FormalPara Key Summary Points

Paroxysmal supraventricular tachycardia (PSVT) is a recurrent episodic condition in which patients suffer from sudden-onset symptoms inducing palpitations, dyspnea, syncope, and psychological distress; current approved treatments require medical supervision.

The phase 3 RAPID trial, NODE-301 part 2, was designed to evaluate a symptom-prompted, optional repeat dose of etripamil, an investigative calcium channel blocker (CCB) that can be self-administered intranasally; RAPID assessed the safety and efficacy of etripamil while noting safety effects from one or two doses that were self-administered by patients.

Eligible adults with a history of PSVT were randomized to etripamil or placebo groups, and they self-administered the study drug upon perceiving PSVT symptoms; significantly superior conversion rates of PSVT to sinus rhythm were observed within 30 min in participants treated with etripamil (64%) versus those treated with placebo (31%).

The increased drug exposure achieved with RAPID’s repeat-dose protocol was well tolerated, without any additional safety signals beyond the transient mild and moderate treatment-emergent adverse events observed with a single dose of etripamil, which were mostly associated with the medication administration site.

These data support the potential use of etripamil as a fast-acting, convenient medication that can be used by patients with PSVT to quickly and safely terminate episodes outside a clinical setting without medical supervision.

Digital Features

This article is published with digital features, including a podcast, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.24243046.

Author Introductions

Bruce Stambler (BS):

Cardiac electrophysiologist at Piedmont Heart Institute in Atlanta, GA.

James Ip (JI):

Associate Professor at the Weill Cornell Medical Center in NY.

James:

Hello, I’m James Ip, cardiac electrophysiologist and Associate Professor at the Weill Cornell Medical Center in NY. I appreciate the time to meet with you, Bruce, and I’m looking forward to today’s conversation.

Bruce:

Thank you, James. It’s a pleasure to be here. I’m Bruce Stambler, a cardiac electrophysiologist from Piedmont Heart Institute in Atlanta, GA. James and I are here today to discuss the unmet needs in treating paroxysmal supraventricular tachycardia, also known as PSVT, and how we may advance clinical practice through new therapies. Treatments for PSVT require intravenous (IV) access, which is often a barrier for many patients. Oral treatments that are available are not that efficacious. We will discuss this information in more depth later in the podcast, but we first want to briefly share about a new article published in The Lancet that highlights a potential drug for self-treating PSVT. The paper is entitled, “Self-administered Intranasal Etripamil Using a Symptom-Prompted, Repeat-Dose Regimen for Atrioventricular-Nodal Dependent Supraventricular Tachycardia: The Randomized, Controlled RAPID Trial” [1].

James:

So, let’s jump right in. Bruce, you were a lead author on the RAPID trial. As you know, the RAPID trial demonstrated that self-administered intranasal etripamil, an investigational drug, was superior to placebo for rapid conversion of AV-nodal-dependent paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. We will be discussing the RAPID trial and its findings. What I would like you to do here is to begin by giving the audience some background to set the stage so that we can have a foundation for the discussion that we are about to have. In particular, please tell us something about PSVT and what you see as a practicing clinical electrophysiologist.


00:01:58

Bruce:

Well, to begin with, PSVTs are commonly seen in clinical practice and represent a significant burden both to the healthcare system and to individuals suffering with this recurrent episodic condition [2,3,4,5]. Published estimates suggest that approximately 200,000–300,000 new patients are diagnosed with PSVT every year in the United States and with anywhere from 500,000 to 2 million Americans are currently affected with PSVT.

Twenty-five percent of patients who present to the ED [emergency department] with PSVT are hospitalized, representing about 50,000 ER visits annually and over half a million healthcare claims per year in the US. PSVT, while not typically life-threatening, can adversely impair quality of life.

Symptoms include palpitations, chest discomfort, dyspnea, lightheadedness, syncope, and psychological distress [2,3,4]. Attacks or episodes can suddenly occur without obvious warnings or triggers at any time of the day or night and often occur unpredictably in otherwise healthy individuals.

The atrioventricular (AV) node is an obligatory component of the majority of PSVT circuits [6], which include either AV nodal reentrant tachycardia (commonly known as AVNRT) or AV reciprocating tachycardia (also known as AVRT) in the vast majority of cases. Therefore, a pharmaceutical agent capable of transiently prolonging AV nodal refractoriness represents a targeted strategy for tachycardia termination and the restoration of sinus rhythm.


