| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute conversion to sinus rhythm (SR) in subjects with recent onset of symptomatic paroxysmal atrial fibrillation (AF). |
|
| E.1.1.1 | Medical condition in easily understood language |
| An irregular, rapid heart rate that may cause symptoms like heart palpitations, fatigue, shortness of breath, dizziness or chest discomfort |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034039 |
| E.1.2 | Term | Paroxysmal atrial fibrillation |
| E.1.2 | System Organ Class | 100000004849 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Objective Part A: The main objective of Part A is to evaluate the feasibility of single and repeat administration of flecainide acetate inhalation solution (30, 60, 90 and 120 mg estimated total lung dose (eTLD) for acute conversion of recent onset of paroxysmal AF to SR.
Objective Part B: Efficacy objectives: To evaluate the conversion of AF to SR and symptom relief by flecainide acetate inhalation solution in subjects with recent onset of paroxysmal AF.
Objective Part C:
• To explore the feasibility of patient-led self-administration of flecainide acetate inhalation solution in a hospital setting under medical supervision
• To explore the PK/PD of flecainide acetate inhalation solution in subjects with recent onset of paroxysmal AF for patient-led administration relative to medically-led administration, including resumption of SR
• To explore the feasibility of implementing a portable cardiac ultrasound (HHE) at screening in an emergent setting
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objective(s) Part B:
To assess the safety and tolerability of flecainide acetate inhalation solution in subjects with recent onset of paroxysmal AF.
Pharmacokinetic (PK) and pharmacodynamic (PD) objective(s):
• To evaluate the pharmacokinetics of flecainide acetate inhalation solution in subjects with recent onset of paroxysmal AF.
• To evaluate the electrocardiographic effects (PD) of flecainide acetate inhalation solution in subjects with recent onset of paroxysmal AF.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Exploratory Objective(s): (Handheld Echo Sub-Study) To explore the feasibility of implementing a portable cardiac ultrasound (handheld echocardiogram [HHE]) at screening in an emergent setting. This is applicable to all US sites, and to select EU sites participating in the optional HHE Sub-Study. |
|
| E.3 | Principal 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:
a) First detected episode of paroxysmal AF
b) Recurrent episode of paroxysmal AF
c) Episode post-cardiac ablation for paroxysmal AF
4) Part C Patient-Led Under Medical Supervision Cardioversion Study only: Subjects whose AF converted to SR with inhaled flecainide and without difficulties or issues with inhalation (in the opinion of the investigator), serious AE(s), or serious AESI(s) in Part A, Part B, or the Part C Medically-Led Cardioversion Study
NOTE: 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. |
|
| E.4 | Principal 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 > 160 bpm. 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 does not exceed 320 mg within a 24-hour period, per site standard of care.
4) History of acute decompensated heart failure (HF)
5) 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%
ii) For subjects in the EU who are participating in the optional HHE Sub-Study, the subject must undergo an 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
6) Evidence of current ongoing MI, such as signs, symptoms, and/or being medicated with anti-anginal medication. In addition, subjects with signs of prior MI who are also taking concomitant medications for AP 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 valve 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, except subjects who received ablation for atrial flutter at least 3 months prior to screening and had no subsequent recurrence of atrial flutter prior to enrollment
12) History of any of the following heart abnormalities:
a) Long QT syndrome
b) Conduction disease (e.g. second- or third-degree heart block, bundle branch block)
c) 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.2
d) Brugada Syndrome
e) Torsades de pointes (TdP)
13) Any of the following ECG-related features:
a) QTc interval > 480 msec at screening (estimated by the Fridericia’s formula1)
b) QRS duration ≥ 120 ms or history of previous documented wide QRS tachycardia
c) Predominantly (i.e., > 30 %) paced heart rhythm
d) Ventricular tachycardia (VT, sustained or nonsustained), 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 medical history of abnormal liver function prior to enrollment
16) Uncorrected hypokalemia (defined as serum potassium < 3.6 mEq/L) at screening.
required as long as a value of ≥ 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 unsuitable for the trial by the Investigator
26) Previous treatment in this study
27) Female of childbearing potential
28) Previous administration of flecainide for an episode of paroxysmal AF or new AF did not result in conversion of AF to SR
29) Cardiac surgery for any of the exclusionary conditions
30) Respiratory rate of > 22 breaths per minute |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
A: Feasibility is assessed in terms of the following performance characteristics:
a) Rates of study enrollment, screen failures and refusals of IC;
b) The rate of technically successful administration of the two study inhalation regimens;
c) Successful capture of study data according to the schedule of study assessments;
d) Successful remote capture of AF-status at follow-up contacts;
B :The primary efficacy endpoint is the proportion of subjects whose AF converted to SR by inhaled flecainide within 90 minutes after initiation of dosing.
C: - Proportion of subjects who achieved therapeutic dosing (≥ 200 ng/mL) with the study drug in the Part C Patient-Led Under Medical Supervision Cardioversion Study
- Feasibility of patient-led self-administration of study drug, including:
o Percent of subjects who consent to the study
o Percent of subjects who withdraw from the study
o Percent of subjects who are certified for self-administration of study drug
o Percent of subjects who return to clinic with a recurrent episode of PAF within 8 months of signing consent, and the associated timeframe(s) to time(s) of
recurrence
o Percent of subjects that independently set up and inhale study drug according to the provided instructions
- Proportion of subjects whose AF converted to SR
- Proportion of subjects for whom capture and assessment of a diagnostic echocardiogram using a HHE at screening was successful
- Percent of subjects who are considered ineligible for enrollment as a result of the HHE assessment
- Time from HHE administration to availability of HHE report/results
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time point specified in objectives |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints Part B:
- The proportion of subjects with Cmax values ≥ 200 ng/mL (e.g., 200, 300, 400, and 500 ng/mL) post inhalation with inhaled flecainide (excluding plasma levels associated with IV flecainide infusion) whose AF converted to SR by inhaled flecainide within 90 minutes after initiation of dosing.
- The time to conversion of AF to SR from initiation of dosing up to 90 minutes after initiation of dosing;
- The proportion of subjects in SR on Day 2;
- The proportion of subjects with reduced or no AF symptoms at 30 minutes post dose;
- The proportion of subjects with reduced or no AF symptoms at 60 minutes post dose;
- The proportion of subjects with reduced or no AF symptoms at 90 minutes post dose;
- The proportion of subjects who had their AF converted to SR by inhaled flecainide within 90 minutes after initiation of dosing and had no AF recurrence, requiring electrical or pharmacological cardioversion or rate control intervention, up to discharge;
- The proportion of subjects in SR on Day 5.
Time to conversion will be reported in statistical analyses from both initiation of dosing and completion of dosing.
Secondary safety endpoint Part B:
- Incidence of treatment emergent serious adverse events of interest for flecainide
Exploratory endpoints (for Handheld Echo Sub-Study only):
- Proportion of subjects for whom capture and assessment of a diagnostic echocardiogram using a HHE at screening was successful
- Percent of subjects who are considered ineligible for enrollment as a result of the HHE assessment
- Time from HHE administration to availability of HHE report/results
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time point specified in objectives |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Belgium |
| Netherlands |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The telephone contact on day 5 for the Medically-Led Cardioversion part of the study is the final study contact and marks the end of study (EOS) for each subject. Subjects that participate in the Patient-Led Cardioversion part of the study are followed up to their next episode of Atrial Fibrilation with a maximum follow up time of 8 months |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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