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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 28, 2018
Last Update Posted : October 11, 2018
Sponsor:
Information provided by (Responsible Party):
InCarda Therapeutics Australia Pty Ltd.

Brief Summary:
The study consists of 2 parts (Part A and Part B). Part A has an open-label, randomized, multi center design to evaluate the feasibility of administration of inhaled flecainide in two dosing regimens. Part B has a randomized, double-blind, parallel group, placebo-controlled, multi center design to evaluate the safety (including tolerability) and efficacy of inhaled flecainide compared to matched placebo in two dosing regimens.

Condition or disease Intervention/treatment Phase
Paroxysmal Atrial Fibrillation (PAF) Drug: Flecainide Acetate Other: Matched Placebo 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: has 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.

PART B: has a randomized, double-blind, parallel-group, placebo-controlled, multicenter design to evaluate the safety, tolerability and efficacy of inhaled flecainide against matched placebo in the two dosing regimens.

Subjects are randomized at a 1:1 ratio to a single or repeat dose regimen. Within each dose regimen, subjects are randomized in a 2:1 ratio to either inhaled flecainide or matched placebo. Randomization yields the following 4 groups:

  • Single dose inhaled flecainide (N = 30)
  • Single dose matched placebo (N = 15)
  • Repeat dose inhaled flecainide (N = 30)
  • Repeat dose matched placebo (N = 15)

Randomization, for both Part A and Part B, is 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 30 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

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

Part B is randomized with a parallel group, placebo-controlled. Subjects are randomly assigned, in a 1:1 ratio, to a single dose or to a repeat dose regimen. Within each dose regimen, subjects are randomized in a 2:1 rate to ether inhaled flecainide or matched placebo.

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 : April 2019
Estimated Study Completion Date : April 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Single dose inhaled flecainide acetate
A single dose of 30 mg of flecainide acetate will be administered once via oral inhalation for 4.5 minutes
Drug: Flecainide Acetate
Oral inhalation form using a nebulizer
Other Name: FlecIH

Placebo Comparator: Single dose matched placebo
A single dose of placebo will be administered once via oral inhalation for 4.5 minutes
Other: Matched Placebo
Oral inhalation of a Matched Placebo

Active Comparator: Repeat dose inhaled flecainide acetate
Two 30 mg doses of flecainide will be administered via oral inhalation for 4.5 minutes. There will be a 1 minute break before initiation of second inhalation. A new nebulizer will be used for the second dose.
Drug: Flecainide Acetate
Oral inhalation form using a nebulizer
Other Name: FlecIH

Placebo Comparator: Repeat dose matched placebo
Two doses of placebo will be administered via oral inhalation for 4.5 minutes. There will be a 1 minute break before initiation of second inhalation. A new nebulizer will be used for the second dose.
Other: Matched Placebo
Oral inhalation of a Matched Placebo




Primary Outcome Measures :
  1. Efficacy Objective evaluated using ECGs and telemetry to record heart rhythm [ Time Frame: 240 minutes ]
    To evaluate the conversion of AF to SR and symptom relief by inhaled flecainide acetate inhalation solution, compared to matched placebo, 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 240 minutes.


Secondary Outcome Measures :
  1. Safety Objectives by monitoring the patient for AEs and SAEs [ Time Frame: 240 minutes, 24 hours and 7 days ]
    To assess the safety and tolerability of inhaled flecainide compared to matched placebo, under two oral inhalation dosing regimens in subjects with recent onset of paroxysmal AF. All subjects are monitored for safety for 240 minutes while in the hospital. Two follow up telephone assessments will be completed 24 hours and 7 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: 240 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: 240 minutes ]
    To explore the electrocardiographic effects of inhaled flecainide under two oral inhalation dosing regiments in subjects with recent onset of paroxysmal AF. Serial 12-Lead ECG readings are recorded 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 and older   (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

Exclusion Criteria:

  1. Subjects <18 years of age
  2. Hemodynamic instability, with systolic blood pressure <90 mmHg or heart rate >170 bpm
  3. Current AF episode has been treated with anti arrhythmic drugs or electrical cardio version
  4. History of acute decompensated heart failure (HF)
  5. History of HF with reduced ejection fraction (EF)
  6. Signs or symptoms of myocardial ischemia
  7. History of myocardial infarction (MI)
  8. Known uncorrected severe aortic or mitral stenosis
  9. Hypertrophic cardiomyopathy with outflow tract obstruction
  10. History of persistent AF
  11. 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. Sick sinus syndrome
    4. Brugada Syndrome
    5. Torsades de pointed (TdP)
  13. Any of the following ECG-related features:

    1. QTc interval >450 msec for male or QTc >460 msec for females subjects, at screening (estimated by the Fridericia's formula)
    2. QRS duration >/= 120 ms or history of previous documented wide QRS tachycardia
    3. Predominantly paced heart rhythm
  14. Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis
  15. Known abnormal liver function prior to randomization (including hepatic disease or biochemical evidence of significant liver derangement known prior to randomization)
  16. Uncorrected hypokalemia (defined as serum potassium <3.8 mEq/L) at screening
  17. Patients with established pulmonary disease in need of inhalation medication
  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, propranolol, ritonavir, some antihistamines) or CYP 2D6 inducers (e.g. phenytoin, phenobarbital, carbamazepine)
  20. Treatment with Class I or Class II antiarrhythmic drugs within the last week
  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 congenital heart disease, history of AF refractory to pharmacological or electrical cardioversion, AF is secondary to electrolyte imbalance, thyroid disease, or other reversible or non-cardiovascular cause, episodes of syncope, any serious or life threatening medical condition, any acute infection)
  23. Known drug or alcohol dependence within the past 12 months a judged by the Investigator
  24. A body mass index > 40 Kg/m2
  25. Legally incompetent to provide informed consent (IC)
  26. Previous randomization 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

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

Locations
Belgium
Imelda Recruiting
Bonheiden, Belgium
Contact: Tom Rossenbacker         
Principal Investigator: Tom Rossenbacker         
UZ Brussel Recruiting
Brussels, Belgium
Contact: Carlo de Asmundis         
Principal Investigator: Carlo de Asmundis         
Hopital Civil Marie Curie Recruiting
Charleroi, Belgium
Contact: Marko Gujic         
Principal Investigator: Marko Gujic         
Jessaziekenhuis Hasselt Recruiting
Hasselt, Belgium
Contact: Pascal Vranckx         
Principal Investigator: Pascal Vranckx         
Netherlands
Noordwest Ziekenhuisgroep Recruiting
Alkmaar, Netherlands
Contact: Giovanni Tahapary         
Principal Investigator: Giovanni Tahapary         
Admiraal De Ruyter Ziekenhuis Recruiting
Goes, Netherlands
Contact: Ismail Aksoy         
Maastricht University Medical Center Recruiting
Maastricht, Netherlands
Contact: Harry Crijns         
Principal Investigator: Harry Crijns         
Erasmus Medical Center Recruiting
Rotterdam, Netherlands
Contact: Tamas Szili-Torok         
Principal Investigator: Tamas Szili-Torok         
UMCU Recruiting
Utrecht, Netherlands
Contact: Jeroen van der Heijden         
Principal Investigator: Jeroen van der Heijden         
Isala Klinieken Recruiting
Zwolle, Netherlands
Contact: Arif Elvan         
Principal Investigator: Arif Elvan         
Sponsors and Collaborators
InCarda Therapeutics Australia Pty Ltd.
Investigators
Study Director: Luiz Belardinelli, MD Chief Medical Officer at InCarda Therapeutics

Responsible Party: InCarda Therapeutics Australia Pty Ltd.
ClinicalTrials.gov Identifier: NCT03539302     History of Changes
Other Study ID Numbers: FLE-002
First Posted: May 28, 2018    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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 Australia Pty Ltd.:
Inhaled Flecainide

Additional relevant MeSH terms:
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