00:03:52

James:

Thank you, Bruce. In that context, we should mention that in clinical practice and in supraventricular (SVT) guidelines, vagal maneuvers (such as Valsalva maneuver or carotid sinus massage) are often recommended for termination of an acute PSVT attack. However, these self-performed techniques have very low rates of efficacy for acute conversion of PSVT, leaving many individuals suffering from a PSVT attack no choice but to seek urgent medical attention either via emergency medical services or in an emergency department or urgent care setting.

Bruce:

Agreed, James, that vagal maneuvers are the typical first line of intervention, and these can be performed in the at-home setting. Nonetheless, current standard-of-care treatments for an acute PSVT episode which is not responsive to one or more vagal maneuvers have to be administered in a healthcare setting by medical personnel.

First-line therapies primarily include intravenous calcium channel blockers (CCBs) such as verapamil or diltiazem or beta-adrenergic blockers. Although these agents are effective in terminating PSVT [6], again, they must be administered under medical supervision and require IV access.

Oral agents may be used acutely to self-treat PSVT, as what is commonly known as a “pill-in-pocket” approach with, for example, a beta blocker or a CCB, and are often tried due to the paucity of therapeutic alternatives. However, this approach has limited efficacy that is oral therapy, potential adverse side effects (such as syncope and hypotension), and delayed onset and variable onset of action due to prolonged bioavailability, resulting in often slow PSVT resolution.

James:

That’s right, and daily administration of oral medication likewise is limited due to lack of efficacy or side effects (such as fatigue and bradycardia) [6,7,8]. In addition, breakthrough episodes requiring visits to the ED or urgent care often occur despite patients taking daily suppressive medication [8].

Catheter-based ablations are an important option for management of PSVT, as they can prevent or attenuate many types of PSVT. However, these invasive ablations may not be readily available to or preferred by all patients. Published data indicate that catheter ablations for PSVT are performed in only a minority of patients with sustained SVT despite their being available for more than three decades now [9, 10].


00:06:11

Bruce:

Exactly, I agree. And therefore, there is an unmet need for an acute rapid treatment for PSVT that allows patients to safely self-treat their PSVT to reduce their symptom burdens and reduce emergency medical care visits. This forms the basis for the development of a new potential treatment, etripamil, which is the subject of our discussion today. James, can you tell us about this drug and provide us with an overview of earlier studies with etripamil?

James:

Well, to begin with, etripamil is a fast-acting, intranasally administered, L-type calcium channel blocker (CCB), which is currently investigational but is in active clinical trial development for self-administration outside of the healthcare setting during PSVT [11]. Therefore, etripamil is not yet approved by the US FDA.

Phase 1 studies demonstrated that intranasal etripamil is quickly absorbed by the nasal mucosa, with maximum concentration reached within ≤ 7 min (70-mg dose). Because of its unique chemical design with an ester moiety, it is also designed to be metabolized rapidly by blood esterases.

A phase 2 study published in 2018 demonstrated for the first time the potential efficacy and safety of etripamil for PSVT conversion. Intranasal etripamil at doses ≥ 70 mg administered by medical personnel was superior to placebo for rapid termination of PSVT induced in an electrophysiology laboratory [12].

Bruce:

That’s right, James, and then next, the NODE-301 phase 3 study published in 2022 was the first in-human study of etripamil administration during PSVT conducted outside the hospital without direct medical supervision. This event-driven study evaluated single-dose etripamil (70 mg), self-administered, outside a healthcare setting, during symptomatic PSVT [12, 13]. In this study, etripamil self-administration during PSVT was safe and well tolerated, the most frequent adverse events (AE) were local reactions such as nasal discomfort, nasal congestion, rhinorrhea, and the majority were mild to moderate in severity. These data supported continued development of etripamil nasal spray for self-administration during PSVT in a non-healthcare setting. While confirming safety and feasibility, the study did not show statistically significant efficacy for PSVT conversion at 5 h for etripamil over placebo (a period substantially longer than the drug’s pharmacodynamic effects). Interestingly, earlier time points, such as earlier than 30–45 min, demonstrated significant efficacy of single-dose treatment with 70 mg etripamil.

I think that is a key point. It is important to develop a drug that acts rapidly and shows significant improvement early on after administration. James, with this reviewed background in mind, tell us about the objectives of the RAPID trial.


