Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial
Bruce Stambler
,
a John Camm
,
Marco Alings
,
Paul Dorian
,
Hein Heidbuchel
,
Jaco Houtgraaf
,
Peter Kowey
,
Jose Merino
,
Blandine Mondésert
,
Jonathan Piccini
,
Sean Pokorney
,
Philip Sager
,
Atul Verma
,
J Marcus Wharton
,
David Bharucha
,
Francis Plat
,
Silvia Shardonofsky
,
Michael Chen
,
James Ip
,
James Ip
,
Alonzo Jones
,
Bruce Stambler
,
David Schleinkofer
,
Stephen Winters
,
Wilson Lam
,
Robert Goldstein
,
Isaac Dor Dor
,
Sandeep Talwar
,
Padraig O'Neill
,
Michael Koren
,
Sean Beinart
,
Srivani Ambati
,
Sean Mazer
,
Robert Kinn
,
Karine Roy
,
Ramin Manshadi
,
Richard Kuk
,
Aditya Verma
,
Timothy Phelan
,
Alexandru Stoian
,
Kenneth Ellenbogen
,
J Vijay Jayachandran
,
Terence Connelly
,
Marcos Daccarett
,
Gaurang Gandhi
,
Suneet Mittal
,
Amir Abdel-Wahab
,
Ralph Augostini
,
John Ip
,
Denise Sorrentino
,
Jean-Francois Roux
,
Ramandeep Brar
,
Clarence Khoo
,
Matthew Bennett
,
Eric Lo
,
Benoit Coutu
,
Laurence Sterns
,
Gerald Greer
,
Pradeep Gujja
,
Robert Gianfagna
,
Vijendra Swarup
,
Felix Sogade
,
Stephen Wilton
,
Christopher Ruisi
,
Saverio Barbera
,
Javier Banchs
,
Victoria Korley
,
Christopher Schulze
,
Roger Damle
,
Jeffrey Sean Healey
,
a Shekhar Pandey
,
Jeffrey Anderson
,
K Venkatachalam
,
Peter Noseworthy
,
Blandine Mondésert
,
Atul Verma
,
Douglas Friars
,
Thomas Kambur
,
Evan Lockwood
,
Glenn Meininger
,
Greg Olsovsky
,
Alonzo Jones Sr
,
Gerald Greer
,
Rohit Mehta
,
Saleem Akbar
,
Malik Salman
,
Bhola Rama
,
Ramesh Arora
,
Dhirenkumar Shah
,
Rakesh Shah
,
Michael Cammarata
,
Andrew Owens
,
Katherine Ludington
,
Marcus Wharton
,
Michael Bagheri
,
Mohammed Khan
,
Kenneth Warren Carr
,
Sultan Siddique
,
Sunthosh Parvathaneni
,
Subodh Devabhaktuni
,
Assad Mouhaffel
,
George Mark
,
Luigi Di Biase
,
Sunil Rangappa
,
Jared Morton
,
Hirad Yarmohammadi
,
Amin Karim
,
Aldo Martinez Fleites
,
Thomas Nero
,
Qaiser Shafiq
,
Benoit Coutu
,
Shekhar Pandey
,
Yaariv Khaykin
,
Jacqueline Joza
,
Gilbert Gosselin
,
Allen Skanes
,
John Vyselaar
,
Daniel Savard
,
Hein Heidbuchel
,
Olivier Xhaet
,
Emmanuel Catez
,
Johan Vijgen
,
Pascal Godart
,
Ruben Casado
,
Georges Mairesse
,
Tom Rossenbacker
,
Peter Haemers
,
Etienne Hoffer
,
Pierre Hausman
,
Andras Vertes
,
Gabor Duray
,
Erzsebet Szolnoki
,
Zoltan Csanadi
,
Ferenc Lakatos
,
Marco Alings
,
Reinhart Dorman
,
Y Tuininga
,
W Jansen
,
Sebastiaan Velthuis
,
B van Bemmel
,
Gerhard Jan Willem Bech
,
Ron Pisters
,
Suzanne Valk
,
Tjeerd Romer
,
Justin Luermans
,
Driek Beelen
,
Martijn van Eck
,
Jaco Houtgraaf
,
Thijs Vet
,
Dirk Shellings
,
T Oosterhof
,
Pawel Miekus
,
Waldemar Bebenek
,
Agata Bielecka-Dabrowa
,
Jacek Gniot
,
Witold Zmuda
,
Michal Kasprzak
,
Wojciech Balak
,
Pawel Ptaszynski
,
Jacek Nowak
,
Janusz Prokopczuk
,
Andrzej Przybylski
,
Iwona Wozniak-Skowerska
,
Pawel Derejko
,
Danuta Czarnecka
,
Adam Janas
,
Jose Luis Merino Llorens
,
Luis Tercedor
,
Andres Iniguez Romo
,
Ricardo Ruiz Granell
,
Jose Ramon Gonzalez Juanatey
,
Domingo Pascual-Figal
,
Manuel Martinez-Selles
,
Ignacio Anguera Camos
,
Alicia Ibanez Criado
,
Javier Matrinez Basterra
,
Alvaro Izquierdo
,
Nuria Rivas Gandara
,
Josep Alegret Colome
,
Diego Perez Diez
,
Miguel Ángel Martínez Hervás
,
Maria Medina
,
Jose María Segura Saint-Gerons
,
Alonso Pedrote Leal
,
Ignacio Fernandez Lozano
,
Aurelio Quesada
,
Jose Guerra Ramos
,
Axel Sarrias
,
Javier Ramos Maqueda
,
Jacques Mansourati
(1, 2)
,
Pascal Defaye
,
Laurence Guedon-Moreau
,
Antoine Milhem
,
Maxime de Guillebon
,
Philippe Chevalier
,
Marc Badoz
