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

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ClinicalTrials.gov Identifier: NCT03539302
Recruitment Status : Recruiting
First Posted : May 29, 2018
Last Update Posted : March 15, 2021
Sponsor:
Information provided by (Responsible Party):
InCarda Therapeutics, Inc.

Brief Summary:
The study consists of 2 parts (Part A and Part B). 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 is an open-label, multicenter design to confirm the safety (including tolerability) and efficacy of the optimal inhaled flecainide dose determined from Part A.

Condition or disease Intervention/treatment Phase
Paroxysmal Atrial Fibrillation (PAF) Drug: Flecainide Acetate Phase 2

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 2 parts (PART A and PART B) 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 are randomized at a 1:1 ratio to a single (N = 10) or repeat (N = 10) dose regimen.

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 eTLD, 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: is 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).

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).

Once study regimen is allocated, the subject will self-administer the study treatment and inhalation regimen.

If at 60 minutes after initiation of dosing, no conversion to SR is observed, the Investigator may offer the subject another appropriate therapy. Discharge is left up to the discretion of the treating physician but no less than 240 min after initiation of dosing. Heart rhythm will be confirmed with event recorder in follow up.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description:

Part A is open-label however subjects will be randomized to either a single dose or a double dose.

Part B is an open-label, multicenter design to confirm the safety (including tolerability) and efficacy of the optimal dose from Part A.

Primary Purpose: Treatment
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
Actual Study Start Date : May 29, 2018
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Repeat dose inhaled flecainide acetate
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.
Drug: Flecainide Acetate
Oral inhalation form using a nebulizer
Other Name: FlecIH




Primary Outcome Measures :
  1. Efficacy Objective evaluated using ECGs and telemetry to record heart rhythm [ Time Frame: 90 minutes ]
    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.


Secondary Outcome Measures :
  1. Safety Objectives by monitoring the patient for AEs, SAEs, AESIs and SAESIs [ Time Frame: 90 minutes, 24 hours and 5 days ]
    To assess the safety and tolerability of inhaled flecainide under two oral inhalation dosing regimens in subjects with recent onset of paroxysmal AF. All subjects are monitored for safety for 90 minutes while in the hospital. Two follow up telephone assessments will be completed 24 hours and 5 days post treatment. The clinical safety of inhaled flecainide is evaluated by comparing the frequency of treatment emergent SAEs between the treatment groups.

  2. PK Objectives by analyzing blood samples to evaluate peak plasma concentration (Cmax) [ Time Frame: 90 minutes ]
    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.

  3. PD Objectives by performing serial 12-Lead ECG recordings [ Time Frame: 90 minutes ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subjects with recent-onset symptomatic AF at presentation,
  2. With a duration at onset of symptoms from 1 hour to 48 hours,
  3. And from one of the following categories:

    1. First detected episode of paroxysmal AF
    2. Recurrent episode of paroxysmal AF
    3. Episode post-cardiac ablation for paroxysmal AF

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.

Exclusion Criteria:

  1. Subject < 18 or > 85 years of age
  2. 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.
  3. 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.
  4. History of acute decompensated heart failure (HF)
  5. 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.
  6. 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.
  7. History of myocardial infarction (MI) within 3 months of screening
  8. Known uncorrected severe aortic or mitral stenosis
  9. Hypertrophic cardiomyopathy with outflow tract obstruction
  10. Current diagnosis of persistent AF
  11. One or more episodes of atrial flutter within 6 months prior to screening or atrial flutter at presentation
  12. History of any of the following heart abnormalities:

    1. Long QT syndrome
    2. Conduction disease (e.g. second- or third- degree heart block, bundle brach block)
    3. Diagnosed with sinus node dysfunction (e.g., sick sinus syndrome) and/or one of the following:

    (i) 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)

  13. Any of the following ECG-related features:

    1. QTc interval >480 msec at screening (estimated by the Fridericia's formula)
    2. QRS duration ≥ 120 ms or history of previous documented wide QRS tachycardia
    3. Predominantly (i.e., >30%) paced heart rhythm
    4. 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
  14. Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis
  15. Known abnormal liver function prior to randomization/allocation (including hepatic disease or biochemical evidence of significant liver derangement known prior to randomization/allocation)
  16. 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.
  17. 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.
  18. Known hypersensitivity to flecainide acetate or any of its active metabolites
  19. 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)
  20. 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.
  21. Treatment with amiodarone within the last 12 weeks
  22. 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.
  23. Known drug or alcohol dependence within the past 12 months as judged by the Investigator
  24. A body mass index > 40 Kg/m2
  25. Legally incompetent to provide informed consent (IC)
  26. 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
  27. Female of childbearing potential

    1. Who are not surgically sterile, or post-menopausal (defined as no menses for 2 years without an alternative cause), or
    2. For whom a negative pregnancy test is unavailable before study entry, or
    3. Who are pregnant or breast feeding at study entry
  28. 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)
  29. 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
  30. Respiratory rate of > 22 breaths per minute

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03539302


Contacts
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Contact: Meisa Propst 510-422-5522 ext 111 propst.meisa@incardatherapeutics.com

Locations
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United States, California
Memorial Long Beach Medical Center Active, not recruiting
Long Beach, California, United States, 90807
United States, New Jersey
The Valley Hospital Completed
Ridgewood, New Jersey, United States, 07450
United States, New York
Weill Cornell Medicine Completed
New York, New York, United States, 10021
Belgium
Imelda Recruiting
Bonheiden, Belgium
Contact: Tom Rossenbacker         
Principal Investigator: Tom Rossenbacker         
Jessaziekenhuis Hasselt Completed
Hasselt, Belgium
Netherlands
Noordwest Ziekenhuisgroep Completed
Alkmaar, Netherlands
OLVG Recruiting
Amsterdam, Netherlands
Contact: Jonas de Jong         
Principal Investigator: Jonas de Jong         
Deventer Ziekenhuis Recruiting
Deventer, Netherlands
Contact: Ype Tuininga         
Principal Investigator: Ype Tuininga         
Admiraal De Ruyter Ziekenhuis Recruiting
Goes, Netherlands
Contact: Ismail Aksoy         
Martini Hospital Recruiting
Groningen, Netherlands
Contact: Robert Tieleman         
Principal Investigator: Robert Tieleman         
UMCG Recruiting
Groningen, Netherlands
Contact: I.C. van Gelder         
Principal Investigator: I.C. van Gelder         
Spaarne Gasthuis Recruiting
Haarlem, Netherlands
Contact: A.F.M. Kuijper         
Principal Investigator: A.F.M. Kuijper         
Maastricht University Medical Center Recruiting
Maastricht, Netherlands
Contact: Harry Crijns         
Principal Investigator: Harry Crijns         
UMCU Completed
Utrecht, Netherlands
Gelre Ziekenhuizen Recruiting
Zutphen, Netherlands
Contact: Nadea Al-Windy         
Principal Investigator: Nadea Al-Windy         
Isala Klinieken Recruiting
Zwolle, Netherlands
Contact: Arif Elvan         
Principal Investigator: Arif Elvan         
Sponsors and Collaborators
InCarda Therapeutics, Inc.
Investigators
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Study Director: Luiz Belardinelli, MD Chief Medical Officer at InCarda Therapeutics
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Responsible Party: InCarda Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03539302    
Other Study ID Numbers: FLE-002
First Posted: May 29, 2018    Key Record Dates
Last Update Posted: March 15, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by InCarda Therapeutics, Inc.:
Inhaled Flecainide
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Flecainide
Anti-Arrhythmia Agents
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action