Clinical trial NCT03539302
Conditions: Paroxysmal Atrial Fibrillation (PAF)
Keywords: Inhaled Flecainide
Sponsor: InCarda Therapeutics, Inc.
Start date: 2018-05-29; Completion date: 2022-01-17
Enrollment: 176 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
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.

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 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.

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 (120 mg, using the FlecIH-103 inhalation solution).

Part C: was an open-label, multi center design 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.

Upon return to the clinic with a recurrent episode of AF, eligibility was reconfirmed and the subjects self-administered the study treatment and inhalation regimen under medical supervision.

If at 90 minutes after initiation of dosing, no conversion to sinus rhythm (SR) was observed, the Investigator was allowed to offer the subject another appropriate therapy. Discharge was left up to the discretion of the treating physician but no less than 90 min after initiation of dosing. Heart rhythm was confirmed with an Event Recorder during follow up.

An independent Data and Safety Monitoring Board (DSMB) was responsible for monitoring safety during the study.

Arms: arm 1: 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.
Interventions: intervention 1: Flecainide Acetate
Intervention descriptions: intervention 1: Oral inhalation form using a nebulizer

Protocol documents:
SAP_002.pdf: 
 
 
 
 
 
 
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Statistical Analysis Plan (SAP) 
 
 
FLE-002 (INSTANT) – Final Analysis 
A prospective, randomized, multicenter study of flecainide acetate 
oral inhalation solution in single and repeat dose regimens for 
acute conversion to sinus rhythm (SR) in subjects with recent onset 
of symptomatic paroxysmal atrial fibrillation (AF) 
 
Protocol FLE-002 Revision History 
Version 
Date 
1.0 
21-FEB-2018 
2.0 
10-OCT-2018 
3.0 
12-DEC-2018 
4.0 
02-MAY-2019 
T1`/25.0 
15-JUL-2019 
5.0 EU-1 
13-AUG-2019 
5.0 EU-2 
01-NOV-2019 
6.0 
06-MAR-2020  
(not implemented) 
7.0/EU-1 
27-JUL-2020 
7.0/US-1 
14-AUG-2020 
7.0/EU-2 
03-NOV-2020 
8.0 EU-1 
16-FEB-2021 
8.0/ US-1 
26-FEB-2021 
 
 
 
Version 5.0 
23 June 2022  
A.J. de Vries, Cardialysis B.V. 
 
 
Signature Page 
 
Study Title: 
 
INSTANT 
Version Date: 
 
06 July 2022 
Version Number: 
5.0 
 


 
 
 
 
 
 
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This Statistical Analysis Plan (SAP) is based upon protocol FLE-002 version 8.0 / EU-1 dated 16-FEB-
2021 and protocol FLE-002 version 8.0/US-1 dated 26-FEB-2021. 
 
  
The undersigned have reviewed this analysis plan and approve of it in its entirety.  
 
 
 
Signature 
Date 
J.N. Ruskin, MD 
Principal Investigator 
 
 
H.J.G.M. Crijns, MD 
Principal Investigator  
 
 
Luiz Belardinelli, MD 
Chief Medical Officer 
InCarda Therapeutics, Inc.  
 
 
Chris Dufton, PhD 
SVP of Clinical Development 
InCarda Therapeutics, Inc. 
 
 
Meisa Propst 
VP of Clinical Operations 
InCarda Therapeutics, Inc. 
 
 
Nine Favié 
Project Manager  
Cardialysis B.V. 
 
 
G. Rudez  
Manager Statistical Department 
Cardialysis B.V. 
 
 
A.J. de Vries  
Senior Statistician 
Cardialysis B.V. 
 
 
 


 
 
 
 
 
 
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SAP Version History 
 
Date 
Change 
Reason 
20-Dec-2019 
V2.0 updates SAP V1.0 to include 
modifications in the efficacy endpoints 
and dose cohorts. This SAP only includes 
Part A of the study. 
Protocol amendments 2.0-5.0 
EU-2 necessitated modification 
of SAP V1.0 
7-Apr-2020 
V2.1 updates V2.0 
V2.1 updated SAP for Part A, 
incorporating comments by 
reviewers on V2.0 
9-Jul-2020 
V3.0 updates V2.1 
Revision to expand on analysis 
populations and endpoints to 
take into consideration 
exposure to study medication 
relative to conversion of AF to 
SR 
30- Mar-2021 
V4.0 is first SAP for Part B 
Revision to describe the 
analysis of Part B 
01-July-2021 
V4.1 updates V4.0 
Revision in PK population, 
mITT population, source data 
for Adverse Event reporting of 
Part A FlecIH-103 subjects 
06-July-2022 
V5.0 is the SAP for the final analyses 
Revision to describe the 
analyses of Parts A, B and C 
 
 
 
 


 
 
 
 
 
 
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Table of Contents 
 
1 
Introduction .................................................................................................................................... 9 
 
Final Analysis Report ............................................................................................................... 9 
1.1.1 
Medically-Led Cardioversion Study (Part C MLS study) .................................................. 9 
1.1.2 
Patient-Led Under Medical Supervision Cardioversion Study Patient-Led Cardioversion 
Study (PLS) .................................................................................................................................... 10 
 
Brief description of Part C of the trial ................................................................................... 10 
 
Handheld Echo (HHE) ............................................................................................................ 10 
 
Study Design.......................................................................................................................... 11 
 
Study Population ................................................................................................................... 12 
 
Study procedures .................................................................................................................. 12 
 
Screen Failures ...................................................................................................................... 13 
2 
Study objectives Part C ................................................................................................................. 13 
3 
Definitions and Terminology ......................................................................................................... 14 
 
Conversion to SR, recurrence of AF ...................................................................................... 14 
 
Methods for Cardioversion ................................................................................................... 14 
 
Reported periods .................................................................................................................. 15 
 
Adverse Events ...................................................................................................................... 16 
 
Other definitions ................................................................................................................... 17 
4 
Study Medication .......................................................................................................................... 18 
5 
Source Data ................................................................................................................................... 19 
 
Investigator reported information ........................................................................................ 20 
 
Rhythm monitoring assessment (Holter) .............................................................................. 20 
 
Rhythm status assessments (Remote ECG) .......................................................................... 20 
 
Pharmacodynamic (PD) Assessment ..................................................................................... 20 
 
Pharmacokinetics (PK) assessment ....................................................................................... 21 
 
Safety results ......................................................................................................................... 21 
5.6.1 
Investigator (Part B and Part C)..................................................................................... 21 
5.6.2 
Cardialysis (Part A) ........................................................................................................ 22 
5.6.3 
Analysis Dataset Part B and Part C ................................................................................ 22 
5.6.4 
Analysis Dataset Report Part A ..................................................................................... 23 
5.6.5 
Additional AESI and SAESI information ......................................................................... 23 
 
Handheld Echo (HHE) ............................................................................................................ 24 
 
Protocol Deviations ............................................................................................................... 24 


 
 
 
 
 
 
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6 
Study Endpoints: definition and availability of information ......................................................... 25 
 
Time to conversion ............................................................................................................... 26 
6.1.1 
Time between initiation of study drug and conversion to SR (in minutes) .................. 26 
6.1.2 
Time between completion of study drug and conversion to SR (in minutes) .............. 26 
 
Endpoints, Adverse Events and other assessments .............................................................. 26 
6.2.1 
Primary endpoint .......................................................................................................... 27 
6.2.2 
Secondary efficacy endpoints ....................................................................................... 27 
6.2.3 
Secondary safety endpoint ........................................................................................... 27 
6.2.4 
Exploratory endpoints (HHE) ........................................................................................ 28 
6.2.5 
Additional Assessments ................................................................................................ 28 
6.2.6 
Exploratory Endpoints for Part C PLS ............................................................................ 32 
7 
General Statistical Considerations ................................................................................................ 33 
 
Sample Size and Power ......................................................................................................... 33 
7.1.1 
Treatment Allocation .................................................................................................... 33 
7.1.2 
Blinding and Unblinding ................................................................................................ 33 
 
Handling of Data ................................................................................................................... 34 
7.2.1 
Strata ............................................................................................................................. 34 
7.2.2 
Examination of Patient Subgroups ................................................................................ 34 
7.2.3 
Multiple Testing and Comparisons ............................................................................... 34 
7.2.4 
Visit Windows ............................................................................................................... 34 
7.2.5 
Imputation of Missing Data........................................................................................... 34 
8 
Study Populations ......................................................................................................................... 35 
 
Population of Consented Subjects ........................................................................................ 36 
 
Intention-To-Treat Population (ITT) ...................................................................................... 36 
 
Safety Population .................................................................................................................. 36 
 
PK Population ........................................................................................................................ 36 
 
Modified Intention-To-Treat Population (mITT) ................................................................... 38 
 
Handheld Echo (HHE) Population ......................................................................................... 38 
 
MLS Study Population Cohorts ............................................................................................. 38 
8.7.1 
Part C MLS Cohort (Cohort 1) ........................................................................................ 38 
8.7.2 
Pooled MLS Cohort (Cohort 2) ...................................................................................... 38 
8.7.3 
Pooled MLS No Predose Flecainide Cohort (Cohort 3) ......................................... 383839 
8.7.4 
Pooled MLS Predose Flecainide Cohort (Cohort 4) ....................................................... 39 
 
Patient-Led (PLS) Population ................................................................................................ 39 
9 
Statistical Methods ....................................................................................................................... 40 


 
 
 
 
 
 
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Patient Disposition, Demographic and Baseline Characteristics .......................................... 40 
 
Specification of Analyses ....................................................................................................... 40 
9.2.1 
Primary efficacy endpoint ............................................................................................. 40 
9.2.2 
Secondary efficacy endpoints and other assessments analyses................................... 41 
9.2.3 
Additional Analyses ....................................................................................................... 51 
9.2.4 
Exploratory endpoints: Handheld Echo ........................................................................ 55 
9.2.5 
Exploratory endpoints for Part C PLS study .................................................................. 60 
 
On Pooled results (Part A, Part B and Part C MLS Subjects (120 mg FlecIH-103)) ................ 63 
10 Difference between protocol and SAP .......................................................................................... 63 
11 Changes in the Planned Analyses.................................................................................................. 64 
12 Programming Conventions ........................................................................................................... 64 
13 References .................................................................................................................................... 65 
14 Tables, Figures and Listings ........................................................................................................... 65 
15 Programming Specifications ......................................................................................................... 67 
Annex A: FLE-002 Sponsor Review of Adverse Events of Special Interest ............................................ 68 
1. 
Background and Justification ........................................................................................................ 68 
2. 
Purpose ......................................................................................................................................... 68 
3. 
Responsibilities ............................................................................................................................. 69 
4. 
Definitions ..................................................................................................................................... 69 
5. 
Procedure ...................................................................................................................................... 71 
 
 
 


 
 
 
 
 
 
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Glossary of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
AE of Special Interest 
AECG 
Ambulatory Electrocardiogram 
AF 
Atrial Fibrillation 
BLQ 
Below the Limit of Quantification 
Cmax 
Maximum Plasma Concentration 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ECV 
Electrical Cardioversion 
EOS 
End-Of-Study 
eTLD 
Estimated total lung dose 
FlecIH 
Flecainide acetate inhalation solution 
HHE 
Handheld Echo 
IC 
Informed Consent 
ITT 
Intent-To-Treat 
IV 
Intravenous 
JTc 
Corrected JT interval 
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction (%) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent To Treat 
MLS 
Medically-Led Cardioversion Study  
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PLS 
Patient-Led Under Medical Supervision Cardioversion Study 
PR 
PR interval - measured from the beginning of the P wave to the beginning of the 
QRS complex 
TdP 
Torsades de Pointes 
Q1 
First Quartile 
Q3 
Third Quartile 
QRS 
QRS duration (complex) - a structure on the ECG that corresponds to the 
depolarization of the ventricles 
QTc 
QT interval corrected for heart rate 
RR 
RR interval - time between QRS complexes 
SAE 
Serious Adverse Event 
SAESI 
Serious Adverse Event of Special Interest 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System, software 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
SPAESI 
Sponsor assessed (S)AESI 
SR 
Sinus rhythm 


 
 
 
 
 
 
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Abbreviation 
Definition 
Tmax 
Time (of maximum concentration) 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures, and Listings 
TTM 
Transtelephonic Monitoring 
ULN 
Upper Limit of Normal 
VF 
Ventricular Fibrillation 
VT 
Ventricular Tachycardia 
 
 
 


 
 
 
 
 
 
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1 Introduction 
 
Final Analysis Report  
This SAP describes the final analysis of the INSTANT trial (Parts A, B and C for patients receiving 120 
mg dose of FlecIH-103).  
 
Parts A and B, consisted of a Medically-Led Cardioversion (MLS) only, whereas, Part C consists of a 
Medically-Led Cardioversion Study (MLS) and a Patient-Led Under Medical Supervision Cardioversion 
Study (PLS). Refer to SAP Section 1.4. for a description of the study design for Part C of the trial. 
 
This final Report will primarily focus on data for the MLS populations in the 120 mg FlecIH-103 using 
the prespecified definitions described in Section 8.1 through 8.6. Data for each MLS population will 
be presented for several cohorts, as described in Section 8.0. 
 
Due to the low number of subjects who participated in the PLS, a more limited analysis will be 
conducted on the PLS populations described in Section 8.8. Data for the PLS will only be presented 
for the overall study populations as defined in Section 8.8, with no additional cohort analyses.   
 
Details of all planned analyses for the INSTANT trial are specified in this SAP. Background 
information is provided for the overall study design. The reader is referred to the study protocols for 
details of study conduct. 
The  statistical analysis that will be performed for the final report will be based on this version of the 
SAP;  Flowcharts, Tables, Figures, and Listings (TFLs) will be created.  The report will be accompanied 
by an overview of all TFLs that are included in the report. 
 
1.1.1 
Medically-Led Cardioversion Study (Part C MLS study) 
Study procedures for subjects enrolled in the PART C MLS are identical to those in Part B; subjects 
receive 120 mg (2*60 mg), using the FlecIH-103 inhalation solution. Results for the Medically-Led 
administration will be presented for the prespecified analysis populations (e.g., safety, mITT) for the 
Part C MLS cohort only, and for several pooled cohorts consisting of subjects receiving 120 mg 
FlecIH-103 in Part A, Part B and Part C (i.e., the dose/formulation selected for Phase 3). Refer to SAP 
sections 8.7 for the definition of the pooled MLS cohorts.  
 
Statistical tables, figures and listings will be created. The tables will show study results for MLS Part C 
and for one or two pooled population, refer to SAP section 9.2 for a detailed description. Study 
procedures for the Part A subjects included in the pooled analysis were identical to those in Part B 
and Part C MLS. 
 
In the final analysis all endpoints will be reported that were included in the final report for Part B. 
However, unlike in Part B, all endpoints in Part C are exploratory; no formal hypothesis testing is 
planned for Part C. Summary statistics will be generated, including estimates of the endpoints and 
for the primary efficacy endpoint (refer to SAP section 9.2.1) its 90% confidence interval. 
 
Part C MLS subjects were enrolled in sites in Europe under Protocol Version 7.0 / EU-1 or later. This 
version of the SAP follows the text of the European Protocol Version V8.0 EU-1 as the basis for all 


 
 
 
 
 
 
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analyses, except where additional information from the US Protocol Version V8.0/ US-1 is required 
(e.g., for differences in screening requirements).  Enrollment in the MLS cohort of Part C was 
stopped on 31 December 2021, the last subject signed informed consent and received study 
medication on 07 December 2021. 
 
All analyses will be conducted with the EU and US subjects in a combined study population. 
 
1.1.2 
Patient-Led Under Medical Supervision Cardioversion Study Patient-Led 
Cardioversion Study (PLS) 
 
At sites in the EU, Part C includes an open-label Patient-Led Under Medical Supervision 
Cardioversion Study (PLS), whereby subjects who specifically consent and whose AF episode was 
previously converted to SR following an oral inhalation of flecainide solution in Part A, Part B and/or 
MLS Part C may be eligible to participate. 
 
Part C PLS will serve as a feasibility study to assess the ability of subjects to independently assemble 
the nebulizer, dispense the study medication, and self-administer the study medication with minimal 
supervision during a recurrent episode of recent-onset AF.  
 
Due to the small number of subjects enrolled in the PLS study (18 enrolled, 3 treated), summary 
tables will only be created for a limited amount of data (e.g., primary efficacy endpoint and 
disposition) and no confidence intervals will be reported. A flowchart and a summary table will show 
the main results for the study and all PLS results will be presented in listings. If needed, results from 
the initial MLS (Part A, Part B or MLS study of Part C) may be presented in listings for these PLS 
subjects. 
 
Three (3) out of 18 PLS subjects received a second treatment of 120 mg (2*60 mg) using the FlecIH-
103 inhalation solution. The last subject in the PLS study signed Informed Consent for the PLS study 
on 14 December 2021 and last subject was treated 19 August 2021.   
 
 
Brief description of Part C of the trial 
 
Part C consists of a MLS and PLS part, refer to SAP Section 1.4 for a further description of the study 
design for Part C of the trial.  
 
 
Handheld Echo (HHE) 
 
At selected sites in the EU, subjects in Part B and MLS Part C (Protocol Version 7.0 / EU-1 or later) 
could consent to participate in an optional Handheld Echo (HHE) sub-study and undergo an 
echocardiogram using the HHE during screening to confirm eligibility.  
 
In the US (Protocol Version V8.0/ US-1), an echocardiogram with LVEF within 6 months of screening 
was required to demonstrate eligibility. If no echocardiogram was available, subjects were required 
to undergo an echocardiogram using the HHE during screening to confirm eligibility. 


 
 
 
 
 
 
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HHE images were also reviewed and analyzed by an independent reviewer at a later date. 
 
A HHE was performed for 6 subjects; the last HHE was performed on 11 November 2021.  
 
The flowchart of the statistical report for INSTANT will show the number of subjects who signed IC 
for the HHE sub-study (EU) or for whom an HHE was required at screening (US). 
 
The full statistical analysis of the HHE sub-study is described in this version of the SAP. This analysis 
requires complete information from the HHE, as performed by the investigator and of the HHE 
analysis and as performed by the independent reviewer. 
 