,
Charalampos Kriatselis
,
Gregor Simonis
,
Thorsten Lewalter
,
Markus Zarse
,
Andreas Wilke
,
Fabian Kraemer
,
Ayham Al-Zoebi
Bruce Stambler
- Function : Author
a John Camm
- Function : Author
Marco Alings
- Function : Author
Paul Dorian
- Function : Author
Hein Heidbuchel
- Function : Author
Jaco Houtgraaf
- Function : Author
Peter Kowey
- Function : Author
Jose Merino
- Function : Author
Blandine Mondésert
- Function : Author
Jonathan Piccini
- Function : Author
Sean Pokorney
- Function : Author
Philip Sager
- Function : Author
Atul Verma
- Function : Author
J Marcus Wharton
- Function : Author
David Bharucha
- Function : Author
Francis Plat
- Function : Author
Silvia Shardonofsky
- Function : Author
Michael Chen
- Function : Author
James Ip
- Function : Author
James Ip
- Function : Author
Alonzo Jones
- Function : Author
Bruce Stambler
- Function : Author
David Schleinkofer
- Function : Author
Stephen Winters
- Function : Author
Wilson Lam
- Function : Author
Robert Goldstein
- Function : Author
Isaac Dor Dor
- Function : Author
Sandeep Talwar
- Function : Author
Padraig O'Neill
- Function : Author
Michael Koren
- Function : Author
Sean Beinart
- Function : Author
Srivani Ambati
- Function : Author
Sean Mazer
- Function : Author
Robert Kinn
- Function : Author
Karine Roy
- Function : Author
Ramin Manshadi
- Function : Author
Richard Kuk
- Function : Author
Aditya Verma
- Function : Author
Timothy Phelan
- Function : Author
Alexandru Stoian
- Function : Author
Kenneth Ellenbogen
- Function : Author
J Vijay Jayachandran
- Function : Author
Terence Connelly
- Function : Author
Marcos Daccarett
- Function : Author
Gaurang Gandhi
- Function : Author
Suneet Mittal
- Function : Author
Amir Abdel-Wahab
- Function : Author
Ralph Augostini
- Function : Author
John Ip
- Function : Author
Denise Sorrentino
- Function : Author
Jean-Francois Roux
- Function : Author
Ramandeep Brar
- Function : Author
Clarence Khoo
- Function : Author
Matthew Bennett
- Function : Author
Eric Lo
- Function : Author
Benoit Coutu
- Function : Author
Laurence Sterns
- Function : Author
Gerald Greer
- Function : Author
Pradeep Gujja
- Function : Author
Robert Gianfagna
- Function : Author
Vijendra Swarup
- Function : Author
Felix Sogade
- Function : Author
Stephen Wilton
- Function : Author
Christopher Ruisi
- Function : Author
Saverio Barbera
- Function : Author
Javier Banchs
- Function : Author
Victoria Korley
- Function : Author
Christopher Schulze
- Function : Author
Roger Damle
- Function : Author
Jeffrey Sean Healey
- Function : Author
a Shekhar Pandey
- Function : Author
Jeffrey Anderson
- Function : Author
K Venkatachalam
- Function : Author
Peter Noseworthy
- Function : Author
Blandine Mondésert
- Function : Author
Atul Verma
- Function : Author
Douglas Friars
- Function : Author
Thomas Kambur
- Function : Author
Evan Lockwood
- Function : Author
Glenn Meininger
- Function : Author
Greg Olsovsky
- Function : Author
Alonzo Jones Sr
- Function : Author
Gerald Greer
- Function : Author
Rohit Mehta
- Function : Author
Saleem Akbar
- Function : Author
Malik Salman
- Function : Author
Bhola Rama
- Function : Author
Ramesh Arora
- Function : Author
Dhirenkumar Shah
- Function : Author
Rakesh Shah
- Function : Author
Michael Cammarata
- Function : Author
Andrew Owens
- Function : Author
Katherine Ludington
- Function : Author
Marcus Wharton
- Function : Author
Michael Bagheri
- Function : Author
Mohammed Khan
- Function : Author
Kenneth Warren Carr
- Function : Author
Sultan Siddique
- Function : Author