00:09:29

James:

Yes, absolutely. The landmark RAPID trial was published in The Lancet in 2023. Based on the prior observations and with an objective to improve the efficacy of etripamil while maintaining its favorable safety and tolerability, the RAPID trial [1] sought to evaluate a novel symptom-prompted, optional repeat dose of etripamil on demand for acute conversion of AV-nodal-dependent PSVT within 30 min. RAPID tested a treatment regimen that included a repeat dose (70 mg) if PSVT symptoms persisted 10 min after the first dose, with a primary objective to determine whether etripamil nasal spray is superior to placebo at terminating episodes of PSVT prompted by symptoms within 30 min after drug administration.

Prespecified secondary endpoints assessed symptomatic improvement, the need for additional medical interventions and emergency department use, and safety. Now that we know the broad intent of the RAPID study, Bruce, please tell the audience some of the underpinnings of the trial design. In particular, what were the inclusion and exclusion criteria?

Bruce:

The study population of RAPID included patients ≥ 18 years of age with an electrocardiogram (ECG)-documented history of PSVT that was symptomatic and sustained with episodes lasting at least 20 min in duration.

Key exclusion criteria were patients with manifest pre-excitation on ECG, second- or third-degree AV block, ventricular arrhythmia, or atrial arrhythmia not utilizing the AV node, such as atrial fibrillation or atrial flutter or atrial tachycardia.

Prior to randomization, enrolled patients were administered a test dose consisting of etripamil nasal spray 70 mg, followed by a second dose, 10 min later, during sinus rhythm to evaluate the safety and tolerability of the repeat-dose medication regimen [1]. Notably, 98% of enrolled subjects passed the test dose and proceeded to study drug randomization.


00:11:29

James:

Exactly, and then subjects were randomly allocated in a double-blinded manner (1:1) to the etripamil regimen or the placebo drug regimen. Subsequently, when patients recognized the spontaneous onset of their typical PSVT symptoms, they attached an ECG monitor to their chest, which recorded for 5 h. Subjects then performed the vagal maneuver on which they were previously trained, and if symptoms did not resolve, administered the first intranasal dose of their blinded study drug. Notably, conversions of PSVT to sinus rhythm with a vagal maneuver were actually quite infrequent, occurring in only 3.5% of patients prior to administering their study drug.

Bruce:

Having established the study protocol, an important consideration that comes to mind, James, is what to do if the symptoms of PSVT persisted after that drug was given in the study. James, please provide any information as to whether there were any contingency plans for unresponsive subjects.

James:

The study was well designed with contingency plans. In fact, we established different care pathways for participants depending on the outcomes observed. For example, if symptoms of PSVT persisted 10 min after the first dose, the subjects had the option of administering a repeat dose (using a second device) of study drug. If symptoms of PSVT did not resolve within 30 min after the first drug administration, patients could seek appropriate medical care while continuing the ECG recording for at least 5 h.

Bruce:

That was a very nice summary of the pathways for patient treatment in this trial. Once completed, what was the primary endpoint of the study?

James:

From October 2020 to July 2022, 692 patients were enrolled and randomized throughout sites in the US, Canada, and Europe. The mean age was 54 years and the majority enrolled were female.

The extent of prior PSVT and concomitant use of AV-node-acting medications, such as beta blockers or calcium channel blockers, were similar between the two groups.


00:13:25

The event-driven RAPID trial of subjects with symptomatic sustained AV-nodal-dependent PSVT achieved its primary efficacy outcome of conversion of SVT to sinus rhythm within 30 min.

The primary efficacy endpoint was the time to the adjudicated conversion of an ECG event monitor-confirmed episode of AV-nodal-dependent PSVT to sinus rhythm for ≥ 30 s within 30 min of the drug administration adjudicated by an independent events committee, which was comprised of cardiac electrophysiologists blinded to study drug assignments.

Given this endpoint, in your opinion, Bruce, what were the key findings from the RAPID study that you would like to discuss today?

Bruce:

Well, first and foremost, we were pleased to note that the RAPID trial achieved its primary efficacy outcome of conversion from PSVT to sinus rhythm up to 30 min occurring in 64.3% of subjects in the etripamil group and 31.2% of subjects in the placebo group. This is shown in Fig. 2 of the Lancet publication (hazard ratio of time to conversion was 2.623; 95% CI = 1.659, 4.147; p < 0.001 in favor of etripamil).

A significant treatment effect was observed with prespecified assessments as early as 5 min and up to 5 h.

Additionally, we were pleased to note a more than threefold reduction in median time to conversion with etripamil compared to placebo. The median time to conversion was 17.2 min (95% CI = 13.4, 26.5) with etripamil versus 53.5 min (95% CI = 38.7, 87.3) with placebo, statistically significant difference assessed with time windows greater than 60 min.