 
Study Design 
 
An overview of Part C of the INSTANT trial is shown in Figure 1 below.  
 
Figure 1. Schematic for Part C: 120 mg Dose  
 
 
 
 
For Part C (both the MLS and PLS) subjects if treated receive a repeat dose regimen of 120 mg eTLD 
(2 x 60 mg) FlecIH-103 inhalation solution. 
  
The PLS requires subjects to return to the clinic for training, pass an assessment of their ability to 
self-administer the study drug, and then return to the clinic within 48 hours of the onset of 
symptoms when they experience a recurrent episode of paroxysmal AF to self-administer the study 
drug. Subjects may return and self-administer study drug for one recurrent episode of AF. 
 
 
INSTANT Study
PART C 
FlecIH-103
Medically-Led
FlecIH-103
Patient-Led Under 
Medical Supervision
INSTANT 
Study
PART A
INSTANT 
Study
PART B
Patients whose AF safely converted to SR with study drug in Part A, Part B, or 
the Medically-Led Cardioversion Study in Part C are eligible to consent to the 
Part C Patient-Led Under Medical Supervision Cardioversion Study. 


 
 
 
 
 
 
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Figure 2. Part C Study Design 
 
 
Study Population 
 
Protocol indicates that Part C does not have an enrollment target; enrollment will continue in the 
Part C MLS at the discretion of the Sponsor to support rollover participation in the Part C Patient-Led 
Under Medical Supervision Cardioversion Study. Enrollment in Part C MLS was stopped by Sponsor 
December 31, 2021. 
 
For subjects to be included in the PLS Study, they must undergo rescreening to confirm their 
eligibility according to the same criteria in Part B prior to each treatment of a recurrent AF episode 
with the study drug.  Safety labs and a symptom-driven physical examination may be performed at 
the discretion of the PI (e.g., due to changes in recent medical history); except for those required to 
confirm the subject's eligibility, which must be performed.  
 
If a subject is not eligible, they may be treated as per institutional standard of care and are allowed 
to return in the future for a different recurrent episode of AF. 
 
 
Study procedures 
 
Study procedures for Part C are performed as described in the Schedule of Assessments (Appendix 4 
protocol). 
 
Study procedures are identical in Part C MLS compared to Part B. The Part A subjects analyzed in the 
final report also followed these study procedures. Vital signs and blood samples for PK analysis are 
collected at multiple serial time points just before, during, and after the inhalation regimen, and at 
the time of conversion to SR as detailed in the Schedule of Assessments. AECG (12-lead Holter) data 
are collected from 45 minutes pre-dose until 90 minutes post dose in order to identify the time of 
conversion to SR and to monitor the safety of the study subjects. Additionally, 12-lead ECGs are 
Patient with AF 
treated with 
FlecIH*
Patient not 
eligible for 
study
Successful
Cardioversion 
due to FlecIH
No 
Conversion
Patient returns 
for training on 
assembly/self-
administration
Patient returns to 
the clinic with AF 
to self-administer 
FlecIH under 
supervision
Patient Completes 
Training Successfully
Patient not 
eligible for 
study
Patient Fails to Demonstrate 
Ability to Assemble and 
Self- Administer FlecIH
Up to 8 months
Training Phase
Recurrent Episode of AF
To take place in the clinic
in a setting to mimic 
the home environment
Continued training at 
regular intervals until 
recurrent episodes of 
AF occur
Part A, Part B, or 
Part C Medically-Led
Part C Patient-Led Under Medical Supervision
*Potentially eligible patients from Part A, Part B, and the Medically-Led Cardioversion Study in Part C may provide Informed Consent 
for the Part C Patient-Led Under Medical Supervision Cardioversion Study. 


 
 
 
 
 
 
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extracted in triplicate from the AECG recording at multiple time points. Discharge at or after 90 
minutes post dose (a -10 minute window is allowed). 
 
If a subject's AF does not convert to SR after treatment with the study drug, they may be given an 
alternate therapy in accordance with standard of care after 90 minutes post completion of dosing. 
Only if deemed medically necessary by the investigator, an alternate therapy may be given as early 
as 60 minutes post completion of dosing; however, IV flecainide and propafenone may only be given 
after 90 minutes post completion of dosing. 
 
All subjects have a Day 2 and a Day 5 (± 1 day) telephone assessment (Visit 1 and Visit 2, 
respectively). All enrolled subjects are followed for 5 days, and every effort should be made to 
maintain a subject’s follow-up. End-of-study activities are completed for all enrolled subjects who 
received study drug. Study follow-up is only terminated at the explicit request of the subject. The 
overall duration of subject participation from screening through follow-up is 5 days. 
 
When compared to Part C MLS, in Part C PLS less information is collected, refer to section 6C of the 
study protocol.  
 
 
Screen Failures 
 
Subjects are pre-screened based on the information available from the institutional standard of care. 
For subjects who appear to be candidates for the study based on this available information, IC 
signature and other study-specific screening procedures take place prior to enrollment. A subject 
who withdraws IC before enrollment or who fails the inclusion/exclusion criteria before enrollment 
is defined as a screen failure. No further clinical follow-up is performed for screen failed subjects 
unless they are re-screened and are enrolled. 
 Subjects who are enrolled but who do not receive study drug (e.g., due to spontaneous conversion 
of their AF to SR prior to dosing) are considered early terminations and may be replaced; refer to 
protocol Section 5.5.  
2 Study objectives Part C 
All Part C objectives are exploratory; no formal testing is performed. Study objectives are: 
 
• 
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 
• 
To explore the feasibility of implementing a portable cardiac ultrasound (HHE) at screening in 
an emergent setting  
 


 
 
 
 
 
 
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3 Definitions and Terminology 
 
Conversion to SR, recurrence of AF 
 
This section defines conversion from AF to SR and recurrence of AF after conversion to SR. All 
information will be derived from AECG (Holter) Core Laboratory analysis if available. If AECG 
information is not available or is incomplete, then investigator-reported information (e.g., 12-lead 
ECG and/or telemetry) will be used for the missing Core Lab information.  
 
Conversion from AF to SR  
Conversion of AF to SR is defined as the presence of SR, derived from AECG, lasting for ≥ 1 minute.  
 
Index Conversion 
The first conversion of AF to SR that lasts for ≥ 1 minute is referred to as the index conversion. 
 
Start Time of First Conversion from AF to SR 
Start time of the index conversion 
 
Time to First Conversion from AF to SR (from initiation of study drug) 
Time from the initiation of study drug to the start time of the index conversion, measured as 
minutes and seconds. 
 
Time to First Conversion from AF to SR (from conclusion of study drug) 
Time from the conclusion of study drug dosing to the start time of the index conversion, measured 
as minutes and seconds. Index conversions that start prior to the end of dosing result in a negative 
value.  
 
Recurrence of AF 
Recurrence of AF is defined as the return of a subject's heart rhythm to AF for ≥ 1 minute after the 
index conversion. 
 
Start Time of Recurrence of AF 
Start time of the first recurrence of AF occurring after the index conversion.  
 
Methods for Cardioversion 
 
Conversion of AF to SR by the study drug 
Index Conversion occurred ≤ 90 minutes after initiation of study medication, without the 
administration of any other intervention to induce conversion of AF to SR (e.g., IV flecainide, 
electrical cardioversion [ECV]).  
 
Spontaneous conversion 
Index Conversion occurred > 90 minutes after initiation of study medication, without administration 
of any other intervention to induce conversion of AF to SR (e.g., IV flecainide, ECV).  
 


 
 
 
 
 
 
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Conversion due to adjunct medication 
Index Conversion occurred following administration of an adjunct medication (e.g., IV flecainide) to 
induce cardioversion.  
 
Conversion due to adjunct procedure 
Index Conversion occurred following ECV to induce cardioversion. 
 
 
Reported periods 
 
-TPre: Pre-dose  
 
–TAdmin: Just before the start of inhalation 
 
-Tbetween admin: In the 1-min break between inhalations 
 
-T0: Time zero is the initiation time of study drug.  
 
-Tx: Time after initiation of study drug  
 
TSR: At the time of index conversion, which requires at least 60 seconds of SR. The time of index 
conversion is defined as the start time of this 60-second period. 
 
Data related to the TSR time point will either be reported at the start time of the index conversion 
(e.g., time of conversion reported from continuous ECG monitoring), or at the nearest time after the 
start of the index conversion (e.g., PK values that may have been obtained within or just after the 
60-second period). 
 
Time points measured after initiation of study drug are compared with T0, e.g., 11 minutes post 
initiation of study drug (T11) is recorded as 11 minutes after T0. 
 
In case time points are measured post dose, time points are compared with the conclusion of study 
drug administration. Note, all assessment time points after dosing in the Protocol Schedule of 
Assessments are calculated post the completion of study drug administration. 
 
Day 1  
Day 1 is the date of study enrollment (day of dosing). All values for Study Day are defined relative to 
Day 1.  
 
 


 
 
 
 
 
 
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Adverse Events 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding for example), symptom, or disease temporally associated with the use of a 
(investigational) medicinal product, whether or not considered related to the (investigational) 
medicinal product. 
 
All adverse events will be recorded on the Adverse Event electronic case report form (eCRF). For the 
purposes of this study, a recurrence of AF will not be reported as an adverse event. AF recurrence 
will be collected in a specific eCRF designed to capture this data. However, recurrences of AF that 
meet the definition of a serious adverse event (SAE) will be captured on the AE CRF. 
For the definition of an SAE, please refer to protocol Section 17.2.1.2. 
Treatment-emergent Adverse Event  
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges on or after initiation of 
study drug (having been absent pre-treatment), or an AE that existed pre-treatment and worsened 
on treatment (relative to the pre-treatment state) through Day 5 (end of study).  
 
 Adverse Events of Special Interest (AESI) 
Protocol 8.0/EU-1 uses a new definition of AESI, meaning in the data used for the final report, more 
than one AESI definition is used.  
Protocol 8.0/EU-1 additionally introduces a new category: Serious Adverse Events of Special Interest 
(SAESI), meaning SAESI was not captured for AESIs reported prior to the introduction of Protocol 
8.0/EU-1. The secondary safety endpoint (refer to SAP section 6.2.3.) reports on Serious AESI. 
 
In order to be able to report all AESI and SAESI using the Protocol 8.0/EU-1 definitions, additional 
source data will be provided by the Sponsor (refer to SAP sections 5.6.5 and Annex A).  These data 
will use a slightly adjusted definition than in protocol 8.0/EU-1 definition for AESI and SAESI, refer to 
SAP section  Annex A . 
 
The protocol 8.0/EU-1 definition of AESI and SAESI is as follows: 
Four categories of adverse events of special interest (AESI) are defined. The fourth category 
described is a subcategory of the third type. For the complete definition of these AESI refer to 
protocol Section 9.1.2 B: 
1. AEs related to inhalation device 
Events related to the inhalation device (AeroEclipse® II BAN)  
2. Pregnancies 
Any female study subject or female partner of a study subject that becomes pregnant 
3. AEs known to be related to other flecainide formulations (i.e., IV and oral) 
The following events are known to be related to other formulations of flecainide (i.e., IV and 
oral) and are considered AESI if they occur after the initiation of study drug.  


 
 
 
 
 
 
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• 
Hypotension- an acute hypotensive episode (AHE) is a sudden drop in BP resulting in 
a BP < 90/60 mmHg (MAP < 70 mmHg) that lasts for at least 5 minutes and is based 
on multiple sequential readings (≥ 3). MAP is calculated as 1/3 (SBP – DBP) + DBP.  
• 
Ventricular tachycardia ≥ 3 beats 
• 
Bradycardia- an ECG derived rate < 50 bpm for ≥1 minute  
• 
Sinus pauses post conversion of AF to SR- an ECG-derived pause > 3 seconds  
• 
Atrial flutter with 1:1 conduction with fast ventricular response (ventricular heart 
rate ≥ 200 bpm) 
4. Serious Adverse Events of Special Interest (SAESI)  
 
 
The following potential Serious AESI are defined for study purposes: 
• 
Hypotension, with symptoms/signs of clinical instability (i.e., severe chest 
pain/dyspnea or altered mental status), requiring vasopressor or inotropic agent 
• 
Ventricular tachycardia, sustained (> 30 seconds or requiring intervention before 
that time) VT, TdP or VF 
• 
Bradycardia, with symptoms/signs of clinical instability (i.e., severe chest 
pain/dyspnea, altered mental status or hypotension) requiring pacing or 
chronotropic agent 
• 
Sinus pauses post conversion of AF to SR, causing syncope, or requiring pacing or 
CPR 
• 
Atrial flutter with 1:1 conduction with fast ventricular response (ventricular heart 
rate ≥ 200 bpm), requiring intervention (DC cardioversion) for termination, or an IV 
AV nodal blocking agent (β-blocker or Ca2+-channel blocker) to slow the ventricular 
rate 
• 
Any arrhythmia with symptoms/signs of clinical instability (i.e., severe chest 
pain/dyspnea, altered mental status or hypotension) and requires DC cardioversion, 
defibrillation, pacing, or vasopressor, inotropic or chronotropic agent. SAESIs in this 
category will also be included in the broader category of AESI described above. 
 
Other definitions 
 
AECG (Holter) 
Ambulatory ECG device used to collect heart rhythm monitoring data over an extended period of 
time 
 
PD 
Pharmacodynamics; quantitative characteristics of ECGs 
 
PK 
Pharmacokinetics; concentration of flecainide in the blood plasma 
 


 
 
 
 
 
 
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Remote ECG (TTM) 
Event recording ECG device used to collect heart rhythm status assessments over a brief period of 
time 
 
Concomitant Medications 
Medications taken during the study after signing IC   
 
Prior Medications 
Medications taken prior to signing informed consent for the study; captured for at least 30 days 
prior to enrollment 
 
Baseline Value 
Measurement(s) taken prior to initiation of study drug. If at a specific planned time point multiple 
measurements are taken (e.g., 3 ECGs analyzed at 15 minutes prior to study drug initiation) then the 
mean of these measurements will be used to represent the baseline value for the specific time point. 
 
Baseline (seated) 
The mean of all available Baseline Values at these time points: 15 minutes pre-initiation of study 
drug and just before initiation of study drug (T0) 
 
Baseline (semi-recumbent) 
The mean of all available Baseline Values at these time points: 45 and 30 minutes pre-initiation of 
study drug 
 
Cmax 
Cmax is defined as the peak plasma level of flecainide after initiation of study medication and prior to 
administration of any alternative pharmacological agent (e.g., IV flecainide). 
 
tmax 
tmax is Protocol defines tmax  as the time to Cmax (from the time of the start of dosing).  
 
 
 
4 Study Medication  
 
The study drug dose and regimen are: 120 mg FlecIH-103 (75 mg/mL) administered in 1 single 
AeroEclipse® II breath-actuated nebulizer in 2 inhalation stages of 3.5 seconds each, separated by a 
1-minute break (2 x 60 mg). 
  
Subjects continue to inhale according to the assigned regimen until the conversion of AF to SR is 
observed, or until the assigned dose is completed, whichever comes first ("dose/inhale to 
conversion").  


 
 
 
 
 
 
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5 Source Data 
 
This section describes all source data used for the final statistical report.  
For each data source is indicated which information is available for the MLS part of the trial and 
which information is available for the PLS part of the trial.  
The data collection tool for this study is a validated electronic data capture (EDC) system called 
MARVIN (from XClinical). Data required according to this protocol are recorded by Investigator/study 
site personnel via data entry into the EDC. All eCRF data used in the statistical analysis are 
downloaded from the EDC system in the form of XML files and are converted into SAS datasets and 
formats. 
 
Depending on the EDC version, different information can be required to be filled out by investigator 
for the enrolled subjects. For instance: SAESI is only included in the EDC since Protocol 8.0/EU-1. 
 
 
For subjects enrolled in Part C of the trial EDC version 21 (or later) is applicable, the final EDC version 
for these subjects was version 25. The final EDC version for subjects enrolled in Part A of the trial 
was EDC version 16. The final EDC version for subjects enrolled in Part B of the trial was EDC version 
20. When pooling MLS results from Part A, B and C, the information will be reported as defined in 
EDC version 25. For Part C the EDC captures information for both the PLS and the MLS part of the 
trial. 
 
 


 
 
 
 
 
 
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Investigator reported information 
 
All investigator reported data for the PLS and MLS study are entered into the EDC.  
 
Rhythm monitoring assessment (Holter) 
The Holter analysis is performed by a Core Laboratory. Heart rhythm information is provided in two 
SAS datasets to the statistical department of Cardialysis. The first dataset shows summary data for 
the complete monitoring period, including if subject converted to SR during the Holter recording and 
if so:  time of conversion and if recurrence of AF was observed. If recurrence of AF was observed the 
time of first recurrence of AF is indicated. 
 
The second dataset shows details for separate phases in the recording being: 
-If a subject converted to SR: Pre-Dose, start of dosing to time of conversion, time of conversion to 
End of Recording  
-If a subject did not convert to SR: Pre-Dose, Dosing, Post-Dose  
 
Information is available for Part A, Part B and Part C MLS subjects and for Part C PLS subjects. 
 
Additionally, in Part A, Part B and Part C MLS  Heart Rates (BPM) recorded for each rhythm strip 
within the Holter Report are entered by the Core Laboratory directly into the EDC, as these data 
cannot be provided within the SAS datasets. In the Part C PLS, the Heart Rate data from the rhythm 
strips was not collected in the EDC.  
 
Rhythm status assessments (Remote ECG) 
ECG analysis is performed by a Core Laboratory and results are provided to the statistical 
department of Cardialysis as a single cumulative SAS dataset. The length of each recording is 
expected to be 30 seconds. 
Additionally, the duration (seconds) that a subject has been in: 
- Sinus Rhythm, 
- Atrial Fibrillation, 
- Atrial Flutter, 
- Atrial Tachycardia, 
- Ventricular Tachycardia. 
Results include a flag (Yes/No) indicating if subject is or is not in SR. Subject is defined by the Core 
Laboratory as being in SR if the number of seconds the subject is in Sinus Rhythm is greater than the 
number of seconds the subject is in any other rhythm, listed above.  Refer to SAP section 6.2.2 for 
the secondary endpoints for which the Remote ECG information is used and to SAP section 9.2.2. for 
the statistical analysis of these endpoints.   
 