Sunthosh Parvathaneni
- Function : Author
Subodh Devabhaktuni
- Function : Author
Assad Mouhaffel
- Function : Author
George Mark
- Function : Author
Luigi Di Biase
- Function : Author
Sunil Rangappa
- Function : Author
Jared Morton
- Function : Author
Hirad Yarmohammadi
- Function : Author
Amin Karim
- Function : Author
Aldo Martinez Fleites
- Function : Author
Thomas Nero
- Function : Author
Qaiser Shafiq
- Function : Author
Benoit Coutu
- Function : Author
Shekhar Pandey
- Function : Author
Yaariv Khaykin
- Function : Author
Jacqueline Joza
- Function : Author
Gilbert Gosselin
- Function : Author
Allen Skanes
- Function : Author
John Vyselaar
- Function : Author
Daniel Savard
- Function : Author
Hein Heidbuchel
- Function : Author
Olivier Xhaet
- Function : Author
Emmanuel Catez
- Function : Author
Johan Vijgen
- Function : Author
Pascal Godart
- Function : Author
Ruben Casado
- Function : Author
Georges Mairesse
- Function : Author
Tom Rossenbacker
- Function : Author
Peter Haemers
- Function : Author
Etienne Hoffer
- Function : Author
Pierre Hausman
- Function : Author
Andras Vertes
- Function : Author
Gabor Duray
- Function : Author
Erzsebet Szolnoki
- Function : Author
Zoltan Csanadi
- Function : Author
Ferenc Lakatos
- Function : Author
Marco Alings
- Function : Author
Reinhart Dorman
- Function : Author
Y Tuininga
- Function : Author
W Jansen
- Function : Author
Sebastiaan Velthuis
- Function : Author
B van Bemmel
- Function : Author
Gerhard Jan Willem Bech
- Function : Author
Ron Pisters
- Function : Author
Suzanne Valk
- Function : Author
Tjeerd Romer
- Function : Author
Justin Luermans
- Function : Author
Driek Beelen
- Function : Author
Martijn van Eck
- Function : Author
Jaco Houtgraaf
- Function : Author
Thijs Vet
- Function : Author
Dirk Shellings
- Function : Author
T Oosterhof
- Function : Author
Pawel Miekus
- Function : Author
Waldemar Bebenek
- Function : Author
Agata Bielecka-Dabrowa
- Function : Author
Jacek Gniot
- Function : Author
Witold Zmuda
- Function : Author
Michal Kasprzak
- Function : Author
Wojciech Balak
- Function : Author
Pawel Ptaszynski
- Function : Author
Jacek Nowak
- Function : Author
Janusz Prokopczuk
- Function : Author
Andrzej Przybylski
- Function : Author
Iwona Wozniak-Skowerska
- Function : Author
Pawel Derejko
- Function : Author
Danuta Czarnecka
- Function : Author
Adam Janas
- Function : Author
Jose Luis Merino Llorens
- Function : Author
Luis Tercedor
- Function : Author
Andres Iniguez Romo
- Function : Author
Ricardo Ruiz Granell
- Function : Author
Jose Ramon Gonzalez Juanatey
- Function : Author
Domingo Pascual-Figal
- Function : Author
Manuel Martinez-Selles
- Function : Author
Ignacio Anguera Camos
- Function : Author
Alicia Ibanez Criado
- Function : Author
Javier Matrinez Basterra
- Function : Author
Alvaro Izquierdo
- Function : Author
Nuria Rivas Gandara
- Function : Author
Josep Alegret Colome
- Function : Author
Diego Perez Diez
- Function : Author
Miguel Ángel Martínez Hervás
- Function : Author
Maria Medina
- Function : Author
Jose María Segura Saint-Gerons
- Function : Author
Alonso Pedrote Leal
- Function : Author
Ignacio Fernandez Lozano
- Function : Author
Aurelio Quesada
- Function : Author
Jose Guerra Ramos
- Function : Author
Axel Sarrias
- Function : Author
Javier Ramos Maqueda
- Function : Author
Pascal Defaye
- Function : Author
Laurence Guedon-Moreau
- Function : Author
Antoine Milhem
- Function : Author
Maxime de Guillebon
- Function : Author
Philippe Chevalier
- Function : Author
Marc Badoz