PSVT recurrence was extremely low following conversion (3.4% in etripamil group vs. 4.3% in placebo group) over the 5-h ECG monitoring observation window. With respect to single- versus repeat-dose administration, what we can say is that among the 99 patients in the etripamil group, two-thirds (66.3%) of patients self-administered two doses of study drug (140 mg), and one-third administered only one dose (70 mg), whereas among the 85 patients in the placebo group, 79.2% administered two doses and 20.8% administered one dose (of placebo that is).

Finally, as you know, the RAPID study was not powered to detect differences in medical intervention use outside the study or emergency department (ED) visits, so we performed a separate prespecified pooled analysis of the NODE-301 data that I talked about earlier along with the RAPID data that we just discussed. In this pooled analysis, results indicated that 25.4% (n = 34) of patients randomized in the placebo group and 14.6% (n = 30) of patients randomized in the etripamil group received additional interventions including oral or intravenous medications (p = 0.013). Patients on placebo (n = 30, 22.4%) and on etripamil (n = 27,13.1%) required an emergency department visit with an episode of PSVT (p = 0.025).


00:17:00

One of the things that always comes up in study trial design is whether there were any subpopulation differences between the groups and, if so, were they significant. James, would you be able to comment on this?

James:

Certainly, it’s an important consideration. Fortunately, primary efficacy assessments on predefined subpopulations (based on demographics, duration from symptom onset to first dose, use of concomitant medications, age groups) showed no substantial difference in hazard ratios, with all point estimates favoring etripamil. Now that we have described the primary outcomes, what were the secondary outcomes in this study?

Bruce:

Thank you for asking about these data, which are also important. After the resolution of a PSVT episode, patients completed a patient-reported outcomes questionnaire and were evaluated via study visits and via telephone follow-up. Secondary endpoints were assessed by changes in defined PSVT symptoms from a Patient Symptom Global Impressions of Improvement [14] (PGI-I)-based questionnaire, as well as additional medical interventions and emergency department use.

Secondary outcomes, that included assessments of improvement in defined symptoms following drug receipt, showed greater proportions of responders among patients reporting “rapid pulse”, “palpitations”, “feeling dizzy”, “shortness of breath”, and “anxiety” for etripamil versus placebo arms.

Now that we have discussed primary and secondary endpoints, we should consider another important aspect of any drug trial, which is safety. Were there any adverse events associated with use of etripamil, James? Was the use of etripamil well tolerated?

James:

Agreed that this is important to talk about, and thank you for asking for some information about safety. The safety population included all randomized patients who took the randomized study drug, and safety analyses focused on any adverse event occurring within 24 h of drug receipt.

Etripamil was well tolerated when administered in an ambulatory care setting during a PSVT episode or as a test dose. The most common treatment-emergent adverse events were localized to the nasal administration site, and these were mild and transient.


00:19:25

Rates of adverse events during the test dose or randomized drug administration were similar whether patients received one or two doses. Rates of epistaxis were low; none were severe or needed treatment. Direct examination of the continuous ECG data showed, most importantly, there were no second- or third-degree AV block episodes. Even after SVT episodes terminated, there were no prolonged pauses after termination. Finally, no serious adverse events such as syncope or hypotension were reported within 24 h of etripamil administration.

Bruce:

James, thank you very much for reviewing these data and helping our audience to get your perspective on it. Would you also be able to provide us with some conclusions?

James:

Bruce, thank you very much for having me. I think we did an excellent job of covering all of the major findings of this trial. I would like to highlight several conclusions.

First of all, RAPID demonstrated that intranasal etripamil was significantly superior to placebo for rapid conversion of AV-nodal-dependent PSVT to sinus rhythm within 30 min using a symptom-prompted, self-administered, repeat-dosing regimen in a population representative of patients with sustained PSVT. Conversion rates were observed at 64% with the drug compared to 31% with placebo.

Conversion of PSVT within 30 min was greater than twofold better with etripamil compared to placebo, and there was a greater than threefold improvement in median time to conversion using the repeat-dose treatment regimen as you spoke about (comparing 17.2 min with etripamil versus 53.5 min with placebo).

Lastly, etripamil was safe and well tolerated without serious adverse events or significant safety concerns using a symptom-prompted repeat-dosing regimen to increase drug exposure.