Information is only available for Part A, part B and Part C MLS, not for Part C PLS.  
 
Pharmacodynamic (PD) Assessment 
 
PD analysis is performed by a Core Laboratory conducting rhythm monitoring and status 
assessments. 12-lead ECG recordings are extracted by the Core Laboratory from the Holter (AECG) 
recordings (refer to SAP section 5.2).  Consequently, if the Holter data are not analyzed, the PD 
information will be missing.   
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SAS dataset. Results are provided to the statistical department of Cardialysis as a single SAS dataset. 
 
Information is available for Part A, Part B and Part C MLS subjects and for Part C PLS subjects. 
 
Pharmacokinetics (PK) assessment 
 
Blood plasma samples are analyzed by a single Core Laboratory, reporting plasma concentrations of 
flecainide (ng/mL) at pre-specified time points. Results are provided to the statistical department of 
Cardialysis in the form of a single, cumulative csv file.  
 
Information is available for Part A, Part B and Part C MLS subjects and for Part C PLS subjects, 
however, for Part C PLS plasma concentrations are measured at only a limited number of time 
points. 
 
 
Safety results 
5.6.1 
Investigator (Part B and Part C) 
For subjects enrolled under Part B and Part C of the trial, investigator reported information is used in 
the analysis. Refer to section 5.6.2 for the source data for subjects enrolled under Part A of the trial. 
 
For investigator assessments of AEs that were reported in Part B and Part C of the trial, the verbatim 
term is entered into the EDC, as well as an indication if event is related to inhaled flecainide, if event 
is related to study device, if event is an adverse event of special interest (AESI) and if event is a 
Serious Adverse Event of Special Interest (SAESI).  
 
Protocol 8.0/EU-1 uses a new definition of AESI, meaning in the data used for the final report more 
than one AESI definition is used. SAESI is introduced in Protocol 8.0/EU-1, meaning in the data used 
for the final report SAESI is not captured for AESI events reported prior to the introduction of 
Protocol 8.0/EU-1. In the final report AESI and SAESI will however be reported using a uniform 
definition that differs slightly form the study protocol. Refer to SAP sections 5.6.5. and Annex A for 
the source data that enable reporting AESI and SAESI according to the Protocol 8.0/EU-1 definition 
for all AE included in the final report. Refer to SAP section Annex A and to section 3.4.  for the 
Protocol 8.0/EU-1 definitions of AESI and SAESI.  
Based on answers to below questions, the EDC concludes if the AE is a Serious Adverse Event (SAE): 
Did the adverse event result in the following: 
- Death? 
- Life-threatening event? 
- Hospitalization or prolongation of hospitalization? 
- Persistent or significant disability or incapacity? 
-Congenital anomaly/birth defect? 
-Other medically important event? 
 
If any of these six questions is answered with “Yes” the EDC automatically indicates AE is an SAE. 
Protocol indicates that recurrent AF is not considered an adverse event as it is an expected event in 
this patient population and is not considered to be related to study drug. AF recurrence is captured 
in a separate form in the EDC, will be reported in a separate listing in the statistical report, and will 
be excluded from AE summary tables in the statistical report. However, AF recurrences that meet 


 
 
 
 
 
 
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the definition of an SAE (e.g., death, hospitalization, life-threatening, etc.) will be captured on the AE 
eCRF as an SAE and will be included in the relevant summary tables reporting on AEs. 
 
For the HHE population compared to other subjects, an additional HHE analysis is performed. Any 
new findings on the HHE determined by the Investigator to be clinically significant will be reported 
as AEs in the EDC. The independent reviewer will not make a determination of clinical significance on 
HHE abnormalities. Findings from the independent reviewer will be documented in their analysis and 
presented in a listing for the HHE population.  
5.6.2 
Cardialysis (Part A) 
Cardialysis assigns MedDRA coding to all investigator reported AEs. The verbatim terms used in the 
EDC by Investigators to identify AEs are coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 23.1 or higher) by System Organ Class (SOC) and Preferred Term, additionally is 
indicated if Adverse Event was an Adverse Event of Special Interest (AESI).  
 
The definition used for AESI differs from the Protocol 8.0/EU-1 definition of AESI and SAESI was not 
defined yet.  Refer to SAP section 5.6.5. for the source data that enable reporting AESI and SAESI 
according to the Protocol 8.0/EU-1 definition for all AE included in the final report. Refer to SAP 
section 3.4. for the Protocol 8.0/EU-1 definitions of AESI and SAESI. 
 
Results of the MedDRA coding by Cardialysis are provided in a single SAS dataset; by combining 
these with the investigator reported AE results in the EDC the complete AE analysis dataset is 
created. In the remainder of the SAP the resulting analysis dataset is indicated as “Clinical AE 
database”. 
5.6.3 
Analysis Dataset Part B and Part C 
PrimeVigilance (PVL) is responsible for providing drug safety and Pharmacovigilance (PVG) support, 
in relation to the FlecIH investigational medicinal product (IMP) clinical development program by 
InCarda.  
 
The PVL safety database only contains SAEs, AESIs, and Serious AESIs.  
 
The verbatim terms used in the EDC by Investigators to identify AEs are coded using MedDRA by SOC 
and Preferred Term. Seriousness of the event and relationship to inhaled flecainide are assessed. 
 
The statistical report for Part C will report information as follows for Parts B and C: 
The Clinical AE database (refer to section 5.6.2 of SAP) is the only source when reporting the AE 
results in the Tables in the statistical report for Part B and Part C MLS subjects of the trial.  
 
Before the Clinical AE database of Part C is considered final, a reconciliation will take place with 
results as reported by PVL. Part B has already been reconciled and is considered final. 
  
In case of differences relating to information filled out by investigator in the EDC, queries can be 
added in the EDC, requesting investigator to re-assess the AE. All these queries need to be answered 
before the Clinical AE database is considered final. 
 
In case of differences relating to MedDRA coding by Cardialysis, Cardialysis can be requested to re-
evaluate the assigned MedDRA codes. Re-evaluation needs to be final before the Clinical AE 


 
 
 
 
 
 
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database is final. 
 
Information is available for Part B and Part C MLS subjects and for Part C PLS subjects. 
5.6.4 
Analysis Dataset Report Part A 
The statistical report for the INSTANT study will include AE results for subjects enrolled in Part A of 
the trial (2*60 mg, FlecIH-103). The statistical report for Part A reported AE by using the Safety 
Database maintained by Cardialysis, not by using the clinical AE database. The same database will be 
used in the final statistical report when showing results for FlecIH-103 subjects enrolled in Part A of 
the trial. 
 
This implies that for subjects enrolled in Part A (2*60 mg, FlecIH-103 subjects) the AE results that 
were reported in the statistical report for Part A are identical to the AE results as reported in the 
final statistical report.  
 
In the Cardialysis safety database some Adverse Events were reported twice: as the original AE and 
as “Condition Aggravated”.  In these cases, there was no MedDRA coding available for the worsening 
of the event, the worsening was registered under a general MedDRA coding: 
 
-“General disorders and administration site conditions” 
 - Preferred Term:  “Condition Aggravated”. 
 
In total this occurred 2 times for subjects receiving 2*60 mg, FlecIH-103 
 
In the statistical tables these cases are reported twice:  
 
-under the MedDRA coding of the original event 
-under the “Condition Aggravated” coding 
 
To prevent double counting of these events, in summary tables when showing the total number of 
AE, these AEs are counted only once.  
5.6.5 
Additional AESI and SAESI information 
In order to be able to report AESI and SAESI according to the Protocol V8.0/EU-1 definition, AEs that 
were reported using a previous AESI definition need to be re-assessed to see if the AE is an AESI 
according to the new definition. Additionally, these AEs must be reviewed to determine if they met 
the criteria for a SAESI, as before Protocol V8.0/EU-1, SAESI was not yet defined. Refer to SAP 
section 3.4. for the Protocol 8.0/EU-1 definitions of AESI and SAESI. 
 
Sponsor will provide a file showing for all AEs:  
  -Is AE an AESI (yes/no) according to the Protocol 8.0/EU-1 definition? 
  -If yes: is AESI Cardiovascular (Y/N) 
  -Is AE a SAESI (yes/no) according to the Protocol  8.0/EU-1 definition? 
  -If yes: is SAESI Cardiovascular (Y/N) 
 
Additional relevant information may also be included. 
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agreed terms for Phase 3, which may facilitate pooling of these data across multiple studies. Please 
refer to SAP section Annex A for final Sponsor definitions. 
 
Refer to SAP section Annex A for the definition of Cardiovascular. 
 
When reporting AESI and SAESI in the final report, an analysis dataset will be used that combines: 
 
- AESI (Y/N) filled out by investigator  
- SAESI (Y/N) filled out by investigator 
- (S)AESI information assessed by Sponsor with 5 options: 
1. Non-AESI 
2. Non-Cardiovascular Non-Serious AESI 
3. Non-Cardiovascular Serious AESI 
4. Cardiovascular Non-Serious AESI 
5. Cardiovascular Serious AESI 
 
Refer to SAP Annex A for a specification of the process used by Sponsor to create the Sponsor 
assessments for AESI information. 
  
 
Handheld Echo (HHE)  
 
For subjects who are included in the EU HHE Sub-Study the HHE is used by the investigator to assess 
if subject is eligible for enrollment. Additionally, for subjects who are enrolled in the US, an HHE is 
required if an echocardiogram with LVEF within 6 months of screening required to demonstrate 
eligibility is not available. HHE assessments are entered into the EDC by investigator. 
 
The HHE images will also be analyzed by an independent reviewer at a later date, and the statistical 
analysis will compare the HHE results between the investigator and the independent reviewer. 
 
Results from the independent reviewer are provided to the statistical department of Cardialysis in 
the form of a single, cumulative Excel file. 
 
The HHE sub-study was not included in the PLS. 
 
Protocol Deviations  
 
Protocol Deviations are registered in the CTMS system. After eCRF database lock and after approval 
by InCarda, the final listing of Protocol Deviations will be provided to STAT in the form of an Excel 
file. This file will include: an indicator if Protocol Deviation is major or minor, and the type of 
Protocol Deviation (e.g. ECGs). 
 
Information is available for Part A, Part B, Part C MLS subjects and for Part C PLS subjects.  
 


 
 
 
 
 
 
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6 Study Endpoints: definition and availability of information 
 
The final report will be in line with the final statistical report for Part B, reporting all endpoints that 
were included in the final report of Part B of the trial. As in the Part B report all Part A and Part B 
subjects receiving 2*60 mg FlecIH-103 are included in the analysis, in the final report these subjects 
are pooled with the Part C MLS subjects. Sections 6.1 to 6.2.5 describe these study endpoints as 
defined in version 8.0/EU-1 of the protocol. Section 6.2.6 describes the additional exploratory 
endpoints for the Part C PLS. 
  
For the endpoints Conversion from AF to SR and Recurrence of AF, in principle, only Core Laboratory 
information will be used, this applies for the Holter and TTM AF monitoring period.  
 
In Core Laboratory results, Conversion of AF to SR is reported by filling out column SRTM (Date and 
Time Rhythm Switched to SR). In the statistical analysis then is reported: Subject did convert, time of 
conversion is the Date and Time shown in SRTM. Refer to section 3.1. of the SAP for the definition of 
Conversion (Rhythm Switch) to SR.  If data in the column SRTM is missing, subject did not convert 
during the period analyzed by the Core Laboratory. 
 
For subjects who converted from AF to SR, the column AFIBAFTER (Atrial Fibrillation Recurrence 
Post-Rhythm Change) indicates if AF recurred (value: “YES”) or did not recur (value: “NO”). If AF did 
recur, column AFIBRTM (Atrial Fibrillation Recurrence Time) shows the Date/time of the first AF 
recurrence. 
  
Investigator reported information on conversion and recurrence of AF is also reported for the 90 
minutes after the end of dosing. This information will not be used in the statistical analysis unless 
Core Laboratory information is Completely Missing (no analysis at all) or Partly Missing (e.g., 
analyzed only up to only 28 minutes of the planned 90 minutes post dose).  
 
If Core Laboratory information is Completely Missing then only investigator reported information 
will be used. The following information is used, as filled out by investigator in the EDC: 
- Did the patient convert to SR? (SAS dataset: DSCONV, column CONVYN, values 1 (Yes), 0(No) 
 -If subject did convert to SR: 
    -Date/Time of Conversion to SR (SAS dataset: DSCONV, column DSSTDAT/DSSTTIM, measured     in  
    seconds) 
    - Was AF recurrence observed? (SAS dataset RECURYN, value 1=Yes, 0=No) 
     -If AF recurrence was observed, per AF recurrence the Date/Time of the AF recurrence  
     (SAS dataset: DSCONVAF, column: RECURDAT/RECURTIM, measured in seconds), the date   
      and time of the first AF recurrence is used in the analysis. 
 
If Core Laboratory information is Partly Missing then available Core Laboratory information (e.g. up 
to 28 minutes post end of dose) will be supplemented with Investigator Reported information for 
the period that was not analyzed by the Core Laboratory (e.g. from 28 to 90 minutes post dose). The 
final report will indicate the reason(s) why Core Laboratory analysis was Partly Missing. Before 
combining the information, the Core Laboratory and investigator reported information will be 
checked for consistency on a case-by-case basis. Afterwards these rules will be followed for 
Conversion of AF to SR: 
 


 
 
 
 
 
 
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-If Core Laboratory did not report Conversion of AF to SR, then the investigator reported information 
is used for the period for which no Core Laboratory information is available.  
 
-If Core Laboratory reported Conversion of AF to SR, then the investigator reported information is 
not used. Subject already converted within the period analyzed by Core Laboratory. 
 
These rules will be followed for recurrence of AF: 
 
-If Core Laboratory did not report Recurrence of AF, then the investigator reported information is 
used for the period for which no Core Laboratory information is available.  
 
-If Core Laboratory reported Recurrence of AF, then the investigator reported information is not 
used. This applies for recurrences during the Holter or TTM monitoring period. If AF recurrence 
occurs outside of the monitoring period but prior to Day 5, the event will be entered in the EDC as a 
recurrent AF episode by the investigator.  
 
Time to conversion  
 
The protocol indicates that all endpoints reporting on time to conversion need to be reported in the 
following two ways. 
6.1.1 Time between initiation of study drug and conversion to SR (in minutes) 
Subject should be in AF at the initiation of study medication (if not, the subject is not included in the 
population for which the endpoints are measured); conversion should thus not occur before 
initiation of study drug. The time between initiation of study drug and conversion to SR (in minutes) 
is thus expected to be non-negative.  
6.1.2 
Time between completion of study drug and conversion to SR (in 
minutes) 
Study drug inhalation is discontinued after conversion from AF to SR is observed, or once the entire 
dose is completed, whichever comes first. 
 
Subject should be in AF at the initiation of study medication (if not, the subject is not included in the 
population for which the endpoints are measured); conversion should thus not occur before 
initiation of study drug. Subject may however convert prior to completing inhalation of study drug.   
 
The time of conversion will be compared with the end of dosing time. If conversion occurred prior to 
the end of dosing, for the time to conversion a negative value will be calculated and reported.  
 
 
Endpoints, Adverse Events and other assessments  
 
The final report will include all endpoints that were included in the final Part B report. However, 
unlike in the Part B report, no formal testing will be performed for the primary efficacy endpoint. 
Additionally, the exploratory endpoints for Part C as indicated in the protocol will be reported.  
 
Section below first report the endpoints reported for Part B of the trial (as indicated in section 7.5 B 
of the Protocol).  Additionally, Adverse Events, PK assessments and PD assessments as indicated in 


 
 
 
 
 
 
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section 8 B and 9.1 B of the protocol are described.  These should be considered as (exploratory) 
endpoints. Finally, section 6.2.6. lists the exploratory endpoints for the Part C PLS Study. 
 
Section 9 of the SAP describes the statistical analyses of the endpoints, Adverse Events and other 
assessments.  
 
6.2.1 
Primary endpoint 
The primary efficacy endpoint is: 
 
The proportion of subjects whose AF converted to SR by inhaled flecainide within 90 minutes after 
initiation of dosing. 
 
The first conversion to SR that lasts for at least 1 minute is referred to as the index conversion and is 
reported in endpoints measuring conversion. Any conversion not lasting for at least one minute is 
not considered an index conversion. Refer to SAP section 9.2.1 for the analysis of the endpoint. 
6.2.2 
Secondary efficacy endpoints  
Refer to SAP section 9.2.2 for the statistical analysis of these endpoints.  
 
• 
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 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 study drug and 
completion of study drug. 
 
The analysis of the primary and secondary efficacy endpoints will be performed on the mITT 
population (refer to section 8.5 SAP). If applicable, methods for conversion (e.g., Conversion to SR by 
inhaled flecainide, refer to section 3.2 SAP) will be specified in the overview of TFLs.  
 
 
6.2.3 
Secondary safety endpoint 
The secondary safety endpoint is:  
 
Incidence of treatment emergent serious adverse events of special interest for flecainide (SAESI)  


 
 
 
 
 
 
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The analysis of the secondary safety endpoints will be performed on the Safety population (refer to 
section 8.3 SAP). Refer to SAP section 5.6 for the source data of the SAESI information. Refer to 
section 3.4 SAP for the definition of SAESI. 
 
6.2.4 
Exploratory endpoints (HHE) 
The HHE data will be submitted to an independent reviewer to compare with the HHE assessments 
made by the site staff during the screening period; however, this independent review will not be 
used for the assessment of subject eligibility during screening. This independent review will only be 
used to explore whether site staff made a successful assessment of subject eligibility using the HHE 
data obtained during screening.  
 
The exploratory endpoints for the Handheld Echo are:  
 
• 
Proportions of subjects for whom capture and assessment of a diagnostic echocardiogram using 
a HHE at screening was successful. 
 
