A Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial of Flecainide Acetate Inhalation Solution for Cardioversion of Recent-Onset, Symptomatic Atrial Fibrillation to Sinus Rhythm
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 54
- 试验地点
- 40
- 主要终点
- Assessment of proportion of patients whose AF converts using continuous ECG monitoring
研究概览
简要总结
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled clinical study designed to evaluate the efficacy and safety of FlecIH-103 (flecainide acetate inhalation solution) compared with placebo in patients with recent-onset, symptomatic newly diagnosed or paroxysmal AF. Approximately 400 patients are expected to be enrolled in this study. Patients will be randomized 3:1 to receive FlecIH-103 at a total dose of up to 120 mg estimated total lung dose (eTLD) (n=300) or placebo inhalation solution (n=100). Randomization will be stratified by geographic region (US and ex-US) and duration of symptoms of the current AF episode (≥1 hour to ≤24 hours and >24 hours to ≤48 hours).
详细描述
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled clinical study designed to evaluate the efficacy and safety of FlecIH-103 (flecainide acetate inhalation solution) compared with placebo in patients with recent-onset, symptomatic newly diagnosed or paroxysmal AF. Approximately 400 patients are expected to be enrolled in this study. The study will consist of the following periods: Screening, Observation, and Follow-up.
The Screening Period comprises the time from the patient signing informed consent to the time of randomization. Screening begins at least 45 minutes prior to dosing and may be extended as needed due to site logistics. During screening, the patient will be evaluated for study eligibility, have a standard triplicate 12-lead ECG to confirm the diagnosis of AF, have a single-lead patch electrode applied for continuous ECG (cECG) recording, undergo a targeted physical examination (including cardiovascular and respiratory systems), have blood drawn for laboratory assessments and a predose pharmacokinetic (PK) sample, have their AF-related symptoms assessed, have vital signs assessed periodically, and be monitored via telemetry to ensure they remain predominantly in AF prior to dosing (ie, no period of SR ≥1 minute in duration or any abnormal rhythm other than AF). After confirmation that the patient meets all applicable eligibility criteria, randomization will take place using a central randomization system. The patient is considered enrolled at the time of randomization.
The Observation Period comprises the time from randomization through 90 minutes after initiation of dosing. After randomization and just prior to the start of dosing (T0), the patient's AF will again be confirmed by a standard triplicate 12-lead ECG; patients who are not in AF at this time must be withdrawn. The patient will inhale the study drug until conversion of AF to SR occurs for ≥1 minute or the complete dose is administered, whichever occurs first. The complete dose of study drug comprises 2 separate 3.5-minute inhalations separated by a 1-minute break. Telemetric recording of ECG and cECG monitoring will continue and vital signs will be monitored periodically. A PK sample will be collected 2 minutes after completion of dosing followed by another standard triplicate ECG collected 5 minutes after completion of dosing. Finally, AF-related symptoms will be checked and a final PK sample will be collected at 90 minutes after initiation of dosing. Wherever a time point requires collection of ECG and/or vital signs in addition to a PK sample, the PK sample is collected last.
If the patient's AF converts to SR (sustained for ≥1 minute) as observed on telemetry during the Observation Period, vital signs and a standard triplicate 12-lead ECG will be recorded immediately following the time of conversion. The Investigator may not offer the patient another rhythm control therapy to cardiovert their AF to SR until after 90 minutes after initiation of dosing. At the end of the Observation Period (ie, 90 minutes after initiation of dosing), the cECG patch will be removed and a standard triplicate 12 lead ECG will be recorded. If the patient's AF converts to SR (sustained for ≥1 minute) after the Observation Period but prior to discharge (eg, due to ECV or other PCV), a standard triplicate 12-lead ECG will be recorded at the time of conversion.
The patient may be discharged per the Investigator's discretion any time after completion of the 90-minute time point assessments. If patient discharge occurs >1 hour after completion of the last 90-minute time point assessment, all 90-minute time point assessments must be repeated just prior to discharge, excluding the PK sample.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •≥18 and ≤85 years of age
- •Recent onset of symptomatic newly diagnosed or paroxysmal AF
- •Recent onset is defined as a symptom duration ≥1 and ≤48 hours at time of dosing
- •Newly diagnosed AF is AF that has not been diagnosed previously, independent of its duration
- •Paroxysmal AF is defined as recurrent AF in a patient whose previous AF episode(s) self-terminated (ie, without treatment) or terminated with intervention ≤7 days of onset.
