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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 176
- 试验地点
- 9
- 主要终点
- Percentage of Participants With Successful Conversion of Atrial Fibrillation to Sinus Rhythm
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Part A was open-label however subjects were randomized to either a single dose or a double dose. There was no masking and this was a single-arm study.
Part B was an open-label, multicenter design to confirm the safety (including tolerability) and efficacy of the optimal dose from Part A.
Part C was an open-label, multicenter design study to assess the feasibility of self-administration of FlecIH-103 under medical supervision. Part C also included a sub-study to evaluate a hand-held echocardiogram device to assess the feasibility of its use in an emergent setting.
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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.
- •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:
- •(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)
- •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
研究组 & 干预措施
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.
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.
干预措施: Flecainide Acetate (Drug)
结局指标
主要结局
Percentage of Participants With Successful Conversion of Atrial Fibrillation to Sinus Rhythm
时间窗: 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.
次要结局
- PK Objectives by Analyzing Blood Samples to Evaluate Peak Plasma Concentration (Cmax)(90 minutes)
- Pharmacodynamics (PD) Objectives by Performing Serial 12-Lead ECG Recordings (Changes in QRS)(90 minutes)