A Phase 1, Double-Blind, Randomized, Placebo-controlled, Single Ascending Dose Study of Flecainide Acetate Inhalation Solution to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers

The investigational agents are: 1. Sterile flecainide acetate inhalation solution 35 mg/mL 2. Sterile placebo inhalation solution 3. Intravenous flecainide acetate (Tambocor (Trademark) Injection 10 mg/mL). A single inhaled dose of flecainide acetate inhalation solution or placebo inhalation solution will be administered per participant in the dose escalation part of the study. Single ascending doses will be administered in a sequential ascending manner from Cohorts 1 through to 4. Part A participants will receive a single Ascending Dose (inhalation only) in the following amounts: Cohort 1: 20mg Flecainide Acetate or Placebo Cohort 2: 40mg Flecainide Acetate or Placebo Cohort 3: 60mg Flecainide Acetate or Placebo Given that this is the first time that flecainide is administered to people as an inhalation, an additional of up to 6 participants (4 active, 2 placebo) may be enrolled in Cohort 2 (dose level of 40 mg), at the discretion of the SMG, in order to confirm safety, PK or PD results prior to proceeding to Part B and to further dose escalation of Part A. In Part C the dose level will be selected by the SMG following completion of Cohort 3 in Part A and will not exceed 60 mg. A washout period not shorter than 10 days and not longer than 14 days will separate Period 1 from Period 2. The SMG may recommend not to proceed with Part C on safety grounds. Part B, the open label crossover part of the study consists of one Cohort that is scheduled for two Periods, Period 1 and Period 2. In Period 1 the administration of open label flecainide will be via inhalation for all participants, whereas in Period 2 for the same participants the administration of open label flecainide will be intravenous for all participants. The two Periods will be separated by a 10 day washout period. The Period 1 inhalation dose will be determined by the safety management group after reviewing all of the data and safety data for the Part A. The Period 2 dose of intravenous flecainide will be 2mg/kg. All dose levels will begin with the administration of the study treatment to two sentinel participants (one randomized to receive flecainide acetate and one to receive placebo). The decision to dose the remaining six (6) participants in each cohort will be taken based on the safety and tolerability data obtained from the sentinel group as determined by review of the cardiac, hemodynamic, pulmonary function and other safety/tolerability information by the Principal Investigator (PI), the Study Cardiologist (SC) and the sponsor’s Medical Monitor (MM). If no significant adverse events (SAEs) or significant adverse device effects (SADEs) are observed for any participant in a cohort for a period of nine (9 +/-1) days of the last participant dosed, dosing may begin for the next cohort. The decision to escalate to the next dose level will be made following evaluation of the safety data (i.e., safety clinical labs, ECGs, pulmonary function, vitals and AEs) by the Safety Monitoring Group (SMG). The SMG will consist of the PI, the SC, and the sponsor MM. The SMG will review available safety data on Days 5-6 and tentatively decide on dose escalation. Final decision to dose escalate will be on Days 9-11 following review of all safety data (including Day 9 (+/- 1) follow up assessments) by the PI (the PI may consult with the SMG at his discretion). Escalation to the next highest dose level will proceed in cohorts of eight (8) until the dose level of 110.0 mg inhaled flecainide is completed. The trial may be halted prematurely by the PI or the sponsor due to safety or other concerns. There will be no intra-participant dose-escalation. In Part A, blinding will be preserved. However, treatment un-blinding may occur for an individual participant, at the PI’s discretion (in consultation with the sponsor MM), where deemed necessary for treatment of an Adverse Event (AEs) or Adverse device effect (ADE) or for a decision to be made regarding trial continuation. Clinically significant changes including AEs or ADEs will be followed up until resolution is achieved. Part C is an open label crossover comparing the PK/PD of inhaled flecainide administered using two different sources of compressed air through a nebulizer. In Part C participants will receive 2 inhaled doses of flecainide acetate, one using the AeroEclipse XL nebulizer connected to a compressed medical air source from a cylinder and the other using the AeroEclipse XL nebulizer connected to a battery operated portable compressed medical air source (Ombra portable). In Period 1, up to 3 participants will receive a single dose of flecainide acetate solution by inhalation using the AeroEclipse XL nebulizer connected to a compressed medical air source from a cylinder whereas up to 3 participants will receive a single dose of flecainide acetate solution by inhalation using the AeroEclipse XL nebulizer connected to a battery operated portable compressed medical air source (Ombra portable). In Period 2, the participants who were administered flecainide using the AeroEclipse XL nebulizer connected to a compressed medical air source from a cylinder in Period 1 will now receive a single dose of flecainide acetate solution by inhalation using the AeroEclipse XL nebulizer connected to a battery operated portable compressed medical air source (Ombra portable), while participants who were administered flecainide using the AeroEclipse XL nebulizer connected to a battery operated portable compressed medical air source (Ombra portable) in Period 1 will now receive a single dose of flecainide acetate solution by inhalation using the AeroEclipse XL nebulizer connected to a compressed medical air source from a cylinder.