These characteristics are assessed: 
-LV size 
-LVEF 
-LV hypertrophy 
-Valvular disease 
-Other clinically significant findings 
 
• 
Percentage 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 
 
The analysis of these exploratory endpoints will be performed on the HHE population (refer to SAP 
section 8.6). 
 
All except the last endpoint listed above (being "Time from HHE administration to availability of HHE 
report/results”) will be analyzed for both the Investigator reported results as well as the results of 
the independent reviewer. 
 
In the SAP this endpoint is added:  
 
• 
Agreement between subject eligibility between site staff and independent reviewer. 
 
Refer to SAP section 9.2.4 for the analysis of the HHE endpoints. 
6.2.5 
Additional Assessments 
In the final report the following additional assessments are reported but are not associated with an 
endpoint.  
 Pharmacokinetic (PK) assessment(s) 


 
 
 
 
 
 
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Whole blood samples of about 4.0 mL are collected for measurement of plasma concentrations of 
flecainide acetate components. PK sampling occurs only over a 90 min period on Day 1 (day of 
dosing). 
 
For all reported subjects (i.e., Part A (2*60 mg FlecIH-103 subjects) Part B, and Part C MLS) sample 
collection times are as follows: 
1. Pre-dose inhalation –TPre (any time up to 45 minutes prior to dosing and after treatment 
assignment) 
2. During dose regimen administration – T between admin (in the 1-minute break in between 
inhalations), if applicable 
3. At the time of conversion to SR – TSR.  A PK sample should be taken at SR regardless of method of 
conversion.  If conversion is, for example, by ECV, the PK sample should be taken at the earliest 
time feasible. 
4. After administration of study drug regimen is complete – Tx (1, 3, 10, 30, 60 and 90 minutes post 
dose).   
 
All available information will be reported. The analysis will be performed for the PK population (refer 
to SAP section 8.4). 
 
For the subjects in Part C PLS who received study medication only three samples are collected: pre-
dose, at 3 minutes post end of dose and at 90 minutes post end of dose, additionally at the time of 
conversion to SR – TSR  a PK sample should be taken regardless of method of conversion.  If 
conversion is, for example, by ECV, the PK sample should be taken at the earliest time feasible. 
 
 


 
 
 
 
 
 
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 Pharmacodynamic (PD) assessment(s) 
Electrocardiographic effects of the study drug will be evaluated based on 12-lead ECG recordings. 
An independent central review of ECGs is conducted. The ECG recordings will be extracted in 
triplicate from the recorded AECG data by the ECG Core Laboratory after receiving the data. 12-lead 
ECGs will be extracted at or after each specified time point within up to 5 minutes or up to the next 
scheduled time point, whichever comes first.  
 
Triplicate 12-lead ECG readings are collected at pre-defined collection time points for a given subject 
and are over-read on the same lead by the same ECG Core Laboratory reader. 
 
Extraction times for ECG recordings under both regimens are as follows: 
1. Pre-dose inhalation – TPre - at -45, -30 and -15 minutes 
2. Just before the start of inhalation – TAdmin  
3. During dose regimen administration – Tbetween admin (in the 1-minute break in between inhalations) 
4. At the time of conversion to SR – TSR (if applicable) 
5. After administration of study drug regimen is complete – Tx (1, 3, 10, 30, 60, and 90 minutes post 
dose) 
 
The following ECG parameters are determined: 
-Heart rate (HR) 
-RR interval 
-PR interval 
-QRS duration 
-QTcF duration 
-JTc duration (QTc-QRS) 
 
This analysis will be performed for the Safety population (refer to SAP section 8.3). However, for QRS 
and ∆QRS, additional analyses will be performed using the PK population (refer to SAP section 8.4). 
 
Results for the PLS subjects will be listed, but not summarized. 
 
 Adverse Events 
Adverse events will be reported for the safety population (refer to SAP section 8.3). 
Refer to SAP section 3.4 for the definitions for AEs, SAEs, AESI and SAESI.  The clinical safety of 
inhaled flecainide is evaluated by the frequency of treatment emergent AEs and SAEs. Treatment 
emergent SAEs (TESAE) are those SAEs defined as following dose administration.  AESIs and Serious 
AESIs are reported. Adverse events are reported from time of IC through EOS (Day 5).  
 Clinical laboratory evaluation analyses 
Section 9.7.2.1.B of the protocol indicates statistical analysis will be performed for laboratory data.  
 
Laboratory analysis is performed twice: (i) at screening (Day 1) and (ii) at 90 minutes after initiation 
of dosing or at discharge. Tests can be repeated. 
For the subjects treated with inhaled flecainide in Part C PLS the laboratory analysis is only 
performed at screening.  
 


 
 
 
 
 
 
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The following laboratory safety variables can be measured and analyzed at the local laboratory and 
are registered in the EDC: 
 
Panel 
Variable 
Hematology Panel 
White blood cell (WBC) count 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
 
Red Blood Cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
Mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin (MCH) 
 
Mean corpuscular hemoglobin 
concentration (MCHC) 
 
Red cell distribution width (RDW) 
 
Platelet count 
 
Mean Platelet Volume (MPV) 
Comprehensive Metabolic Panel (CMP) 
Glucose 
 
Calcium 
 
Serum Creatinine 
 
Creatinine Clearance (derived in EDC) 
 
BUN (blood urea nitrogen) 
 
Total Protein 
 
Albumin (Protein) 
 
Potassium 
 
Sodium 
 
Chloride 
 
Bicarbonate 
 
Total Bilirubin (TBL) 
 
Conjugated Bilirubin 
 
Aspartate Aminotransferase (AST) 
 
Alanine Aminotransferase (ALT)  
 
Alkaline Phosphatase (ALP) 
Coagulation Panel 
PTT 
 
PT 
 
TT 
 
Fibrinogen 
Other 
Pregnancy Test 
 
Refer to SAP section 9.2.3.4 for the analysis of these characteristics. 
 
 


 
 
 
 
 
 
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6.2.6 
Exploratory Endpoints for Part C PLS  
Study protocol includes these exploratory endpoints for the Part C PLS:  
 
 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  
Endpoint will be reported, refer to SAP section 9.2.5. for the analysis of the endpoint 
 
 Feasibility of patient-led self-administration of study drug, 
including: 
 
Feasibility is measured by: 
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 
Endpoint will be reported, refer to SAP section 9.2.5. for the analysis of the endpoint 
 
 Proportion of subjects whose AF converted to SR  
Endpoint will be reported, refer to SAP section 9.2.5. for the analysis of the endpoint 
 
 Hand Held Echo (HHE) endpoints 
Protocol includes HHE endpoints for Part C: 
 
o Proportion of subjects for whom capture and assessment of a diagnostic 
echocardiogram using a HHE at screening was successful 
o 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 
 
 
The HHE sub-study was not included in Part C PLS; hence the above endpoints will not be reported 
for this part of the trial. 
 
 


 
 
 
 
 
 
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7 General Statistical Considerations 
 
Sample Size and Power  
 
Part C MLS and PLS did not have an enrollment target; enrollment was planned to continue in the 
Part C MLS at the discretion of the Sponsor to support rollover participation in the Part C PLS. 
December 31, 2021 Sponsor decided to stop enrollment in Part C MLS.  
 
No formal hypothesis testing is planned for Part C. Summary statistics will be generated, including 
estimate of the endpoints and for the primary efficacy endpoint (refer to SAP section 9.2.1) its 90% 
confidence interval. 
7.1.1 
Treatment Allocation 
All subjects in the Part C MLS and in the Part C PLS study who are enrolled are assigned to a 120 mg 
eTLD (2 x 60 mg) FlecIH-103 dose regimen.  
 
The site is permitted to enroll a subject before the monitoring period is finished. Thus, between time 
of enrollment and the end of the screening period, a subject can cease to be considered eligible if 
there is a change in the subject's status with regard to the study Inclusion or Exclusion criteria. In this 
case, the subject will not start study drug. These subjects are not reported as screen failures. 
 
Subjects who are screened but did not start study drug (regardless of if the subject was enrolled or 
considered a screen failure) can re-enter the study when a new AF episode occurs. The statistical 
report will describe the reason(s) the subject did not start study drug when initially screened. 
Furthermore, the result of the secondary screening will be reported (e.g., if subject was enrolled and 
started study drug). 
 
In the final report along with the Part C MLS subjects Part A and Part B subjects are reported who 
were assigned to a 120 mg eTLD (2 x 60 mg) FlecIH-103 dose regimen.  
7.1.2 
Blinding and Unblinding 
This is an open-label trial of a single study drug treatment. Thus, the processes of blinding and 
unblinding are not applicable in this study.  
 
 


 
 
 
 
 
 
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Handling of Data 
7.2.1 
Strata 
Subjects are not stratified to any criterion. 
7.2.2 
Examination of Patient Subgroups 
For the HHE population (refer to section 8.6) results will only be reported for the specific HHE 
endpoints. 
7.2.3 
Multiple Testing and Comparisons 
There will be no multiplicity adjustments for the analyses outlined in this SAP. 
7.2.4 
Visit Windows 
After discharge two follow-up visits are planned, both are telephone assessments. 
The first visit is planned on Day 2, 1 day after study drug administration. 
Visit 2 is planned on Day 5, which is 4 days after study drug administration and coincides with End Of 
Study. Visit 2 may be completed within a ± 1 day window, meaning the visit can take place on Day 4, 
5 or 6. 
 
The statistical report will not take into account whether the visit occurred on the planned day or 
within the specified window; all visits will be reported, and visit dates will be included, along with 
the name of the corresponding visit (e.g., Visit 1, Visit 2) and its defined visit window.  
 
If multiple assessments occur within a visit window, then the average of those assessments will be 
used for summarization and analysis. 
 
For PLS subjects, Day 5 assessments of the Part C MLS study are not considered for the End of Study 
visit. Subjects who receive inhaled flecainide in the PLS part of the study are followed until Visit 2 
(Day 5) of the PLS treatment. For PLS subjects who are enrolled for follow-up but do not receive 
inhaled flecainide, the End of Study form will show the reason why EOS was reached for the PLS.  
7.2.5 
Imputation of Missing Data 
 
Imputation of date and time values 
Date and time values will only be imputed if the missing value impacts the reporting of Adverse 
Events, Conversion of AF to SR or recurrence of AF: 
• 
For adverse events or recurrence of AF, the earliest possible date or time will be imputed. 
Example:  For AEs occurring after initiation of study medication for which the start time of the 
AE is missing, the time of initiation of study medication will be imputed to be the start time of 
the AE 
• 
In conversion from AF to SR, the last possible date or time will be imputed. 
Example: If conversion to SR is known to have occurred between initiation of study medication 
and 60 minutes post initiation of study medication, but the time of conversion to SR is 
unknown: 60 minutes post initiation of study drug is imputed for time of conversion to SR. 
• 
For Treatment Emergent Adverse Events: a worst-case approach is used. If AE can be 
Treatment Emergent, event is assumed to be Treatment Emergent.  
For instance: if medication started at 12h:12m:45s and Adverse Event started at 12h:12m 
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Conversion of AF to SR and recurrence of AF: frequency analysis. 
No missing information is expected: if Core Laboratory analysis is missing or incomplete, then 
investigator reported information is available (refer to section 6 SAP) for analysis. Should however 
information regarding the status of conversion to SR or recurrence of AF be incomplete, then the 
subject is assumed to be free of the event between time of last available information and the end of 
the reported period.  
 
Laboratory values below the limit of quantification 
If a laboratory reports a value below the limit of quantification (e.g., “<0.1” or “BLQ”) the value 0 will 
be imputed. Additionally, the value 0 will be imputed if the PK value for the sample taken just before 
initiation (at T0) is not available unless additional information indicates otherwise (refer to SAP 
section 9.2.2.10). 
 
Imputation of other missing values 
No imputation is planned for other missing values, nor is any sensitivity analysis planned.  
Missing values are assumed to be Missing Completely at Random (MCAR).  
8 Study Populations 
 
The final analysis for the INSTANT study will primarily focus on data for the MLS populations (Part A, 
part B and Part C) receiving 2x60mg FleIH-103 formulation using the prespecified definitions 
described in Section 8.1 through 8.6. Data for each MLS population will be presented for several 
cohorts, as described below and further defined in Section 8.7.  
 
Due to the low number of subjects who participated in the PLS, a more limited analysis will be 
conducted on the PLS populations described in Section 8.8. Data for the PLS will only be presented 
for the overall study populations as defined in Section 8.8, with no additional cohort analyses.   
 
Cohorts of the MLS populations include the Part C MLS Cohort (Section 8.7.1) and a Pooled MLS 
Cohort (Section 8.7.2); the latter of which consists of all MLS subjects enrolled to receive 120 mg 
FlecIH-103 in Part A, Part B and Part C of the study. The Pooled MLS Cohort will be further 
subdivided into two additional sub-cohorts: 1) patients in the Pooled MLS Cohort with no evidence 
of flecainide present in their predose PK sample (Pooled MLS No Predose Flecainide Cohort; Section 
8.7.3), and 2) patients in the Pooled MLS Cohort with flecainide present in their predose PK sample 
(Pooled MLS Predose Flecainide Cohort; Section 8.7.4). 
 
A consort diagram will present the number of subjects included in each MLS population (i.e., safety, 
mITT etc.), including the overall number of subjects in the study population and the number of 
patients in each cohort of that population.  
 
Individual tables will summarize data for each MLS population as described below in the table. The 
numbers in the table denote the 4 cohorts that will be analyzed. Each Cohort is defined in the table 
footnote below. The specified Cohorts will be presented as columns within each table for the study 
population analyzed. For example, for adverse events, the table will be based on the Safety 
population with columns for each Cohort specified in the table below (i.e., Cohorts 1, 2, 3, and 4). 


 
 
 
 
 
 
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Table 1: Analysis Populations by Characteristics 
 
MLS Populations 
Data Type 
Safety1 
PK1 
mITT1 
   Demographics2 
1,2,3,4 
1,2,3,4 
1,2,3,4 
   Efficacy 
- 
- 
1,2,3,4 
   Safety 
1,2,3,4 
- 
- 
   PK 
 
2,3 
 
   PD 
1,2,3,4 
2,3 
 
The numbers in the table denote each Cohort as follows (each are further defined in section 8.7):  
1-Part C MLS Cohort;  
2-Pooled MLS Cohort;  
3-Pooled MLS No Predose Flecainide Cohort;  
4-Pooled MLS Predose Flecainide Cohort.  
1  Safety, PK and mITT populations are defined below in section 8 of the SAP  
2Including medical history, prior and concomitant medications, patient characteristics, etc. 
 
 
Population of Consented Subjects 
 
The population of consented subjects includes all subjects who signed the informed consent form 
(IC) for the MLS.  Population includes Part A, Part B and Part C MLS subjects receiving 120 mg FlecIH-
103. 
 
Intention-To-Treat Population (ITT) 
 
The intention-to-treat (ITT) population includes all subjects that were enrolled (allocated). Compared 
to the Population of consented subjects, the ITT population excludes subjects who are not enrolled.  
Population includes Part A, Part B and Part C MLS subjects receiving 120 mg FlecIH-103. 
 
Safety Population 
 
The Safety population includes all enrolled subjects who started the inhalation of study medication, 
whether the subject was in AF or not and whether the subject received the full assigned dose of 
study medication or not. Compared to the ITT population, the Safety population excludes subjects 
who are enrolled but did not start the inhalation of study medication.  
Population includes Part A, Part B and Part C MLS subjects receiving 120 mg FlecIH-103.  
 
PK Population 
 
The PK population includes all enrolled subjects who received the full assigned dose of study drug 
irrespective of whether the subject was in AF or not at the initiation of dosing. Compared to the 
Safety population the PK population excludes subjects who did not receive the full assigned dose of 
study drug. The full 120 mg dose of study medication is defined as completing both inhalation 
stages, for a total dose of 120 mg eTLD (2 x 60 mg eTLD). 
 
Population includes Part A, Part B and Part C MLS subjects receiving 120 mg FlecIH-103. 


 
 
 
 
 
 
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Subject is in PK population, thus receiving the “full 120 mg dose of study medication”, if both 
conditions below apply:  
 
Condition 1:  Medication was administered for a sufficient period of time 
According to protocol medication should be administered for at least 3.5 minutes in two inhalation 
stages, separated by a 1-minute break. To measure if subject completed study medication according 
to protocol the following information, as registered in the EDC, is used: 
• 
Was first dose taken? 
SAS Dataset: EX, record for first dose, column: EXYN=1 (Yes) or 0 (No) 
• 
If not: Reason first dose was not taken 
SAS dataset: EX, record for first dose, column: EXREASNS  
• 
Was repeat dose started? 
SAS Dataset: EX, record for repeat dose, column: EXYN=1 (Yes) or 0 (No) 
• 
If not: Reason repeat dose was not taken 
SAS dataset: EX, record for repeat dose, column: EXREASNS  
• 
Start Time of First Dose  
SAS Dataset EX, record for first dose, column: EXSTTM (measured in seconds) 
• 
End Time of First Dose 
SAS Dataset EX, record for first dose, column: EXENTM (measured in seconds) 
• 
Start Time of Repeat Dose  
SAS Dataset EX, record for repeat dose, column: EXSTTM (measured in seconds) 
• 
End Time of Repeat Dose 
SAS Dataset EX, record for first dose, column: EXENTM (measured in seconds) 
• 
(Start) Time of Conversion to SR 
SAS dataset DSCONV, record for first or second dose, column: DSSTIM (measured in 
seconds) indicates the time of conversion. This is the start of the 60 second period of SR that 
is required for index conversion.   
These conditions must apply for subject to meet Condition 1: 
• 
Was first dose taken: Yes  
• 
Was repeat dose taken: Yes 
• 
Total time of the administration of the First Dose and Second Dose is at least 6 minutes and 
30 seconds (390 seconds), total administration time is measured as the sum of: 
 - The difference between End Time of First Dose and Start Time of First Dose   
 - The difference between End Time of Second Dose and Start Time of Second Dose.  
 
