripamil NS 70 mg not earlier than 10 minutes and
not later than 15 minutes after the first dose) to evaluate tolerability and to
train patients on the study procedures.
First PSVT episode during study; Self-administration of the study drug regimen
during a PSVT episode is as follows: an initial dose of etripamil NS 70 mg (or
placebo) followed by a second dose 10 minutes later if the patient continues to
experience PSVT symptoms.
Second PSVT episode during study: Self-administration of the study drug regimen
during a PSVT episode is as follows: an initial dose of etripamil NS 70 mg
followed by a second dose 10 minutes later if the patient continues to
experience PSVT symptoms.
Study burden and risks
the burden and risk of the study mainly consist out of extra time spend in
comparision to standard treatment (going to the study site
and completing surveys) and side effects.
possible side effects of etripamil NS:
• Nasal congestion (stuffy nose)
• Nasal discomfort
• Eyes watering
• Rhinorrhea (runny nose)
• Sore throat
• Cough
• Sneezing
• Bleeding from the nose
• Decrease in heart rate and/or a drop in blood pressure (hypotension), with
symptoms that include dizziness and fainting. In severe
cases, low blood pressure can be life-threatening.
• A condition called heart block, where a naturally occurring electrical signal
that controls the heartbeat is partially or completely
blocked from reaching the heart*s ventricles (the 2 large chambers in the heart
that collect and distribute blood from the heart to the
rest of the body). In severe cases, heart block can be life-threatening.
Patients have the benefit of the possibility to self administer the study drug
to stop a PSVT episode and do not need to go to a
hospital directly when having a PSVT episode.
Dr. Frederik-Philips Boulevard Suite 420 1111
Montreal, Quebec CA H4M 2X6
CA
Dr. Frederik-Philips Boulevard Suite 420 1111
Montreal, Quebec CA H4M 2X6
CA
Listed location countries
Age
Inclusion criteria
Patients who meet all of the following criteria will be eligible to participate
in the study:
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 who are sexually active with a male
partner who is not surgically sterile (i.e., vasectomy) must agree to use a
highly effective form of contraception from the time of signed informed consent
until 30 days after the last administration of study drug. Females of
childbearing potential should have a negative serum pregnancy test result at
the Screening Visit and at the Final Study Visit, a negative urine pregnancy
test at the Test Dose Randomization Visit and must use a highly effective form
of contraception between the visits.
The following categories define females who are NOT considered to be of
childbearing potential:
• Premenopausal females with 1 of the following:
a. Documented hysterectomy;
b. Documented bilateral salpingectomy or tubal ligation; or
c. Documented bilateral oophorectomy; or
• Postmenopausal females, defined as having amenorrhea for at least 12 months
without an alternative medical cause;
5. Male patients, except those who are surgically sterile, must use a 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 (SBP) <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, patients may be rescreened once, and chronic use of the drug cannot
be restarted after randomization.
2. History of severe symptoms of hypotension, especially syncope, during
episodes of PSVT;
3. 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);
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 chronic therapy with oral amiodarone, or have taken oral 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 ventricular tachycardia);
10. Current congestive heart failure defined by the New York Heart Association
Class II to IV;
11. Stroke in the last within 6 months of screening;
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 End-Stage Renal Disease as determined by an estimated
glomerular filtration rate assessed at the Screening Visit of <15mL/min/1.73m2
or requiring hemodialysis;
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. Participation in any investigational drug or device study or the use of any
investigational drug or device within 30 days of the Screening Visit; or
17. Previously enrolled in a clinical trial for etripamil and received study
drug during a perceived episode of PSVT.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000308-41-NL |
| ClinicalTrials.gov | NCT03464019 |
| CCMO | NL75081.100.20 |