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Paroxysmal Atrial Fibrillation (PAF)Phase 2INSTANTNCT03539302

INhalation of Flecainide to Convert Recent Onset SympTomatic Atrial Fibrillation to siNus rhyThm (INSTANT)

A Phase 2 study testing Flecainide Acetate in people with Paroxysmal Atrial Fibrillation (PAF), run by InCarda Therapeutics, Inc. at 9 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The study consisted of 3 parts (Part A, Part B and Part C). Part A was an open-label, randomized, multi center design to evaluate the feasibility of administration of inhaled flecainide in two dosing regimens. Read more about this study

Who is it for?
Ages 18 to 85 years
Conditions the study is for
Paroxysmal Atrial Fibrillation (PAF)
What is being tested?
Flecainide Acetate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
176 participants
Where
9 sitesin 2 countries
Study dates
29 May 2018to 17 Jan 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Subjects with recent-onset symptomatic AF at presentation,
  • With a duration at onset of symptoms from 1 hour to 48 hours,
  • And from one of the following categories:
  • First detected episode of paroxysmal AF
  • Recurrent episode of paroxysmal AF
  • Episode post-cardiac ablation for paroxysmal AF
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  • Subjects who:
  • are prescribed a pill-in-the-pocket regimen (flecainide or propafenone) for paroxysmal AF, or
  • are within 3 months of having undergone ablation of paroxysmal AF, or
  • have experienced an episode of new AF but are not currently experiencing an episode of recent-onset paroxysmal AF, or
  • are known to have paroxysmal AF (or previously diagnosed with paroxysmal AF) and have one or more previous symptomatic episodes but are not currently experiencing an episode of recent-onset paroxysmal AF may consent to pre-study screening prior to presenting with recent-onset symptomatic AF. These subjects will be eligible to receive study drug only when presenting with symptomatic paroxysmal AF of recent-onset (i.e., ≤ 48 hours), consenting to the full study, and after meeting all eligibility criteria.