Condition 2: The subject was not under-dosed 
Study drug preparation instructions require 4.2 mL of study drug to be dispensed into a single 
nebulizer for administration of drug to the subject. If less than 4.2 mL is dispensed to a subject, then 
the subject is excluded from the PK population. If at least 4.2 mL is dispensed to a subject, the 
subject is included in the PK population.  
Three subjects are indicated by sponsor to be under-dosed where investigator filled out below 
information in a comment column of the eCRF (quoted literally): 
NL004-1009: “dose lower than 4,2 ml administered” 
NL025-2006: “patient was in panic and stopped the inhalation for a short moment” 
NL033-2006: “not deeply breathing through nebulizer because of coughing 
Only these three subjects will be excluded from the PK-population due to under-dosing. 


 
 
 
 
 
 
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Modified Intention-To-Treat Population (mITT) 
 
The modified ITT population includes all enrolled subjects who completed the full assigned dose of 
study drug and were in AF at the time of start of the inhalation of the study drug. Subjects whose AF 
converted to SR prior to completion of the assigned full dose of study drug will also be included in 
the mITT population. 
 
Completing the assigned dose of study medication in accordance with the protocol (i.e., dose/inhale 
to conversion) is defined as completing both inhalation stages, for a total dose of 120 mg eTLD (2 x 
60 mg eTLD), OR completing the dosing early due to conversion of AF to SR. All subjects who 
converted prior to completion of the assigned 120 mg dose of study medication will be included in 
the mITT population, regardless if they stopped dosing or continued. 
 
The mITT population will be used to evaluate all primary and secondary efficacy endpoints.  
Population includes Part A, Part B and Part C MLS subjects receiving 120 mg FlecIH-103. 
 
Handheld Echo (HHE) Population 
 
At selected sites in the EU, subjects in Part B and Part C can participate in an optional Handheld Echo 
(HHE) Sub-Study, where subjects who specifically consent will undergo an additional screening 
procedure using a portable hand-held ultrasound device to obtain an HHE   
 
In the US, an echocardiogram with LVEF within 6 months of screening is required to demonstrate 
eligibility. If no echocardiogram is available, subject must undergo an HHE during screening to 
confirm eligibility.  
 
The HHE population (refer to SAP section 8.2.6) thus consists of EU subjects who signed the IC for 
participating in the HHE Sub-Study and of US subjects without an available recent echocardiogram at 
screening that contains an LVEF value. 
 
For this population, the HHE exploratory endpoints as indicated in section 6.2.4 of the SAP will be 
reported. As HHE results are not available in Part A of the trial, the statistical report for Part C will 
only report subjects who were enrolled in Part B or MLS Part C of the trial. 
 
 
MLS Study Population Cohorts 
8.7.1 
Part C MLS Cohort (Cohort 1) 
This Cohort includes all subjects in the study population (i.e., safety, mITT etc.) who were enrolled in 
the Part C MLS. This Cohort will be referred to as Cohort 1. 
8.7.2 
Pooled MLS Cohort (Cohort 2) 
This Cohort includes all subjects in the study population (i.e., safety, mITT etc.) who were enrolled to 
receive the 120 mg (2 x 60 mg) FlecIH-103 study medication in Part A, Part B or Part C of the MLS. 
This Cohort will be referred to as Cohort 2. 
 
8.7.3 
Pooled MLS No Predose Flecainide Cohort (Cohort 3) 


 
 
 
 
 
 
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This Cohort includes all subjects in the study population (i.e., safety, mITT etc.) who are part of the 
Pooled MLS Cohort (Cohort 2) and have no evidence of flecainide present in their predose PK 
sample. This includes subjects whose pre-dose PK sample had flecainide plasma concentrations = 0 
ng/mL and subjects whose pre-dose PK sample was missing. This Cohort will be referred to as Cohort 
3. 
8.7.4 
Pooled MLS Predose Flecainide Cohort (Cohort 4) 
 
This Cohort includes all subjects in the study population (i.e., safety, mITT etc.) who are part of the 
Pooled MLS Cohort (Cohort 2) and have flecainide present in their predose PK sample (i.e., flecainide 
plasma concentrations > 0 ng/mL). This Cohort will be referred to as Cohort 4. 
 
 
Patient-Led (PLS) Population 
 
The PLS analysis will include all subjects who signed Informed Consent for the Part C Patient-Led 
Study (i.e., the PLS Population of Consented Subjects). All further PLS Populations (safety, mITT, etc.) 
will be based on the PLS Population of Consented Subjects and will use the population definitions 
described in Sections 8.2 through 8.6.  
 
A consort diagram will present the number of subjects included in each PLS Population (i.e., safety, 
mITT etc.); however due to the small number of PLS subjects who received study drug, all PLS data 
will be presented for the overall study populations (i.e., no Cohort analysis). 
 
All PLS subjects were previously successfully treated with inhaled flecainide earlier in Part A, B or C 
of the MLS. 
 
 
 
 
 
 


 
 
 
 
 
 
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9 Statistical Methods 
Statistical programming and analyses will be performed using established statistical methods.  
The study data will be reported using tables, figures, and data listings.  Descriptive statistical 
methods will be used to summarize the data from this study.  
Continuous variables will be descriptively summarized using number of subjects (n), mean and 
standard deviation (SD), additionally coefficient of variation (CV (%), as appropriate), median, 
minimum, maximum, and, as appropriate, geometric mean may be reported. If required, a 95% two-
sided confidence interval will be reported for the mean, using Student’s t-distribution. 
Categorical variables will be descriptively summarized by presenting the number (frequency) and 
percentage in each category.  If required, a 95% exact two-sided confidence interval will be reported 
for each proportion using the binomial distribution. 
A selection of data collected during the study will be included in data listings.  Unless otherwise 
noted, the data will be sorted by subject identifier, and (where applicable) by date within each 
subject identifier.   
The statistical analyses will be conducted using SAS® System version 9.3 or higher. Validation will be 
performed in accordance with applicable Cardialysis SOPs.  
 
Patient Disposition, Demographic and Baseline Characteristics 
Patient disposition will be presented for all subjects who signed Informed Consent, i.e., Population 
of Consented Subjects.  The number of subjects who completed the study and discontinued from the 
study will be summarized. The reasons for early discontinuation at any time in the study will be 
described by dose cohort. Screen failures are defined as subjects who signed Informed Consent but 
were not enrolled (randomized or allocated). 
Disposition, demographic and baseline characteristics data, including age, gender, race, ethnicity, 
etc. will be summarized in tables for each MLS population and cohort as described in Section 8, but 
no statistical testing will be performed. 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) (version 23.1 or higher) for the study period. Medical history and AEs may be summarized 
in tables and will be presented in data listings. 
Prior and concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (version WHO September 2019 or later). Prior and concomitant medications may be 
summarized in tables and will be presented in data listings.   
 
A separate consort diagram will be provided for the pooled analysis (Part A, part B and Part C MLS) 
and for Part C PLS. 
 
Specification of Analyses 
9.2.1 
Primary efficacy endpoint 
The primary efficacy endpoint is the proportion of subjects whose AF converted to SR by inhaled 
flecainide within 90 minutes after initiation of dosing.  
 


 
 
 
 
 
 
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Analysis is performed for the mITT population. A Subject meets the endpoint if conversion occurred 
within 90 minutes after initiation of dosing without the use alternative medication (e.g., IV flecainide 
and propafenone) or procedures (e.g., ECV). If a subject’s conversion status is unknown, then the 
analysis will assume that the subject did not convert. 
 
The percentage is calculated as: 
 
p= 100 * (number of converted subjects/number of subjects in mITT population)  
  
A 90% exact binomial confidence interval will be calculated for the percentage. 
  
No formal testing will take place. Analysis will not be performed for the PLS population.  
9.2.2 
Secondary efficacy endpoints and other assessments analyses 
 The proportion of subjects with Cmax values ≥ 200ng/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  
 
This endpoint is reported for the mITT population. 
 
The definition of conversion is identical as used for the primary efficacy endpoint meaning that If 
subject converts due to alternative medication (e.g., IV flecainide and propafenone) or procedures 
(e.g. ECV) patient fails the endpoint. 
  
For the purpose of this study, Cmax is defined as the peak plasma level of flecainide prior to 
administration of any alternative pharmacological agent (e.g., IV flecainide). 
 
The endpoint will be reported as percentages for eight different Cmax cut-off values as will the 
corresponding 95% Clopper-Pearson two-sided Confidence Intervals.  
 
The first percentage measures the conversion rate within 90 minutes after initiation of dosing, 
regardless of PK values, implying a Cmax cut-off value of 0.  
 
P1=100% * (number of converted subjects/number of subjects in mITT population)  
 
The other seven percentages measure the conversion rate within 90 minutes after initiation of 
dosing using a specific cut-off value of Cmax.  In order to be included in the analysis for subject 
sufficient information must be available to calculate Cmax. The proportions are defined as:  100* 
Numerator divided by Denominator. 
 
 
Proportion 
Numerator: number of 
converted subjects with: 
Denominator: 
Number of subjects with 
P2 
Cmax <200 
Cmax <200 
P3 
Cmax ≥200 
Cmax ≥200 


 
 
 
 
 
 
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P4 
Cmax ≥300 
Cmax ≥300 
P5 
Cmax ≥400 
Cmax ≥400 
P6 
Cmax ≥500 
Cmax ≥500 
P7 
Cmax ≥600 
Cmax ≥600 
P8 
Cmax ≥700 
Cmax ≥700 
 
Analysis will not be performed for the PLS population. 
 Statistical analysis of time-to-conversion to SR from initiation of 
dosing up to 90 minutes after initiation of dosing 
 
The Modified ITT Population will be used for this analysis. 
 
The cumulative incidence for the time to conversion from initiation of study medication up to 90 
minutes post dose will be determined using the Kaplan-Meier methods. Subjects who converted 
within 90 minutes post dose due to adjunct medication or procedure are reported as not converted 
and will not be censored at the time the subject converted due to the adjunct treatment. Results are 
shown in a Kaplan-Meier curve. 
 
 Kaplan-Meier figures will be created for the following:  
 
  -A figure with a single curve, showing results of Part C MLS Cohort (Cohort 1). 
 
  -A figure with a single curve, showing results of the Pooled MLS Cohort (Cohort 2)  
 
- A figure with a single curve, showing results of the Pooled MLS No Predose Flecainide Cohort 
(Cohort 3)  
 
- A figure with two curves, for the Pooled MLS Cohort (Cohort 2) and the Pooled MLS No Predose 
Flecainide Cohort (Cohort 3)  
 
Analysis will not be performed for the PLS population. 
 
 The proportion of subjects in SR on Day 2 
 
The Modified ITT Population will be used to determine the proportion of subjects in SR on Day 2.  
The rhythm status used for the evaluation of this secondary efficacy endpoint is derived from the 
remote ECG system, in which the subject’s heart rhythm is recorded. A subject is considered in SR on 
Day 2 if the subject's sinus rhythm during the recording is longer in duration (in seconds) than any of 
the other reported rhythms (refer to SAS section 5.2). The variable is set to missing if no evaluable 
remote ECG recording is available for analysis. 
 
The proportion is estimated by the number of subjects in SR on Day 2, divided by the total number 
of subjects with available data. The estimate for the proportion will be reported. 
 
Analysis will be performed for: 
 


 
 
 
 
 
 
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- the complete Modified ITT population 
 
- mITT subjects whose AF converted to SR by inhaled flecainide within 90 minutes after initiation of 
dosing  (subjects meeting the primary efficacy endpoint) 
 
- mITT subjects whose AF was not converted to SR by inhaled flecainide within 90 minutes after 
initiation of dosing  (subjects not meeting the primary efficacy endpoint) 
 
Analysis will not be performed for the PLS population. 
 The proportion of subjects with reduced or no AF symptoms at 
30 minutes post dose 
 
The Modified ITT Population will be used to determine the proportion of subjects with reduced or no 
AF symptoms (compared to baseline) at 30 minutes post dose.    
 
The evolution of symptoms (no symptoms, improved, unchanged or worsened) is a categorical 
variable, a subject is considered to have reduced or no AF symptoms at 30 minutes post initiation of 
dose (compared to baseline) if the symptoms are reported as either 'no symptoms' or 'improved'.  
 
The proportion is estimated by the number of subjects meeting the endpoint divided by the total 
number of subjects with available data. The estimate for the proportion will be reported. The 
variable is set to missing if no information is available. 
 
 
Analysis will be performed for: 
 
-the complete Modified ITT population 
 
-miTT subjects whose AF converted to SR by inhaled flecainide within 30 minutes post dose 
 
-mITT subjects whose AF was not converted to SR by inhaled flecainide within 30 minutes post dose 
 
 
Analysis will not be performed for the PLS population. 
 The proportion of subjects with reduced or no AF symptoms at 
60 minutes post dose 
 
The Modified ITT Population will be used to determine the proportion of subjects with reduced or no 
AF symptoms (compared to baseline) at 60 minutes post dose.  
 
The evolution of symptoms (no symptoms, improved, unchanged or worsened) is a categorical 
variable, a subject is considered to have reduced or no AF symptoms at 60 minutes post initiation of 
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The proportion is estimated by the number of subjects meeting the endpoint divided by the total 
number of subjects with available data. The estimate for the proportion will be reported. The 
variable is set to missing if no information is available. 
 
Analysis will be performed for: 
 
-the complete Modified ITT population 
 
-mITT subjects whose AF converted to SR by inhaled flecainide within 60 minutes post dose 
 
-mITT subjects whose AF was not converted to SR by inhaled flecainide within 60 minutes post dose 
 
Analysis will not be performed for the PLS population. 
 The proportion of subjects with reduced or no AF symptoms at 
90 minutes post dose 
 
The Modified ITT Population will be used to determine the proportion of subjects with reduced or no 
AF symptoms (compared to baseline) at 90 minutes post dose. 
  
The evolution of symptoms (no symptoms, improved, unchanged or worsened) is a categorical 
variable, a subject is considered to have reduced or no AF symptoms at discharge dose (compared to 
baseline) if the symptoms are reported as either 'no symptoms' or 'improved'.  
 
The proportion is estimated by the number of subjects meeting the endpoint divided by the total 
number of subjects with available data. The estimate for the proportion will be reported. The 
variable is set to missing if no information is available. 
 
 
Analysis will be performed for: 
 
-the complete Modified ITT population 
 
-mITT subjects whose AF converted to SR by inhaled flecainide within 90 minutes post dose 
 
-mITT subjects whose AF was not converted to SR by inhaled flecainide within 90 minutes post dose 
 
 
Analysis will not be performed for the PLS population. 
 
 The proportion of subjects who had their AF converted to SR 
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 Modified ITT MLS Population will be used to determine this endpoint.  
 


 
 
 
 
 
 
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This endpoint is derived from the primary efficacy endpoint at 90 minutes after initiation of dosing. 
The endpoint is met if the subject's AF converts to SR within 90 minutes after initiation of dosing 
without an alternative therapy and without subsequent AF recurrence up to discharge requiring 
additional intervention, either by electrical or pharmacological cardioversion or by rate control 
treatments. 
 
This proportion of subjects that convert to SR without AF recurrence is estimated as the number of 
subjects who meet the endpoint, divided by the total number of mITT subjects. The estimate for the 
proportion and its associated 95% Clopper-Pearson CI will be derived.  
 
The requirements for meeting the endpoint are thus as follows: 
- the start time of the conversion of AF to SR is within 90 minutes (including 90 minutes) after the 
initiation of study drug, AND EITHER  
 
-no recurrence of AF occurred between time of conversion and discharge, OR 
-recurrence of AF occurred between time of conversion and discharge but for subject none of the 
indicated interventions (as reported by investigator) was started between initiation of dosing and 
discharge. 
 
Discharge is left to the discretion of the treating physician 90 minutes post dose (-10 minute 
window). 
 
Additionally, analysis is repeated for the proportion of subjects whose AF converted to SR within 90 
minutes post dose.  
 
No imputation will take place, i.e., the subject is assumed to be free of event (No Conversion, No AF 
Recurrence, None of the three Interventions) after the time last information is available. 
 
Analysis will not be performed for the PLS population. 
 
 Proportion of subjects in SR on Day 5 
 
The Modified ITT Population will be used to determine the proportion of subjects in SR on Day 5 
(second follow-up visit).   
The rhythm status used for the evaluation of this secondary efficacy endpoint is derived from the 
remote ECG system, in which the subject’s heart rhythm is recorded.  
 
A subject is considered in SR on Day 5 if the subject's sinus rhythm during the recording is longer in 
duration (in seconds) than any of the other reported rhythms (refer to SAS section 5.2). The variable 
is set to missing if no evaluable remote ECG recording is available for analysis. 
 
The proportion is estimated by the number of subjects in SR on Day 5, divided by the total number 
of subjects with available data.  
 
The Modified ITT Population will be used to determine the proportion of subjects with reduced or no 
AF symptoms (compared to baseline) at discharge. Discharge is left to the discretion of the treating 
physician 90 minutes post dose (-10 minute window). 


 
 
 
 
 
 
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Analysis will be performed for: 
 
-the complete Modified ITT population 
 
-mITT subjects whose AF converted to SR by inhaled flecainide within 90 minutes after initiation of 
dosing  (subjects meeting the primary efficacy endpoint) 
 
-mITT subjects whose AF was not converted to SR by inhaled flecainide within 90 minutes after 
initiation of dosing  (subjects not meeting the primary efficacy endpoint) 
 
Analysis will not be performed for the PLS population. 
 
 Adverse Events 
 
Adverse events in the MLS will be reported for the Safety MLS population, meaning for subjects who 
started study medication, regardless of if subject was in AF when starting study medication. 
Refer to SAP section 5.6.3. for the AE results reported for Part B and Part C MLS subjects, refer to 
SAP section 5.6.4 for the AE results reported for Part A subjects. 
 
Adverse Events are coded as serious or non-serious, as related or not related to study medication, 
and as related or not related to study device. Adverse Events of Special Interest (AESI) and Serious 
Events of Special Interest (SAESI) are identified. Results are MedDRA coded (version 23.1 or higher). 
 
In all tables the number of AEs, the number of subjects with at least one occurrence of the AE, and 
the percentage of subjects with at least one occurrence of the AE are reported by cohort (refer to 
SAP section 8.7). 
 