These safety results were similar between patients receiving either single or repeat doses of study drug. The symptom-prompted treatment regimen was associated with significantly improved defined symptoms of PSVT including rapid pulse, palpitations, dizziness, or lightheadedness.

Bruce:

All very thoughtful and succinct conclusions, James. Before we wrap up, do you have any thoughts regarding the implications of these study findings?

James:

Yes, I would like to share a few parting thoughts with the audience. A symptom-prompted, fast-acting, convenient, well-tolerated, and portable medication that can be acutely self-administered by patients on demand outside a healthcare setting could lead to improved management of PSVT if etripamil is approved by the US FDA, and represents a therapeutic opportunity for improved noninvasive management of symptomatic PSVT and satisfies an unmet clinical need.


00:22:01

The current evidence based on etripamil suggests that if it is approved by the US FDA, etripamil may well be able to fill this gap, as it is more efficacious than vagal maneuvers, acts faster than oral therapy, and does not require intravenous access or medical supervision.

Notably, risk reductions observed in RAPID indicate that etripamil can effectively terminate PSVT, with the number needed to treat with etripamil to convert an episode of PSVT within 30 min of drug administration of only 3.0, well within the range for effectiveness of a treatment for a symptomatic condition.

Favorable safety data without significant concerns, consistent with prior studies, are supportive of potential self-administration of etripamil outside of a healthcare setting based on symptoms of sustained PSVT.

A limitation of this study is that RAPID was not powered to detect significantly different rates between groups regarding additional medical interventions and ED or acute care visits. Other limitations in the RAPID study were identical to those in the NODE-301 parent study:

The median and mean ages of the patient population were >55 years, which likely reflects the difficulties recruiting the 18−30-year age group in clinical studies.

The study was not designed to determine the efficacy, safety, or optimal etripamil dosing in pediatric patients or in patients who had low body weight.

Some heterogeneity between baseline PSVT episodes may have occurred between patients, although this factor was likely minimized by the eligibility criteria for having a history of documented PSVT and excluding non-atrioventricular nodal-dependent tachycardia.

The lack of a prespecified time when study drug must be taken after PSVT initiation could also influence the conversion rates and the time to conversion in each group.

The study was designed to reflect how etripamil will be used by patients in a real-world setting.

Adjudication committee reviews were limited to single-channel SVT recordings, and arrhythmia mechanisms (e.g., AVRT, AVNRT) were not definitively identified with an electrophysiology study.

The RAPID study was designed to assess the efficacy and safety of a treatment regimen inclusive of an optional repeat dose of etripamil to be administered 10 min after the first dose if the SVT symptoms persisted; the study was not designed to characterize the difference in efficacy between a single 70-mg dose and the second 70-mg dose.

Equally, no significant differences were demonstrated, although favorable trends were observed, highlighting the potential for reduced patient burdens and healthcare costs.

Finally, the availability of etripamil nasal spray would have the potential to improve the treatment options for symptomatic PSVT if etripamil is approved by the US FDA. Potential patients who would be candidates for etripamil include those who have rare PSVT episodes, those who are reluctant to undergo catheter ablation, or those who wish to avoid taking daily oral suppressive medications that don’t always work.


00:24:57

Bruce:

As we begin to wrap up, can you provide brief comments on what is happening next with this drug in the future?

James:

Sure, I’d be happy to provide some insight into what’s coming up next. Milestone believes results from the RAPID trial together with the data from the already completed NODE-301 trial could fulfill the efficacy requirement for a New Drug Application (NDA) submission for etripamil in patients with PVST. The NDA submission for etripamil in patients with PSVT is on track for the third quarter in 2023.

Also, now that data are available on atrial fibrillation with rapid ventricular rate (also known as AFib-RVR), I’ll mention how that data is being explored clinically.

For some background, atrial fibrillation leads to an irregular heartbeat and can frequently cause severe symptoms and anxiety. Slowing the heart rate quickly, as etripamil appears to have shown, could offer considerable relief. In an oral session at the Heart Rhythm 2023 Annual Meeting, data from a small subset of patients with AFib-RVR was highlighted. This informal analysis represents the first direct clinical evidence of etripamil on heart rate control in patients who experience AFib. Also, there is an ongoing phase 2 placebo-controlled study of etripamil in patients with AFib. Results of that study are expected to be reported in the second half of 2023. Further studies are needed to evaluate etripamil in AFib.

Bruce:

Great, thanks for that information. I think that concludes our podcast. Thank you, James, for your time and insights today, James. We hope that this has been of interest to our listeners.