Who cannot join

  • Subject < 18 or > 85 years of age
  • Hemodynamic and/or cardiac instability, with systolic blood pressure < 100 mmHg or > 150 mmHg, and/or ventricular heart rate < 80 bpm or > 150 bpm. For subjects to meet eligibility criteria, at least 2 of the 3 measurements of vital signs during screening (45, 30, and/or 15 minutes prior to dosing) must meet criteria.
  • Current AF episode treated with Class I or Class III antiarrhythmic drugs or electrical cardioversion. Subjects whose current AF episode has been treated with flecainide are eligible if their total cumulative exposure to flecainide (including the study drug to be administered in this study) does not exceed 320 mg within a 24-hour period, per site standard of care.
  • History of acute decompensated heart failure (HF)
  • History within 6 months prior to screening of, or present HF with a left ventricular ejection fraction (LVEF) < 45%, and/or Class II or higher HF as defined by the New York Heart Association (NYHA), and/or medication history suggestive of HF, in the opinion of the Investigator. An echocardiogram with LVEF within 6 months of screening is required to demonstrate eligibility. If no echocardiogram is available, subject must undergo a diagnostic echocardiogram using a portable handheld ultrasound device (handheld echocardiogram; HHE) during screening to confirm eligibility.
  • Evidence of current ongoing myocardial ischemia, such as signs (e.g., significant [e.g., > 2 mm] ST segment elevation or depression on ECG, echocardiographic findings suggestive of acute myocardial infarction), symptoms (e.g., angina pectoris, atypical angina pectoris), and/or being medicated with anti-anginal medication. In addition, subjects with signs of prior myocardial infarction (such as pathological Q waves) who are also taking concomitant medications for angina pectoris should be evaluated for presence of ongoing ischemia.
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  • History of myocardial infarction (MI) within 3 months of screening
  • Known uncorrected severe aortic or mitral stenosis
  • Hypertrophic cardiomyopathy with outflow tract obstruction
  • Current diagnosis of persistent AF
  • One or more episodes of atrial flutter within 6 months prior to screening or atrial flutter at presentation
  • History of any of the following heart abnormalities:
  • Long QT syndrome
  • Conduction disease (e.g. second- or third- degree heart block, bundle brach block)
  • Diagnosed with sinus node dysfunction (e.g., sick sinus syndrome) and/or one of the following:
  • history of unexplained or cardiovascular syncope, (ii) known bradycardia suggestive of sinus node dysfunction, and/or (iii) prior electrical or pharmacological cardioversion associated with prolonged sinus or ventricular pause (e.g., >3 seconds) and/or slow ventricular rhythm (e.g., <45 bpm) at time of conversion Note: Sinus node dysfunction in AF is more prevalent in subjects >75 years old. d) Brugada Syndrome e) Torsades de pointes (TdP)
  • Any of the following ECG-related features:
  • QTc interval >480 msec at screening (estimated by the Fridericia's formula)
  • QRS duration ≥ 120 ms or history of previous documented wide QRS tachycardia
  • Predominantly (i.e., >30%) paced heart rhythm
  • Ventricular tachycardia (VT, sustained or non-sustained), or excessive premature ventricular complexes (PVCs, > 20 multifocal PVCs per hour), prior to dosing as per site telemetry. Site telemetry should be equipped with an alarm system for VT and PVCs or be continuously visually observed prior to dosing
  • Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis
  • Known abnormal liver function prior to randomization/allocation (including hepatic disease or biochemical evidence of significant liver derangement known prior to randomization/allocation)
  • Uncorrected hypokalemia (defined as serum potassium <3.6 mEq/L) at screening. If serum potassium result is <3.8 mEq/L at screening, therapeutic correction (e.g., potassium supplementation) is strongly encouraged, although reassessing the serum potassium level is not required as long as a value ≥ 3.6 mEq/L is documented at screening.
  • Subjects with established pulmonary disease in need of inhalation medication. Subjects with COPD are excluded. Subjects with mild to moderate asthma that are not experiencing active symptoms at screening and whose asthma is well controlled with steroids and/or as-needed administration of a bronchodilator are eligible for the study.
  • Known hypersensitivity to flecainide acetate or any of its active metabolites
  • Concomitant therapy with systemic drugs that are strong inhibitors of CYP 2D6 (e.g. antidepressants, neuroleptics, ritonavir, some antihistamines) or CYP 2D6 inducers (e.g. phenytoin, phenobarbital, carbamazepine)
  • Treatment with Class I or Class III antiarrhythmic drugs within the last week. Subjects whose current AF episode has been treated with flecainide are eligible if their total cumulative exposure to flecainide (including the study drug to be administered in this study) does not exceed 320 mg within a 24-hour period, per site standard of care.
  • Treatment with amiodarone within the last 12 weeks
  • Subject is deemed unsustainable for the trial by the Investigator (including but not limited to: patients who are considered at high risk for stroke based on screening coagulation panel or medical history (e.g., CHA2DS2-VASc score); patients with congenital heart disease; patients with history of AF refractory to pharmacological or electrical cardioversion; patients whose AF is secondary to electrolyte imbalance, thyroid disease, or other reversible or non-cardiovascular cause; patients with episodes of syncope; patients with any serious or life threatening medical condition; patients with any acute infection). The subject may be deemed unsuitable for the trial by the Investigator if the subject is not able or willing to inhale the study drug.
  • Known drug or alcohol dependence within the past 12 months as judged by the Investigator
  • A body mass index > 40 Kg/m2
  • Legally incompetent to provide informed consent (IC)
  • Previous randomization/allocation in this study or treatment with any other investigational drug within 30 days from screening or 5 half-lives of the drug, whichever is longer
  • Female of childbearing potential
  • Who are not surgically sterile, or post-menopausal (defined as no menses for 2 years without an alternative cause), or
  • For whom a negative pregnancy test is unavailable before study entry, or
  • Who are pregnant or breast feeding at study entry
  • Previous administration of flecainide for an episode of paroxysmal AF or new AF did not result in conversion of AF to SR (i.e., subject is considered a non-responder to flecainide)
  • Cardiac surgery for any of the exclusionary conditions (e.g., valvular disease, hypertrophy, coronary artery disease [CAD], etc.) within the last 6 months prior to screening
  • Respiratory rate of > 22 breaths per minute

Trial locations and contacts

9 sites in 2 countries.