If subject information is not complete up to the end of the planned End of Study (i.e., subject is lost to 
follow-up), subject is assumed to be free of events up to planned End of Study.  
 
These results will be reported:  
1. Any Adverse Event (AE) 
- overall 
- per combination of MedDRA System organ Class and MedDRA Preferred Term: 
  - Any Event 
  - Events occurring between IC and initiation of study medication  
  - Events between study medication and 4 hours after initiation  
  - Events between 4 hours after initiation and 24 hours after initiation 
  - Events between 24 hours after initiation and end of observation period 
 
2. Any Serious Adverse Event (SAE) 
- overall 
- per combination of MedDRA System organ Class and MedDRA Preferred Term: 
  - Any Event 
  - Events occurring between IC and initiation of study medication  
  - Events between study medication and 4 hours after initiation  
  - Events between 4 hours after initiation and 24 hours after initiation 


 
 
 
 
 
 
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  - Events between 24 hours after initiation and end of observation period 
 
- 
Any Treatment Emergent Adverse Event (TEAE) 
- overall 
- per combination of MedDRA System organ Class and MedDRA Preferred Term: 
  - Any Event 
• 
By severity 
• 
By relationship to study medication 
• 
TEAEs that are moderate or severe and related to study medication 
- 
 
  - Events between study medication and 4 hours after initiation  
  - Events between 4 hours after initiation and 24 hours after initiation 
  - Events between 24 hours after initiation and end of observation period 
 
3. Any Treatment Emergent Serious Adverse Event (TESAE) 
- overall 
- per combination of MedDRA System organ Class and MedDRA Preferred Term: 
  - Any Event 
  - Events between study medication and 4 hours after initiation  
  - Events between 4 hours after initiation and 24 hours after initiation 
  - Events between 24 hours after initiation and end of observation period 
 
The end of the extended observation period is defined as Visit 2 (Day 5). Subjects enrolled in Part A, 
Part B or Part C MLS who are also included in the Part C Patient-Led sub-study will be followed until 
a recurrent episode of AF is treated, or approximately 8 months after consent (whichever comes 
first); events starting after Visit 2 will not be included in the MLS part of the final statistical report 
but will be included in the PLS part of the final statistical report.  
 
4. Adverse Events of Special Interest (AESI) 
These results will be reported:  
- Listing of AESI 
-Overall number of AESI  
Specification (per type of AESI, refer to SAP section 3.4) 
AESI will be reported only if starting on or after initiation of study medication (Treatment Emergent). 
 
The definition for AESI was modified during the trial based on examination of the data and 
regulatory interactions with the US FDA. All AESIs will be tabulated using a slightly adjusted 
definition compared to the Protocol version 8.0\EU-1 AESI definition, results are provided by 
sponsor (refer to  SAP section 5.6.5 and Annex A); in the listings all results will be included: as per the 
Cardialysis Safety Team  (Part A, refer to SAP section 5.6.2),  investigator (Part B and C, refer to SAP 
section 5.6.1) and by Sponsor  (Parts A, B and C, refer to  SAP section 5.6.5 and Annex A).  
AESIs will be classified as Cardiovascular or non-Cardiovascular, refer to SAP section Annex A. 
 
 
5. Serious Adverse Events of Special Interest (SAESI) 
These results will be reported:  
- Listing of SAESI 


 
 
 
 
 
 
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-Overall number of SAESI  
 
SAESIs will be reported only if the event start time is on or after initiation of study medication 
(Treatment Emergent). 
 
Only from Protocol version 8.0\EU-1 onwards SAESI was defined in study protocol. SAESI will be 
tabulated according to a slightly adjusted definition compared to the Protocol version 8.0\EU-1 
SAESI definition, results are  provided by Sponsor (refer to  SAP section 5.6.5 and Annex A); in the 
listings all results will be included: as indicated by investigator and by Sponsor  (Parts A, B and C, 
refer to  SAP section 5.6.5 and Annex A).  
 
SAESI will be classified as Cardiovascular or non-Cardiovascular, refer to SAP section Annex A. 
 
Reporting of AE 
All Adverse Events will be included in listings. AE occurring in the PLS part of the study will be listed 
separately. Listings will include flags indicating: 
 
-Is reported event Treatment Emergent? 
-Are reported events categorized by investigator (Parts B and Part C MLS) or Cardialysis Safety Team 
(Part A) as 'AESI'? 
-Are reported events categorized by investigator as ‘Serious AESI’? 
-Are reported events categorized by sponsor as 'AESI'? (refer to Appendix A SAP) 
-Are reported events categorized by sponsor as ‘Serious AESI’? (refer to Appendix A SAP) 
 
 
Adverse events tables will be reported as follows: 
 
1) All AEs from time of MLS consent through MLS Day 5 
2) Treatment Emergent AEs from start of MLS dosing through MLS Day 5 
 
Tables will thus exclude AE that start in the PLS part of the study. 
 
No tables will be reported for the PLS population, AEs will be listed only. 
 
 
 Pharmacokinetic (PK) assessment(s): Flecainide plasma 
concentration over time  
 
PK results will be reported for all evaluable patients in the PK population. For each subject all 
available flecainide plasma (PK) values are reported in a listing and in a figure. The PK results are 
reported according to the time the blood sample was collected since initiation of study medication 
(minutes). If the PK value for the sample taken just before initiation (at T0) is not available or is 
reported as ‘BLQ’ (Below Limit of Quantification) the value 0 will be imputed (unless additional 
information indicates otherwise).  
 
Section 6.2.5.1 indicates the planned time points PK samples are taken. 
 


 
 
 
 
 
 
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Per cohort per planned PK time point the mean value and standard deviation of the flecainide values 
are reported in a table and in a figure. These tables and figures can be repeated for specific types of 
subjects, according to the specific type of conversion to SR (refer to SAP section 3.1, “definition of 
methods for cardioversion”), these additional analyses will be specified in the overview of TFLs that 
will accompany the final report.  
 
No PK results will be tabulated for the PLS population, however for these subjects plasma 
concentrations of flecainide will be presented in listings. 
 
PD results are reported for the PK population. 
 
Summarizing PK statistics 
 
These results are not planned to be included in the final report. The final report will however show 
information on Cmax and tmax, based on the PK results that are indicated in SAP section 5.5.   
 
 
Results will be calculated by Eurofins as: 1) per-subject results, and; 2) summary statistics for a 
selection of subjects. Statistics calculated are: number of observation, mean, standard deviation, 
coefficient of variance, geometric mean, minimum and maximum. Results will be sent by Eurofins to 
Sponsor.  
 
Protocol (refer to section 10.2.3 B) additionally indicates reporting of summarizing statistics for PK 
parameters, which include:  
 
AUC0-10: 
The area under the plasma concentration versus time curve from the 
start of dosing (time zero, T0) to 10 minutes post completion of dosing 
AUC0–90: 
The area under the plasma concentration versus time curve from the 
start of dosing (time zero, T0) to 90 minutes post completion of dosing 
Cmax: 
The peak (maximum) plasma concentration prior to the start time of any 
alternate pharmacological therapy, is to be obtained directly from the 
plasma concentration time profile 
tmax: 
The time to Cmax (from the time of start of dosing) is obtained.  
t½ distribution: 
The distributive half-life is calculated by the equation t½ = ln(2)/kdist 
 
 
 
 Pharmacodynamic (PD) assessment(s): QRS and other 12-lead ECG 
parameters over time  
 
PD results will be reported for the safety, PK and mITT populations. Section 6.2.5.2 indicates the 
planned time points PD information is measured. Information is provided by the Core Laboratory 
performing the analysis by extracting 12-lead ECGs from the AECG (Holter) recording at pre-defined 
time points. 
For each time point triplicate measurements take place, the second and third measurements are 
planned at approximately 30 seconds and approximately 60 seconds after the initial measurement, 
respectively. Per subject per time point the mean value is calculated for the ECG parameters; these 


 
 
 
 
 
 
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mean values are used in all PD analyses. 
 
 The following parameters will be reported: 
 
- Heart Rate (bpm) 
- QRS Interval Duration (msec)  
- QTc Interval Duration (msec)  
- JTc Interval Duration (msec)  
- RR Interval Duration (msec)  
- PR Interval Duration (msec)  
  PR is only available if subject is in SR 
 
Baseline Values will be summarized as Baseline (seated) and Baseline (semi-recumbent) (refer to SAP 
Section 3.5). 
 This information is reported per cohort per time period: 
- a per subject listing of all PD values 
- a per subject listing of the change of PD values compared to baseline value (seated) (delta). 
   For ∆QRS interval (msec) additionally the maximum is shown. 
 
- a per cohort table of mean and standard deviation of PD values 
- a per cohort table of mean and standard deviation of change of PD values compared to baseline  
  values (seated) (delta).  
  For ∆QRS interval (msec) additionally the maximum is shown. 
- a per cohort figure of ∆QRS interval (msec) and its standard error of mean. 
 
Tables and figures can be repeated for specific reasons why subject Converted to SR (refer to SAP 
section 3.1, “definition of methods for cardioversion”), these additional analyses will be specified in 
the overview of TFLs that will accompany the final report. 
 
PD results are reported for the Safety and the PK population. 
 
Results for the Part C PLS study are available for 3 subjects only; results will only be listed, not 
tabulated. 
 Secondary safety endpoint (MLS) 
 
The secondary safety endpoint, the incidence of treatment emergent serious adverse events of 
special interest for flecainide (SAESI, refer to section 3.4 SAP for definition) is reported by analyzing 
AEs that fulfill all of these conditions: 
 
- Events starts between initiation of inhalation of study drug and Visit 2. 
- AE is a SAESI according to sponsor provided information (refer to SAP section Annex A). 
 
Results will be reported for the Safety Population, meaning all subjects who started inhalation of 
study medication. 
 
The MLS statistical report will summarize results as: 
-total number of serious AESI and mean number of serious AESI per subject 


 
 
 
 
 
 
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-total number of subjects with at least one serious AESI, percentage of subjects with at least one 
serious AESI 
 
Additionally details of the Serious AESI will be shown in the listings in the statistical report. 
 
Serious AESIs (SAESI) will be reported as follows: 
 
1) All SAESIs from time of MLS consent through MLS End of Study (EoS) 
2) MLS Treatment Emergent SAESIs from start of MLS dosing through MLS Day 5 
 
 
 Safety endpoint (PLS) 
 
The secondary safety endpoint, the incidence of treatment emergent serious adverse events of 
special interest for flecainide (Serious AESI, refer to section 3.4 SAP for definition) is defined as 
follows:  
 
- Adverse Events starts between initiation of PLS study drug and PLS Day 5 and 
- AE is a SAESI according to sponsor provided information (refer to SAP section Annex A). 
 
AEs reported from the time of PLS consent until the initiation of PLS study drug are thus not 
considered treatment emergent.  
 
Endpoints will not be reported in statistical tables, but a listing will include all information required 
to derive endpoint.  Refer to section 9.2.2.9 SAP for the information included in the listing. 
 
Adverse events will be reported as follows: 
 
1) PLS Treatment Emergent AEs from the initiation of PLS study drug through PLS Day 5 (End of 
Study) 
 
2) All AEs from time of PLS consent through PLS End of Study 
  
9.2.3 
Additional Analyses 
 Vital Signs 
The investigator reported values from vital sign measurements (heart rate, respiration rate, etc.) will 
be used. Vital sign values after initiation of inhalation will be compared with the semi-recumbent 
Baseline value at 30 minutes pre-initiation to study medication, in case this value is missing the  
semi-recumbent Baseline value at 45 minutes pre-initiation will be used. In case also the 45 minutes 
pre-initiation value is missing, the Baseless value nearest to initiation of study medication will be use 
as reference value. 
 
For the MLS part of the study a table will report baseline values, a second table will report the post 
initiation results and the change compared to baseline. 
 


 
 
 
 
 
 
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All data will be provided in a listing, both for the MLS and PLS part of the study. For the PLS study 
results information is available only for subjects who started PLS study drug.  
 
 Prior and concomitant medication 
In the MLS part of the trial prior and concomitant medications that were taken between 30 days of 
enrollment through Day 5 of the MLS part of the study is recorded by investigator. For subjects not 
participating in the PLS Part of the trial this Day 5 visit is the End of Study visit.  
 
For subjects participating in the PLS trial, any additional medications are recorded up to the end of 
the PLS episode, being either Day 5 of the PLS study (for subject who started PLS study medication, 
this visit is the EOS visit for subject) or the EOS visit (for subjects who did not start PLS study 
medication). 
 
All concomitant medications for the reported MLS subjects and  Part C PLS subjects will be listed in 
the statistical report. Additionally, tables will be created to summarize the concomitant medications 
for the Cohorts defined Table 1 in SAP section 8. For the MLS study, in addition, tables will 
summarize the medication by type: 
 
-Antiarrhythmics 
-Antithrombotics 
- Other cardiovascular medication 
- Other medication 
 
Additionally tables will summarize the medication by reporting all observed values (before and after 
start of dosing) of ATC class (e.g. B01AF=DIRECT FACTOR XA INHIBITORS) and within the specific ATC 
class by reporting  all observed values for Standardized Medication name (e.g. Rivaroxaban, 
Apixaban). 
 Treatment satisfaction for subjects meeting Primary Efficacy 
Endpoint 
According to protocol FLE-002 version 8.0 / EU-1 after 90 minutes post dose and prior to discharge, 
subjects whose AF converted to SR within 90 minutes post dose without any alternative treatment 
will be asked questions about their treatment satisfaction.   
 
In the EDC for subjects who were enrolled according to an earlier version of the protocol the 
questions were asked after 60 minutes post dose and prior to discharge.  
 
 
 


 
 
 
 
 
 
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Two questions are asked: 
 
1. If offered, would you take the study treatment again in the future (No/Yes) 
All results will be listed in the statistical report, in the summary tables this percentage will be 
reported: 
 
p= 100% * (Number of subjects who respond “Yes”)/(number of subjects with non-missing value)  
 
2. On a scale of 1 to 10, how satisfied were you with the study treatment (1 being the worst and 10 
being the best) 
All results will be listed in the statistical report, the summary tables include these results: 
 
-Number of non-missing values 
-Frequency and percentage of all possible outcomes (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) 
-Number, mean, and standard deviation of the outcomes. 
 
Results are not available for Part C PLS. 
 
 


 
 
 
 
 
 
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 Clinical laboratory evaluation analysis 
The protocol indicates: 
 
Laboratory data are summarized by type of laboratory test. Reference ranges and clinically 
significant abnormal results are depicted in the summary of clinical local laboratory data, as 
described in the SAP. Descriptive statistics are used for each laboratory parameter at screening (Day 
1) and either at 90 min after initiation of dosing or at discharge.  
 
MLS  
Blood samples for determination of the hematology panel, the comprehensive metabolic panel and 
the coagulation panel are taken at two time points: 
-Approximately 45 minutes preceding initiation of drug administration 
-At 90 minutes post dose (comprehensive metabolic panel only) 
 
PLS  
For subjects who signed IC for the PLS Part C and receive inhaled flecainide in the PLS study, blood 
samples are taken at one time point. Blood samples as described in Part B may be obtained on Day 1 
prior to self-administration of the study drug per the discretion of the treating physician.  
 
For all MLS cohorts, all variables shown in SAP section 6.2.5.4 for the Safety Population results will 
be reported shown for two time points: at screening and at 90 minutes after initiation of dosing 
and/or at discharge. 
Comparisons will be made for changes from baseline (screening) and 90 minutes after initiation of 
dosing or at discharge for all parameters.  
The measuring unit will be shown in all cases.  
 
1) Per Lab test characteristic (at screening, at discharge) 
-Was Lab test performed (Yes/No) 
Reported are: Number of analyzed subjects and the number and percentage of subjects for whom 
the Lab test was performed. The number of subjects for whom Lab test was performed is indicated 
below as: Number of subjects with Lab Test. 
 
2) Per specific test  
-Was the test performed 
Reported are: Number of subjects with Lab Test, and the number and percentage of subjects for 
whom the specific test was performed. 
 
-If test performed: outcome is reported as follows: 
 
2.1) for Categorical characteristics 
Pregnancy Test is only performed for female subjects, a Serum or Urine test can be performed, the 
result is categorized as “Negative” or “Positive”. 
 
Reported are the number of female subjects for whom the overall Lab Test was performed. For 
these subjects the type of test (Serum/Urine) is shown by frequency and by percentage and the 
outcome (Negative/Positive) by frequency and percentage.  
 
 


 
 
 
 
 
 
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2.2) for Numeric characteristics 
For all other tests a numeric outcome is to be indicated in the EDC. However, investigator can also 
fill out “NE” as value in the EDC indicating no exact numeric value is available. The results of the test 
are then specified in an open text field. This option is intended to fill out test results that are Below 
the Limit of Quantification (BLQ), meaning in the comment field e.g., “<0.1” is reported. 
In these cases in the analysis value 0 will be imputed as numeric outcome, this result will be used in 
the analyses described in the remainder of this section of the SAP.  
 
For the MLS study, statistical tables will show the number of subjects in each cohort for whom the 
specific test was performed and the number and percentage of subjects with missing results (after 
performing above indicated imputation of values BLQ). For the PLS study results will only be listed. 
 
A test can be repeated either at screening (e.g., potassium can be measured twice to confirm 
eligibility) or when a test failed, and a second attempt was made to measure the characteristic.  If 
more than one non-missing value is available at screening, only the value closest to dosing (i.e., last 
available non-missing value) will be used in the statistical analysis.  
 
The statistical tables will show the number of subjects in each cohort for whom specific test resulted 
in a numeric value, mean value and standard deviation of the numeric results are reported.  
 
If the numeric value indicated in the EDC is lower than the Lower Limit of Normal (LLN) or higher 
than the Upper Limit of Normal (ULN) a question pops up in the EDC requiring investigator to fill out 
if the reported value is Clinically Significant (“CS”) or not (“NCS”). The statistical tables will show the 
number of subjects with a numeric result and the number and percentage of these subjects for 
whom this numeric result is classified in the EDC as Clinically Significant.  
 Protocol Deviations 
Protocol deviations will be listed, a first listing will show the Major Protocol Deviations, a second 
listing the minor Protocol Deviations. 
 