- •A symptomatic recent-onset AF episode post cardiac ablation for paroxysmal AF would be considered eligible
排除标准
- •History of non self-terminating AF/AFL as defined by
- •One or more failed attempts to restore SR with pharmacological therapy
- •ECV procedure for an AF episode ≤1 year prior to screening. Exception: One (1) prior ECV is allowed if no option for pharmacological conversion was previously available
- •More than 3 ECV procedures in ≤5 years prior to screening
- •Current diagnosis of persistent AF
- •Persistent AF defined as AF that is continuously sustained >7 days, including episodes terminated by cardioversion (drugs or electrical cardioversion) after >7 days. Patients with persistent AF do not have self-terminating AF episodes
- •Patients who have undergone an ablation procedure for persistent AF are not eligible
- •One or more episodes of AFL ≤6 months prior to randomization
- •a. Exception: a patient who has received ablation for AFL ≤3 months prior to screening with no recurrence of AFL prior to randomization is considered eligible Vital signs
- •Hemodynamic or cardiac instability during AF, defined as any of the following:
- •Systolic blood pressure <100 or ≥160 mmHg
- •Diastolic blood pressure ≥95 mmHg
- •Ventricular heart rate <80 or >160 bpm
- •Respiratory rate >22 breaths per minute Relevant structural heart disease
- •History of decompensated heart failure (HF)
- •Evidence of significant HF defined as any of the following:
- •a. Hospitalization in the last 12 months for HF or suspected HF event b. Most recent assessment of left ventricular ejection fraction (LVEF) <45% i. For patients in the United States, a standard diagnostic echocardiogram assessed ≤180 days prior to screening is required to ascertain eligibility. If none is available, the patient must undergo a standard diagnostic echocardiogram or a diagnostic echocardiogram using a portable ultrasound device (handheld echocardiogram [HHE]) during screening to confirm eligibility c. New York Heart Association (NYHA) Class II-IV symptoms d. Medication history suggestive of HF per the Investigator's discretion
- •Signs or symptoms of ongoing myocardial ischemia, including any of the following:
- •Significant ST segment elevation or depression (ie, ≥2 mm) on a standard 12-lead ECG
- •Echocardiogram findings (eg, wall motion abnormalities) suggestive of acute myocardial infarction (MI)
- •Angina pectoris, atypical angina pectoris, or receiving antianginal medication for ischemia
- •History of MI ≤3 months of screening
- •History of uncorrected moderate or severe aortic or mitral valvular stenosis, in the opinion of the Investigator
- •a. If an echocardiogram is performed at screening, moderate or severe valve disease observed during the examination is considered exclusionary
- •History of LV hypertrophy with LV thickness >12 mm as observed in the most recent assessment, ie, an echocardiogram Other CV conditions
- •Stroke (including transient ischemic attack) ≤3 months prior to randomization
- •History of any of the following cardiac abnormalities:
- •Long QT syndrome
- •Conduction system disease (eg, PR interval >200 ms, second- or third degree heart block, bundle branch block)
- •Brugada syndrome
- •Torsade de pointes
- •Diagnosed with sinus node dysfunction (eg, sick sinus syndrome) or any of the following:
- •i. History of unexplained or cardiovascular syncope ii. Bradycardia suggestive of sinus node dysfunction iii. Prior electrical or pharmacological cardioversion associated with sinus or ventricular pause >3 seconds or ventricular heart rate <45 bpm at time of conversion
- •Any of the following ECG-related features at screening:
- •QT interval corrected for heart rate using the Fridericia formula (QTcF) >480 msec
- •Wide QRS complex (ie, duration ≥120 msec) or history of documented wide QRS complex tachycardia (ie, wide QRS complex with ventricular heart rate >100 bpm)
- •Presence of ventricular tachycardia (VT). Site telemetry should be equipped with an alarm system for VT and PVCs or be continuously visually observed prior to dosing
- •Presence of a pacemaker
- •Cardiac surgery for any of the exclusionary conditions (eg, valvular disease, hypertrophy, coronary artery disease) ≤6 months prior to randomization Prior and concomitant non-CV conditions
- •Known severe renal impairment or patient receiving dialysis
- •Known abnormal liver function, including hepatic disease or biochemical evidence of significant liver derangement
- •Uncorrected hypokalemia
- •Hypokalemia is defined as serum potassium below the normal range according to the local laboratory reference ranges at screening
- •If serum potassium is below the normal range at screening, therapeutic correction (eg, potassium supplementation) is required
- •Uncorrected hypomagnesemia
- •Hypomagnesemia is defined as serum magnesium below the normal range according to the local laboratory reference ranges at screening
- •If serum magnesium result is below the normal range at screening, therapeutic correction (eg, magnesium supplementation) is required
- •Chronic obstructive pulmonary disease or other established pulmonary disease in need of inhalation medication
- •a. Exception: patients with intermittent mild asthma who are not experiencing active symptoms at screening, and whose asthma is well controlled with as-needed administration of a bronchodilator ≤2 days/week, and who has not experienced ≥2 exacerbations requiring oral systemic corticosteroids ≤1 year prior to screening
- •History of bronchospasm (eg, hyperreactive airways to inhalants) or difficulty inhaling medications
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研究组 & 干预措施
FlecIH-103 (flecainide acetate inhalation solution)
Up to two 3.5-minute inhalations separated by a 1-minute break, for a total duration of up to 8 minutes on Day 1. Dosing will continue until conversion of AF to SR is observed for ≥1 minute or the full dose (120 mg eTLD) is administered, whichever occurs first.
干预措施: FlecIH-103 (Drug)
Vehicle-matched inhalation solution (placebo)
Up to two 3.5-minute inhalations separated by a 1-minute break, for a total duration of up to 8 minutes on Day 1.
干预措施: FlecIH-103 (Drug)
结局指标
主要结局
Assessment of proportion of patients whose AF converts using continuous ECG monitoring
时间窗: 90 minutes
To compare the efficacy of flecainide acetate inhalation solution and placebo for the conversion of atrial fibrillation (AF) to sinus rhythm (SR) in patients with recent-onset, symptomatic newly diagnosed or paroxysmal AF. Conversion from AF to SR will be monitored via continuous ECG recording. The efficacy of flecainide acetate solution and placebo will be compared using conversion as recorded on the ECG.
次要结局
- Assessing and comparing the AF related symptoms by using a questionnaire(90 minutes post dose)
- Time of conversion to be monitored using continuous ECGs(90 minutes)
- Assessing and comparing the hospital admissions between the active vs. placebo(90 minutes)
- Assessing and comparing the AF-related interventions prior to discharge between the active vs. placebo(90 minutes)
- Assessing and comparing the time of discharge(90 minutes)