9 sites in 2 countries

Netherlands8 sites

  • OLVG

    Amsterdam

  • Deventer Ziekenhuis

    Deventer

  • Admiraal De Ruyter Ziekenhuis

    Goes

  • UMCG

    Groningen

  • Spaarne Gasthuis

    Haarlem

  • Maastricht University Medical Center

    Maastricht

  • Gelre Ziekenhuizen

    Zutphen

  • Isala Klinieken

    Zwolle

Other trials in Netherlands

Belgium1 site

  • Imelda

    Bonheiden

Other trials in Belgium

About this study

Official title: A Prospective Randomized Multicenter Study of Flecainide Acetate Oral Inhalation Solution in Single and Repeat Dose Regimens for Acute Conversion to Sinus Rhythm in Subjects With Recent Onset of Symptomatic Paroxysmal Atrial Fibrillation

The study consisted of 3 parts (Part A, Part B and Part C). Part A was an open-label, randomized, multi center design to evaluate the feasibility of administration of inhaled flecainide in two dosing regimens. Part B was an open-label, multicenter design to confirm the safety (including tolerability) and efficacy of the optimal inhaled flecainide dose determined from Part A. Part C was an open-label, multi center study with exploratory objectives to explore the feasibility of patient-led self administration of flecainide. Part C also included an exploratory sub-study to assess the feasibility of implementing a portable cardiac ultrasound (HHE) at screening in an emergent setting.

Read the detailed description

Subjects eligible to participate in the study must provide written informed consent (IC) before randomization or any study- specific procedures.

The study consists of 3 parts (Part A, Part B and Part C) as described below:

Part A: was completed in March 2020 and was an open-label, randomized, multicenter design to evaluate the feasibility of administration of inhaled flecainide in two dosing regimens.

Subjects were randomized at a 1:1 ratio to a single (N = 10) or repeat (N = 10) dose regimen. Randomization, for the initial 20 patients in Part A was stratified by duration of the presenting AF episode (≥ 1 h up to ≤ 24 hours; > 24h up to ≤ 48h).

After completion of the 60 mg dose cohort and review of safety/tolerability and PK data, additional subjects were enrolled in an additional repeat dose regimen (90 mg estimated total lung dose (TLD), N= up to 30 subjects. An additional dose cohort of 120 mg was added to Part A which utilized a different concentration of flecainide (75 mg/mL) and formulation (FlecIH-103). The final dose of 120 mg was selected as the dose to continue evaluating in Part B.

Part B: was an open-label, multicenter design to confirm the safety (including tolerability) and efficacy of the optimal inhaled flecainide dose determined from Part A (120 mg, using the FlecIH-103 inhalation solution).

Part C: was an open-label, multi center design study with exploratory objectives to explore the feasibility of patient-led self administration of flecainide. Part C also included an exploratory sub-study to assess the feasibility of implementing a portable cardiac ultrasound (HHE) at screening in an emergent setting.

Upon return to the clinic with a recurrent episode of AF, eligibility was reconfirmed and the subjects self-administered the study treatment and inhalation regimen under medical supervision.

If at 90 minutes after initiation of dosing, no conversion to sinus rhythm (SR) was observed, the Investigator was allowed to offer the subject another appropriate therapy. Discharge was left up to the discretion of the treating physician but no less than 90 min after initiation of dosing. Heart rhythm was confirmed with an Event Recorder during follow up.

An independent Data and Safety Monitoring Board (DSMB) was responsible for monitoring safety during the study.