In tables per cohort the Protocol Deviations will be reported: 
- by category of protocol deviation (all, major, minor), 
- by type of protocol deviation (e.g. Vitals, ECGs), 
- by combination of category and type of protocol deviation.  
 
9.2.4 
Exploratory endpoints: Handheld Echo 
All HHE endpoints (refer to section 6.2.4 SAP) will be reported for the HHE population (refer to 
section 8.6 SAP) in listings.  
This section describes the full analysis of the HHE assessments, including non-endpoints. 
 
HHE data will be measured by investigator and filled out in the EDC. Only subjects with assessments 
that are normal, minimal, or absent, will be eligible for the study.  
 
The HHE will also be submitted to an independent reviewer, at a later time, to compare with the 
assessments made by the site staff during the screening period. This independent review will not be 
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HHE echo data are not available for the PLS Part C study. 
 HHE characteristics 
The report for Part C will show HHE characteristics twice: once for the results reported by 
investigator and once for the results reported by an independent reviewer (refer to section 5.7 SAP).  
 
The below characteristics are reported from both reviewers: 
 
- 
Was HHE performed? 
The number of subjects in the HHE population is reported as is the percentage of subjects 
for whom the HHE was performed. If HHE is not performed, the reasons are reported.  
 
- 
LV Size 
Size is classified as “Normal” or “Enlarged”. For subjects for whom the HHE was performed, 
per category the number and percentages of subjects in the category is reported. 
Enlarged is defined as: LV end-diastolic internal dimension > 55 mm for men and > 50 mm for 
females 
 
- 
LV-Function 
Size is classified as “Normal” or “Abnormal”. For subjects for whom the HHE was performed, 
per category the number and percentages of subjects in the category is reported. 
 
- 
LVEF 
For the LVEF value (%) is indicated: 
-Number and percentage of subjects for whom LVEF was not evaluable 
-Number and percentage of subjects for whom LVEF was evaluable 
-Mean and standard deviation of the LVEF value (for subjects for whom LVEF was evaluable) 
-Number and percentage of subjects with a LVEF <45% (for subjects for whom LVEF was 
evaluable)  
 
- 
LV hypertrophy 
The number and percentage of subjects is indicated for whom the HHE was performed but 
information on LV hypertrophy is missing. 
LV Hypertrophy is classified as “Absent”, “Mild”, “Moderate” or “Severe”. For subjects for 
whom the HHE was performed, and information is available, per category the number and 
percentages of subjects in the category is reported, as is the percentage of subjects with 
“Absent” or “Mild”.  
Moderate or Severe: LV thickness > 12mm 
  
Aortic Valve Disease (stenosis or regurgitation)  
The number and percentage of subjects is indicated for whom the HHE was performed but 
information on Aortic Valve Disease is missing. 
Aortic Valve Disease is classified as “Absent”, “Mild”, “Moderate” or “Severe”. For subjects 
for whom the HHE was performed, and information is available, per category the number 
and percentages of subjects in the category is reported, as is the percentage of subjects with 
“Absent” or “Mild”.  
 


 
 
 
 
 
 
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- 
Mitral Valve Disease (stenosis or regurgitation) 
The number and percentage of subjects is indicated for whom the HHE was performed but 
information on Mitral Valve Disease is missing. 
 
Mitral Valve Disease is classified as “Absent”, “Mild”, “Moderate” or “Severe”. For subjects 
for whom the HHE was performed, and information is available per category the number 
and percentages of subjects in the category is reported, as is the percentage of subjects with 
“Absent” or “Mild”.  
 
- 
Other Valve Disease (stenosis or regurgitation) 
The number and percentage of subjects is indicated for whom the HHE was performed but 
information on Other Valve Disease is missing. 
 
Other Valve Disease is classified as “Yes” or “No”. For subjects for whom the HHE was 
performed, and information is available, per category the number and percentages of 
subjects in the category is reported. For subjects with Other Valve Disease, a listing will 
specify the valve disease (as filled out in a comment field in the EDC by investigator or the 
comment field in the dataset from the independent reviewer). 
 
- 
Other Clinically significant findings 
The number and percentage of subjects is indicated for whom the HHE was performed but 
information on Other Clinically significant findings is missing. 
 
Other Clinically significant findings as “Yes” or “No”. For subjects for whom the HHE was 
performed, and information is available, per category the number and percentages of 
subjects in the category is reported. For subjects with Other Clinically significant findings a 
listing will specify the finding (as filled out in a comment field in the EDC by investigator or 
the comment field in the dataset from the independent reviewer). 
 Subject considered eligible based on HHE assessment 
Only If HHE was performed subject is included in the analysis of this endpoint.  
 
Values are “No”, “Yes” or “Not assessable”. Per category the number and percentages of 
subjects in the category is reported. 
 
Values are automatically derived in the EDC by evaluating the answers to four HHE 
characteristics (refer to SAP section 9.2.4.1) as indicated by investigator. For the evaluation 
of the results reported by the independent reviewer the same criteria will be applied in the 
statistical analysis. 
 
Inclusion criteria 5 in section 4.2.B of the Protocol indicates 
 
If participating in the optional Handheld Echo Sub-Study, the subject must have an LVEF ≥ 
45%, absent or mild left ventricular hypertrophy, and absent or mild valvular disease 
(stenosis or regurgitation) to be considered eligible for the study. 
 
Subject is thus considered eligible if all conditions below are applicable: 
 


 
 
 
 
 
 
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     -LVEF is >=45%  
    - LV hypertrophy is “Absent” or “Mild” 
    - Aortic Valve Disease (stenosis or regurgitation) is “Absent” or “Mild” 
    - Mitral Valve Disease (stenosis or regurgitation) is “Absent” or “Mild”  
 
Subject is considered non eligible if any condition below is applicable: 
     -LVEF is <45% 
     - LV hypertrophy is “Moderate” or “Severe”.  
     -Aortic Valve Disease (stenosis or regurgitation) is “Moderate” or “Severe”.  
     - Mitral Valve Disease (stenosis or regurgitation) is “Moderate” or “Severe”.  
 
Subject is considered non assessable if all conditions below are applicable: 
-None of the four conditions indicated in the category “non-eligible”, as indicated above, 
apply 
-For at least one of the four characteristics used in the category “non-eligible” a missing 
value occurs. 
 Subject considered ineligible as a result of HHE assessment 
The independent review will not be used for the assessment of subject eligibility during 
screening. For this endpoint therefore only investigator reported information is used. 
 
As a result of is interpreted in the SAP as: the HHE assessment is the main reason for subject 
being non-eligible for enrollment. For all subjects who are ineligible for enrollment investigator 
fills out maximum three failed Inclusion/Exclusion Criteria in the EDC, the first one filled out is 
considered to be the main reason. Thus, if as first failed IC/EC Criteria Exclusion above cited 
Inclusion criteria 5 is indicated, the HHE is the main reason for subject.  
 
The endpoint is thus met if these two conditions both apply: 
 
  -HHE analysis performed by investigator indicates subject is considered ineligible (refer to SAP 
section 9.2.5.2) and 
  -The HHE assessment is filled out by investigator in the EDC as being the main reason for 
subject being ineligible in the trial. 
  
The endpoint is reported for subjects included in the HHE population for whom the HHE 
assessment resulted in the conclusion ‘Eligible’ or “Non Eligible’, meaning subjects are excluded 
if assessment resulted in “Not Assessable”. 
 
For these subjects the number of and percentage of subjects who were classified as “Ineligible” 
are reported, as is the number and percentage of subjects who meet the endpoint (being 
“Ineligible” with the HHE Echo results as main reason for being Ineligible for enrollment).  
 Time from HHE administration to availability of HHE 
report/results 
These three time points are registered by investigator in the EDC: 
 
-Time of HHE assessment 
(eCRF: dataset HHE, Column ECDAT) 


 
 
 
 
 
 
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-Time HHE report/results are available  
Defined as: Time when results were completed in the source worksheets (eCRF: dataset HHE, 
column REPDAT)  
 
-Analysis time  
Defined as the time analysis was completed (eCRF: dataset HHE, Column ANALDAT) 
 
All three are date-time variables, with number of seconds as measuring unit. 
  
The time from HHE administration to availability of HHE report/results will be reported in 
minutes and will calculated as: 
 
t1= (Time HHE report/results available -/- Time of HHE assessment)/60 
 
The number of available observations and the mean and standard deviation will be reported. 
 
Additionally the time from HHE administration to time of Analysis will be calculated. 
 
t2= (Analysis Time -/- Time of HHE assessment)/60 
 
The number of available observations and the mean and standard deviation will be reported. 
 Agreement between eligibility based on HHE analysis 
investigator and independent reviewer  
Refer to section 9.2.4.3 for the assessment if subject was eligible according to investigator and 
according to independent reviewer. For both sources the result of the analysis can be: “Eligible”, 
“Non Eligible” or “Not Assessable”. 
 
 
The statistical report will include a 3*3 table:  
 
 
Eligible according to independent review 
Total 
Eligible according 
to investigator 
Yes 
No 
Not Assessable 
 
Yes 
N11 
N12 
N13 
N1. 
No 
N21 
N22 
N23 
N2. 
Not Assessable 
N31 
N32 
N33 
N3. 
Total 
N.1 
N.2 
N.3 
N 
 
The percentage agreement is reported in two ways:  
 
The first percentages show agreement using all analyses, meaning also agreement is reached if both 
raters indicate eligibility is “Not Assessable”  
 
p1=100*(N11+N22+N33)/N. 
 


 
 
 
 
 
 
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The number of patients and the percentage agreement will be reported, if required a 95% two-sided 
Clopper-Pearson confidence interval will be shown. 
 
The second percentages show agreement excluding analyses where raters indicate eligibility is Not 
Assessable, thus only including analyses where at least one rater concluded that subject was Eligible 
or Not Eligible.  
 
p2=100*(N11+N22/(N-N33). 
The number of patients and the percentage agreement will be reported, if required a 95% two-sided 
Clopper-Pearson confidence interval will be shown.  
 
Additionally, a listing will show a line per subject, indicating for both investigator as independent 
reviewer the conclusion on eligibility of the subject. 
 
No other inter-rater comparison of HHE characteristics (e.g. LVEF %, LV hypertrophy, refer to section 
9.2.4.1 of SAP) is planned.  
9.2.5 
Exploratory endpoints for Part C PLS study 
 
These endpoints will be reported for the PLS population (refer to SAP section 8.8). 
 
 Proportion of subjects who achieved therapeutic dosing (≥ 200 
ng/mL) with the study drug in the Part C Patient-Led Under 
Medical Supervision  
Due to the small sample size (n=3), this endpoint will not be analyzed, per subject results will be 
listed.  
 
 Feasibility of patient-led self-administration of study drug  
Below endpoints are defined in the protocol. 
 
1) Percent of subjects who consent to the PLS study 
 
A first overview shows if patient consented to the PLS study, three possible options: 
-“Not applicable” 
-“Yes” 
-“No” 
 
Only for subjects whose initial treatment was performed in Part B or the MLS Part C of the trial 
numbers and frequencies will be provided.  The sample size is all subjects who received inhaled 
flecainide in Part B or in the MLS Part C.   
 
For the “non applicable” category the reason is specified: 
    -Subject not Eligible 
     -Site does not participate in patient-Led study 
     -Other (Reason will be provided) 
 


 
 
 
 
 
 
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For the remaining subjects (“Yes”, “No”) the number and percentage of subjects who consented to 
the PLS study is reported. The sample size is the number of remaining subjects (“Yes”, “No”). For 
subjects who did not consent the reason will be provided. 
 
For subjects whose initial treatment was performed in Part A of the trial no information is available 
in the EDC for this endpoint. Only the number of subjects who consented to the PLS study will be 
provided. 
 
2) Percent of subjects who withdraw from the study 
 
For the subjects who consented to the PLS study the End of Study status will be reported. These 
categories are specified in the eCRF:  
 
-Completed  
-Subject received medication in PLS part of Part C due to recurrent AF 
 -Subject completed the 8 months follow-up period without treatment of recurrent AF 
-Adverse Event 
-Death 
-Physicians Decision 
-Lost to Follow-up 
-Withdrawal by Subject 
-Protocol Deviation 
-Site Terminated by Sponsor 
-Study Terminated by Sponsor 
-Screen Failure 
-Other (the reason will be specified) 
 
Information is available for all subjects participating in the PLS study. 
 
3) Percent of subjects who are certified for self-administration of study drug 
The number of subjects who consented to the PLS study will be reported as is the number and 
percentage of subjects who completed training certification. 
 
percentage=100*number of certified/number of consented subjects 
 
Information is available for all subjects participating in the PLS study. 
 
4) 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 
For subjects who consented to the PLS study all AF recurrences after Informed are reported in a 
listing.  
 
If no AF recurrence occurred subject will be listing as having no AF recurrence. 
 
If any AF recurrence occurred for subject all AF recurrences are shown, one line per recurrence. The 
line includes:  


 
 
 
 
 
 
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 -Subject ID 
 -Visit when the AF recurrence was registered 
-If more than one AF recurrence for the visit: sequence number 
 -Date and time of AF recurrence 
 -Did AF recurrence lead to treatment by inhaled flecainide 
  If AF recurrence did not lead to treatment by inhaled flecainide: reason why.  
 This is a comment field, e.g. “conversion with pill in the pocket”  
 
Information is available for all subjects participating in the PLS study. 
 
5) Percent of subjects that independently set up and inhaled study drug according to the provided 
instructions 
For subjects receiving inhaled flecainide in the PLS trial investigator filled out: 
 
“Did the subject self-administer the dose as instructed without assistance” 
 
The number and percentage of subjects for whom “Yes” is filled out is reported. For subjects for 
whom “No” is filled out, a comment field lists the difficulties encountered during self-administration 
 
Information is available for all subjects participating in the PLS study who received inhaled flecainide 
in the PLS trial. 
 
 
 Proportion of subjects whose AF converted to SR 
 
For subjects receiving inhaled flecainide in the PLS trial the number of subjects who converted to SR 
within 90 minutes post end of dose is reported, as is the method of Cardioversion (refer to SAP 
section 3.2) 
 
Information is available for all subjects participating in the PLS study who received inhaled flecainide 
in the PLS trial. 
 
 Hand Held Echo (HHE) Endpoints 
 
 
1) Proportion of subjects for whom capture and assessment of a diagnostic echocardiogram using a 
HHE at screening was successful 
 
2) Percent of subjects who are considered ineligible for enrollment as a result of the HHE assessment 
 
3) Time from HHE administration to availability of HHE report/results 
 
 
In the Part C PLS study no HHE was performed, endpoints will not be reported.   
 


 
 
 
 
 
 
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 On Pooled results (Part A, Part B and Part C MLS Subjects (120 mg FlecIH-
103)) 
 
In Part B, a formal homogeneity test was performed to assess if the primary endpoint results for part 
A subjects receiving the 120 mg FlecIH-103 inhalation solution could be pooled with the primary 
endpoint results for Part B subjects. If results could be pooled, as was the case, a Total column would 
be included in the statistical report showing results for the Pooled population of Part A and Part B 
120 mg FlecIH-103 subjects. 
 
In the final report MLS subjects from Part A, Part B and Part C MLS will be pooled without any formal 
test performed on heterogeneity. Refer to sections 8 and 8.7 of SAP for the definition of the pooled 
cohorts and for an indication per type of data for which pooled cohorts study information will be 
reported. 
 
10 Difference between protocol and SAP 
 
The SAP is in accordance with study protocol V8.0/ EU-1 except for the following deviations: 
• 
The SAP adds Methods for Cardioversion (refer to SAP section 3.2)  
• 
The SAP specifies cohorts of the pre-specified study populations to be analyzed (refer 
to Table 1 in Section 8.0) 
• 
Only 3 subjects were treated with study medication in the PLS study, as a result for 
some endpoints results are only listed and no summarizing statistics will be reported 
• 
No HHE data are available for the PLS study, the endpoints will thus not be reported 
• 
The protocol indicates a 90% confidence interval will be created for endpoints, instead  
(refer to SAP sections 9.2) for a selection of endpoints a 95% confidence intervals will 
be created; only for the primary efficacy endpoint (refer to SAP section 9.2.1) a 90% 
confidence interval will be created.  
• 
The protocol indicated tmax  is measured as the time to Cmax (from the time of end 
of dosing), in the SAP definition  t-max  is measured as the time to Cmax (from the time 
of the start of dosing).  
• 
Adverse Events of Special Interest (AESI) and Serious Adverse Events of Special 
Interest (SAESI) will be tabulated using results as indicted in SAP section Annex A, 
using a slightly different definition than the definition in protocol V8.0/EU-1.  
 
 
 


 
 
 
 
 
 
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11 Changes in the Planned Analyses 
 
Additional analyses that may be included in the Clinical Study Report but are not mentioned in the 
SAP will be identified as such. 
12 Programming Conventions 
 
• 
Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized.   
• 
Group headers: In summary tables group headers will identify the summary group and the 
sample size for the indicated analysis population. The header’s sample size does not 
necessarily equal the number of subjects actually summarized within any given summary 
module; some subjects in the analysis population may have missing values and thus may 
not be summarized. 
• 
Presentation of sample sizes: All TFLs should indicate, in one way or another, the number of 
subjects actually contributing to the summary statistics presented in any given summary 
module.  As mentioned above, this may be less than the number of subjects in the analysis 
population due to missing data. 
− 
In the quantitative modules describing continuous variables (and thus presenting 
sample size, means, and standard deviations), the sample size should be the number of 
non-missing observations. The number of missing observations, if any, should be 
identifiable in the module 
− 
For categorical variables that are presented in frequency tables, the module should 
present the total count in addition to the count in each category.  Percentages should 
be calculated using this total as the denominator, and the percentage corresponding to 
the sum itself (that is, 100%) should be presented so as to indicate clearly to a reviewer 
the method of calculation.  The number of missing observations, if any, will be noted. 
• 
Sorting: Listings will be sorted by subject identifier and (where applicable) then by date 
within each subject identifier.  If a listing is sorted in a different manner, a footnote will 
indicate as such.   
• 
General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures.  No intermediate rounding 
will be performed on derived variables.  The standard rounding practice of rounding 
numbers ending in 0-4 down and numbers ending in 5-9 up will be employed.   
• 
The presentation of numerical values will adhere to the following guidelines:  
− 
Raw measurements will be reported to the number of significant digits as captured in 
the source data  
− 
Mean, standard deviation, median, Q1 and Q3 will all be shown using 1 additional 
decimal compared to the source data, with a maximum of two decimals. Minimum and 
maximum will be shown using the number of decimals in the source data. 