- Function : Author
Charalampos Kriatselis
- Function : Author
Gregor Simonis
- Function : Author
Thorsten Lewalter
- Function : Author
Markus Zarse
- Function : Author
Andreas Wilke
- Function : Author
Fabian Kraemer
- Function : Author
Ayham Al-Zoebi
- Function : Author
Abstract
Background: Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min. Methods: RAPID was a multicentre, randomised, placebo-controlled, event-driven trial, conducted at 160 sites in North America and Europe as part 2 of the NODE-301 study. Eligible patients were aged at least 18 years and had a history of paroxysmal supraventricular tachycardia with sustained, symptomatic episodes (≥20 min) as documented by electrocardiogram. Patients were administered two test doses of intranasal etripamil (each 70 mg, 10 min apart) during sinus rhythm; those who tolerated the test doses were randomly assigned (1:1) using an interactive response technology system to receive either etripamil or placebo. Prompted by symptoms of paroxysmal supraventricular tachycardia, patients self-administered a first dose of intranasal 70 mg etripamil or placebo and, if symptoms persisted beyond 10 min, a repeat dose. Continuously recorded electrocardiographic data were adjudicated, by individuals masked to patient assignment, for the primary endpoint of time to conversion of paroxysmal supraventricular tachycardia to sinus rhythm for at least 30 s within 30 min after the first dose, which was measured in all patients who administered blinded study drug for a confirmed atrioventricular-nodal-dependent event. Safety outcomes were assessed in all patients who self-administered blinded study drug for an episode of perceived paroxysmal supraventricular tachycardia. This trial is registered at ClinicalTrials.gov, NCT03464019, and is complete. Findings: Between Oct 13, 2020, and July 20, 2022, among 692 patients randomly assigned, 184 (99 from the etripamil group and 85 from the placebo group) self-administered study drug for atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia, with diagnosis and timing confirmed. Kaplan-Meier estimates of conversion rates by 30 min were 64% (63/99) with etripamil and 31% (26/85) with placebo (hazard ratio 2·62; 95% CI 1·66–4·15; p<0·0001). Median time to conversion was 17·2 min (95% CI 13·4–26·5) with the etripamil regimen versus 53·5 min (38·7–87·3) with placebo. Prespecified sensitivity analyses of the primary assessment were conducted to test robustness, yielding supporting results. Treatment-emergent adverse events occurred in 68 (50%) of 99 patients treated with etripamil and 12 (11%) of 85 patients in the placebo group, most of which were located at the administration site and were mild or moderate, and all of which were transient and resolved without intervention. Adverse events occurring in at least 5% of patients treated with etripamil were nasal discomfort (23%), nasal congestion (13%), and rhinorrhea (9%). No serious etripamil-related adverse events or deaths were reported. Interpretation: Using a symptom-prompted, self-administered, initial and optional-repeat-dosing regimen, intranasal etripamil was well tolerated, safe, and superior to placebo for the rapid conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm. This approach could empower patients to treat paroxysmal supraventricular tachycardia themselves outside of a health-care setting, and has the potential to reduce the need for additional medical interventions, such as intravenous medications given in an acute-care setting.