Being tested
Flecainide Acetate
Keywords
Inhaled Flecainide
Medical subject headings
Atrial Fibrillation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Flecainide AcetateDrug

    Also called FlecIH

    Oral inhalation form using a nebulizer

Study groups in NCT03539302
Study groupRoleWhat they receive
Repeat dose inhaled flecainide acetateExperimentalOne 120 mg dose of flecainide acetate inhalation solution will be administered via two oral inhalations of 3.5 minutes. There will be a 1 minute break between the two inhalations. A single nebulizer will be used. A subset of enrolled patients will be included in a sub-study in which a Hand Held ECHO device at bedside will be used to confirm eligibility by verifying absence of structural heart disease. Once eligibility is confirmed the treatment for this subset of patients will be the same as described above; one 120 mg dose of flecainide acetate inhalation solution will be administered via two oral inhalations of 3.5 minutes. There will be a 1 minute break between the two inhalations. A single nebulizer will be used.
Receives: Drug: Flecainide Acetate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With Successful Conversion of Atrial Fibrillation to Sinus Rhythm

    To evaluate the conversion of AF to SR and symptom relief by inhaled flecainide acetate inhalation solution, under two oral inhalation dosing regimens in subjects with recent onset of paroxysmal AF. The subjects will be monitored via ECG and telemetry while in the hospital for 90 minutes.

    Measured: 90 minutes

Secondary outcomes (2)

  1. PK Objectives by Analyzing Blood Samples to Evaluate Peak Plasma Concentration (Cmax)

    To explore the population pharmacokinetics (PK) of inhaled flecainide under two oral inhalation dosing regimens in subjects with recent onset paroxysmal AF. Blood samples are collected from each subject for pharmacokinetic analysis.

    Measured: 90 minutes

  2. Pharmacodynamics (PD) Objectives by Performing Serial 12-Lead ECG Recordings (Changes in QRS)

    To explore the electrocardiographic effects of inhaled flecainide under two oral inhalation dosing regimens in subjects with recent onset of paroxysmal AF. Serial 12-Lead ECG measurements are extracted from the Holter recording in triplicate before, after the allocated inhalation regimen and at the time of conversion to sinus rhythm for pharmacodynamic analysis.

    Measured: 90 minutes

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 May 2018
  2. Study start29 May 2018
  3. Primary completion17 Jan 2022
  4. Study completion17 Jan 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Model description
The 3 parts of the study were performed sequentially. Only Part A was randomized to assign subjects to either the 30 mg dose or 60 mg. Parts B and C were not randomized. There were no comparators in this study and no masking.
Masking
None (open label)
Enrolment
176 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03539302
Sponsor's protocol ID
FLE-002
Acronym
INSTANT
Status last verified
Feb 2024
First submitted
26 Feb 2018
Last updated
14 May 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Ruskin JN, Camm AJ, Dufton C, Woite-Silva AC, Tuininga Y, Badings E, De Jong JSSG, Oosterhof T, Aksoy I, Kuijper AFM, Van Gelder IC, van Dijk V, Nuyens D, Schellings D, Lee MY, Kowey PR, Crijns HJGM, Maupas J, Belardinelli L; INSTANT Investigators. Orally Inhaled Flecainide for Conversion of Atrial Fibrillation to Sinus Rhythm: INSTANT Phase 2 Trial. JACC Clin Electrophysiol. 2024 Jun;10(6):1021-1033. doi: 10.1016/j.jacep.2024.02.021. Epub 2024 Apr 10.

    PubMed 38613545

  • Crijns HJGM, Elvan A, Al-Windy N, Tuininga YS, Badings E, Aksoy I, Van Gelder IC, Madhavapeddi P, Camm AJ, Kowey PR, Ruskin JN, Belardinelli L; INSTANT Investigators*. Open-Label, Multicenter Study of Flecainide Acetate Oral Inhalation Solution for Acute Conversion of Recent-Onset, Symptomatic Atrial Fibrillation to Sinus Rhythm. Circ Arrhythm Electrophysiol. 2022 Mar;15(3):e010204. doi: 10.1161/CIRCEP.121.010204. Epub 2022 Feb 24.

    PubMed 35196871

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Flecainide Acetate in people with Paroxysmal Atrial Fibrillation (PAF), run by InCarda Therapeutics, Inc. at 9 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 41 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Successful Conversion of Atrial Fibrillation to Sinus Rhythm (time frame: 90 minutes). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03539302, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 May 2024.

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