 
 
 
 
 
 
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− 
Calculated percentages will be reported to one decimal place. 
• 
Dates will be formatted as DDMMMYYYY.  Partial dates will be presented on data listings as 
recorded in the EDC. 
• 
Time will be presented according to the 24-hour clock (HH:MM or HH:MM:SS as applicable). 
13 References 
 
This version of the SAP only uses references to the study protocol indicated at page 2 of SAP. 
 
14 Tables, Figures and Listings 
 
The Tables, Figures and Listings and Flowchart that are included in the final statistical analysis will be 
created using the analysis described in this SAP. The final report will include an overview of all TFLs 
that are included in the report. 
Each table will reference an associated listing containing data used by the table. If applicable, the 
figures will reference an associated listing and/or an associated table used by the figure. 
 
For the MLS part of the trial all data for subjects that received FlecIH-103 120 mg dose from Parts A, 
B and C will be included in the listings.  If subject also participated in the PLS trial, the results of the 
PLS trial are not included in the MLS part of the final report. 
 
For the PLS part of the trial, the tables and listings will only report on study results for this PLS part 
of the trial, not for the study results of the initial MLS treatment of subject in Part A, B or Part C MLS.  
However, for the PLS subjects the MLS study results can be found in these listings: 
• 
If the MLS treatment took place in Part B or Part C MLS: results are listed in the final MLS 
report under the same subject identifier as in the PLS report  
• 
If MLS treatment took place in Part A and in Part A subject received 2*60 mg FlecIH-103 (and 
is thus included in the pooled MLS analysis): results are listed in the final MLS report. Subject 
however received a new subject identifier in Part C PLS, the PLS report will include 
information showing the subject identifier in the PLS report and the corresponding subject 
identifier in the final MLS report  
• 
If MLS treatment took place in Part A and in Part A subject received a different regimen than 
2*60 mg FlecIH-103 (and is thus not included in the pooled MLS analysis): results were listed 
in the final report for Part A of the trial (as created July 24, 2020). Subject however received 
a new subject identifier in Part C PLS, the PLS report will include information showing the 
subject identifier in the Part C PLS report and the corresponding identifier in the final Part A 
report.  


 
 
 
 
 
 
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Refer to section 8.0 of the SAP for a description on the specific cohorts for which Part C MLS results 
and MLS pooled results will be reported.  
 
 


 
 
 
 
 
 
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15 Programming Specifications 
 
If required, a separate document will provide details necessary to replicate the various data 
derivations outlined in the SAP. 
 
 
 


 
 
 
 
 
 
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Annex A: FLE-002 Sponsor Review of Adverse Events of Special Interest 
 
1. Background and Justification 
1.1 FLE-002 (INSTANT) is the first InCarda Phase 2 clinical study to assess the 
efficacy and safety of flecainide acetate inhalation solution (FlecIH-103), 
administered via oral inhalation in patients with recent onset, symptomatic 
atrial fibrillation (AF). The study is composed of 3 parts which was refined over 
time through successive protocol amendments (Parts A, B, and C). Part A 
examined different formulations of inhalation solutions and dosages, leading to 
the selection of the 120 mg estimated total lung dose (eTLD) of FlecIH-103 
formulation administered as two 3.5-minute inhalations separated by a 1-
minute break (8 minutes total administration time). This treatment regimen 
was further evaluated in Parts B and C of FLE-002 and was selected for 
evaluation in Phase 3.   
1.2 One of the main objectives of the study, and the focus of the final analysis, is to 
assess the safety of 120 mg FlecIH-103 inhalation for acute cardioversion of AF. 
To address this objective, Adverse Events (AEs) were collected by the sites and 
entered in the Case Report Form (CRF), implemented in an Electronic Data 
Capture (EDC) system. The AEs were initially also entered in the CRO's Safety 
Database by the safety team as the MedDRA and WHODrug coding feature in 
the EDC system (Marvin) was not enabled (in Part A). 
1.3 Several AEs of special interest (AESIs) were defined for FLE-002, which were 
progressively refined in subsequent protocol amendments. In February 2021, 
InCarda amended the FLE-002 protocol (v8.0 EU-1; 16 Feb 2021) with the final 
pre-defined AESI list and associated criteria, which included: 1) AEs related to 
the inhalation device; 2) Pregnancy, and; 3) AEs known to be related to other 
well characterized flecainide formulations (i.e., IV and oral).  Criteria for these 
AESIs and serious AESIs are further defined in Section 5.   
1.4 Because the definition of AESIs changed over time, and the process to collect 
them varied between the different parts of the study, InCarda will centrally 
review all AEs and provide a consistent assessment of AESIs per the criteria 
described in Section 4 below. 
2. Purpose 
2.1 This document outlines the steps required to review all AEs reported in patients 
who received 120 mg FlecIH-103 in Parts A, B and C of the FLE-002 study to 
determine if they meet the final AESI criteria as defined in the protocol. 
2.2 This review will generate data that is to be used in the final analysis of the 
study, as described in the FLE-002 Statistical Analysis Plan (SAP). 
 


 
 
 
 
 
 
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3. Responsibilities   
3.1 InCarda Data Management will provide the listing of all AEs, organize data 
entry, and prepare a memorandum that will record the process execution as 
per section 5. 
3.2 InCarda Clinical Development will provide resources to review AEs, enter and 
verify the new assessments. 
3.3 InCarda Clinical Operations will archive all relevant documentation in the study 
Trial Master File (TMF). 
4. Definitions 
4.1 Adverse Event (AE): Any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. 
4.2 AE of Special Interest (AESI): Any AE related to the inhalation device, any 
pregnancy that started while participating to the study, and AEs known to be 
related to other formulations of flecainide (i.e., IV and oral). 
4.3 Non-Cardiovascular Adverse Event of Special Interest (Non-CV AESI):  A subset 
of AEs coded in MedDRA within a System Organ Class (SOC) other than “Cardiac 
disorders” or “Vascular disorders, which includes AEs related to the inhalation 
device and any pregnancy that started while participating to the study as 
defined below: 
• 
Pregnancy: Any female study subject or female partner of a study subject 
that becomes pregnant while participating in this study  
• 
AE related to the inhalation device (nebulizer): AE considered directly 
related to the nebulizer  
4.4 Serious Non-Cardiovascular Adverse Event of Special Interest: Non-CV AESI is 
considered serious if it meets the following criteria.   
• 
Pregnancy: Any female study subject or female partner of a study subject 
that becomes pregnant while participating in this study 
• 
AE related to the inhalation device: AE considered directly related to the 
nebulizer by the Investigator that meets the definition for a SAE  
4.5 Cardiovascular Adverse Event of Special Interest (CV AESI): A subset of AEs 
coded in MedDRA within a System Organ Class (SOC) of “Cardiac disorders” or 
“Vascular disorders, which include AEs known to be related to flecainide as 
defined below. 


 
 
 
 
 
 
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• 
Hypotension: an acute hypotensive episode (AHE) is a sudden drop in BP 
resulting in a BP < 90/60 mmHg (MAP < 70 mmHg) that lasts for at least 5 
minutes and is based on multiple sequential readings (≥ 3). MAP is 
calculated as 1/3 (SBP – DBP) + DBP  
• 
Ventricular Tachycardia (VT): Ventricular tachycardia (i.e., an ECG-derived 
rate >100 bpm) > 3 beats (excludes triplets)  
• 
Bradycardia: an ECG-derived rate < 50 bpm for ≥ 1 minute  
• 
Sinus pause post conversion of AF to SR: an ECG-derived pause > 3 seconds  
• 
Atrial flutter with 1:1 conduction with fast ventricular response: Atrial flutter 
with a ventricular heart rate ≥ 200 bpm  
4.6 Serious Cardiovascular Adverse Event of Special Interest: A CV AESI is 
considered serious as defined below. 
• 
Hypotension per AESI definition in Section 4.5 with symptoms/signs of 
clinical instability (i.e., severe chest pain/dyspnea or altered mental status) 
and requiring a vasopressor or inotropic agent  
• 
Ventricular tachycardia per AESI definition in Section 4.5 that is sustained (> 
30 seconds or requiring intervention before that time) VT, TdP, or VF  
• 
Bradycardia per AESI definition in Section 4.5 with symptoms/signs of 
clinical instability (i.e., severe chest pain/dyspnea, altered mental status or 
hypotension) and requiring pacing or a chronotropic agent  
• 
Sinus pauses post conversion of AF to SR per AESI definition in Section 4.5, 
causing syncope or requiring pacing or CPR  
• 
Atrial flutter with 1:1 conduction with fast ventricular response per AESI 
definition in Section 4.5, and requiring intervention (DC cardioversion) for 
termination or an IV AV nodal blocking agent (β-blocker or Ca2+-channel 
blocker) to slow the ventricular rate  
Any arrhythmia with symptoms/signs of clinical instability (i.e., severe chest 
pain/dyspnea, altered mental status or hypotension), and requiring DC 
cardioversion, defibrillation, pacing, or a vasopressor, inotropic or chronotropic 
agent. Serious AESIs in this category will also be included in the broader 
category of CV AESI described in Section 4.5. 
 
 
 
 


 
 
 
 
 
 
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4.7 Decision Tree 
 
 
 
5. Procedure 
5.1 Listing Preparation 
5.1.1 Data Management will generate a MedDRA coded AE listing, including 
Preferred Term (PT) and System Organ Class (SOC)and will ensure consistency 
with the database and previous study reports. 
5.1.2 The listing will include all information in the safety database and the EDC for 
Part A for patients receiving 120 mg FlecIH-103 and safety data and all 
associated details from the EDC for Parts B and C. 
5.1.3 The Listing will include the necessary columns for entering the review result 
and ensure traceability (see section 6.2.2). 
5.1.4 Data Management will place the listing in a secure area and will grant access 
to designated Reviewers. 
5.1.5 All versions of the listings will be easily accessible for review.  
 
5.2 Listing Review 
5.2.1 The designated person responsible for the review (Reviewer) is provided 
with AESI definitions from section 4 of the present document. 


 
 
 
 
 
 
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5.2.2 Each AE will be reviewed, and documented as follows: 
- 
AE type (select only one option) 
• 
Non-AESI (standard AE) 
• 
Non-CV Non-Serious AESI 
• 
Serious Non-CV AESI 
• 
CV Non-Serious AESI 
• 
Serious CV AESI 
- 
Initials 
- 
Date 
- 
Comment 
 
5.2.3 The Reviewer initials and dates next to each recoded item and provides 
comments as necessary. 
5.2.4 The Reviewer also signs a memorandum to record execution. 
5.3 Listing Verification 
5.3.1 A separate designated Clinical Development member will review all 
assessments and ensure completion and consistency. 
5.3.2 Any issue(s) will be reported to the Reviewers for discussion, adjudication 
and possibly update. The comment field can be updated with initials and date. 
5.3.3 The person in charge of the verification also signs the execution 
memorandum at completion of the process. 
5.4 Archiving  
5.4.1 Annotated listing sand the execution memorandum will be archived upon 
completion in the study TMF by the Clinical Operations team. 
 
 
 

Prot_000.pdf: 
INSTANT Study 
Clinical Study Protocol 
Study no. FLE-002 
Date 
16Feb2021 
Version 
8.0 EU-1 
Page: 1 of 117 
 
 
 
 
I. 
Clinical study title page 
A prospective, randomized, multicenter study of flecainide acetate 
oral inhalation solution in single and repeat dose regimens for 
acute conversion to sinus rhythm (SR) in subjects with recent onset 
of symptomatic paroxysmal atrial fibrillation (AF). 
Short title: 
INhalation of flecainide to convert recent onset SympTomatic Atrial 
fibrillation to siNus rhyThm. (INSTANT) 
Test drug(s): 
FlecIH-101, FlecIH-102, and FlecIH-103 (flecainide acetate inhalation 
solution) 
(INN - Flecainide Acetate) 
Study no.: 
FLE-002 
IND no.: 
147305 
 
 
EudraCT no.: 
2018-000094-76 
 
 
Version no.: 
8.0 EU-1 
Date: 
16 FEB 2021 
Previous version 
no.(s): 
7.0 / EU-2 
7.0 / US-1 
7.0 / EU-1 
6.0*  
5.0 / EU-2 
5.0 / EU-1 
5.0 
4.0 
3.0 
2.0 
1.0 
 
Date(s): 
03 NOV 2020 
14 AUG 2020 
28 JUL 2020 
06 MAR 2020 (*not implemented) 
01 NOV 2019 
13 AUG 2019 
15 JUL 2019 
02 MAY 2019 
12 DEC 2018 
10 OCT 2018 
21 FEB 2018 
 
Sponsor: 
InCarda Therapeutics, Inc. 
39899 Balentine Drive, Suite 185 
Newark, CA, USA 
Sponsor’s medical 
expert: 
Luiz Belardinelli, MD 
Chief Medical Officer 
39899 Balentine Drive, Suite 185 
Newark, CA 94560, USA 
Tel: +1 (650) 704-2805 
Confidential - The information provided in this document is strictly confidential and is intended solely for the guidance of the clinical 
investigation.  Reproduction or disclosure of this document - whether in part or in full - to parties not associated with the clinical 
investigation, or its use for any other purpose, without the prior written consent of the Sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  Hence, the appearance of product names 
without these symbols does not imply that these names are not protected. 
 
 




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III. 
Signature Page Principal Investigator 
 
Study title: 
A prospective, randomized, multicenter study of 
flecainide acetate oral inhalation solution in 
single and repeat dose regimens for acute 
conversion to sinus rhythm (SR) in subjects with 
recent onset of symptomatic paroxysmal atrial 
fibrillation (AF). 
Short title:   
INhalation of flecainide to convert recent onset SympTomatic 
Atrial fibrillation to siNus rhyThm. (INSTANT) 
Study no.: 
FLE-002 
Version:   
8.0 EU-1 (16 FEB 2021) 
 
I have read this protocol and/or amendment and appendices and agree to adhere to the 
requirements. I will provide copies of this protocol and all pertinent information to the study 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed regarding the investigational product and the conduct of the study. 
 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with the Declaration of Helsinki, International Conference on Harmonization 
guidelines on Good Clinical Practice (ICH E6), and applicable regional regulatory requirements. 
 
 
 
Name: 
 
 Role: 
 
Date: 
 
 Signature: 
 


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IV. 
Protocol Synopsis 
Study Title 
A prospective, randomized, multicenter study of flecainide 
acetate oral inhalation solution in single and repeat dose 
regimens for acute conversion to sinus rhythm (SR) in subjects 
with recent onset of symptomatic paroxysmal atrial fibrillation 
(AF). 
 
Note: Part A included a randomized phase; Part B and Part C are 
not randomized. 
 
Short Title 
INhalation of flecainide to convert recent onset SympTomatic 
Atrial fibrillation to siNus rhyThm. (INSTANT) 
 
Study Phase 
Phase 2 
 
Study Objective(s) 
To evaluate the safety, tolerability and efficacy of single and 
repeat doses of flecainide acetate oral inhalation solution in 
subjects with paroxysmal AF. 
 
PART A Objective(s) 
Part A was completed on 05Mar2020. The objective in Part A 
was 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.  
 
Other objectives were exploratory in nature. 
 
PART B Objective(s) 
Efficacy objective(s): 
To evaluate the conversion of AF to SR and symptom relief by 
flecainide acetate inhalation solution in subjects with recent 
onset of paroxysmal AF. 
 
 
Safety objective(s): 
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. 


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• To evaluate the electrocardiographic effects (PD) of 
flecainide acetate inhalation solution in subjects with 
recent onset of paroxysmal AF.  
 
Exploratory objective: 
To explore the feasibility of implementing a portable cardiac 
ultrasound (handheld echocardiogram [HHE]) at screening in an 
emergent setting  
 
PART C Objective(s) 
 
All Part C objectives are exploratory: 
• 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 
 
Study Design 
Subjects eligible to participate in the study must provide written 
informed consent (IC) before enrollment or undergoing any 
study-specific procedures. 
 
The study consists of 3 parts (Part A, Part B, and Part C) as 
described below. The optimal dose identified in Part A will be 
used for Part B and Part C. 
 
PART A was an open-label, multicenter design and studied the 
feasibility of administration of inhaled flecainide in four dosing 
regimens (30, 60, 90, and 120 mg). Part A was closed to 
enrollment on 05Mar2020, after a total of 101 subjects were 
treated with the study drug (10 with 30 mg, 22 with 60 mg, 21 
with 90 mg, and 48 with 120 mg). The final dose in Part A (120 
mg FlecIH-103) was selected as the dose to continue evaluating 
in Part B. 
 
PART B is an open-label, multicenter design to confirm the 
safety (including tolerability) and to provide a more precise 
estimate of efficacy of the optimal inhaled flecainide dose 


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determined from Part A (120 mg, using the FlecIH-103 
inhalation solution). Subjects are enrolled to receive a repeat 
dose regimen of 120 mg eTLD (2 x 60 mg); N = approximately 25 
subjects.  
 
PART C consists of two distinct studies: 1) a Medically-Led 
Cardioversion Study (study procedures are identical to those in 
Part B), and 2) a Patient-Led Under Medical Supervision 
Cardioversion Study (study procedures include the subject self-
preparing and self-administering the study drug under medical 
supervision in the clinic). Part C is only conducted in Europe 
(EU). 
 
Subjects with recent-onset AF who have not been previously 
treated with flecainide acetate inhalation solution will first be 
enrolled into the Medically-Led Cardioversion Study to 
determine eligibility for the Patient-Led Under Medical 
Supervision Cardioversion Study. 
 
Subjects that complete Part A, Part B, or the Part C Medically-
Led Cardioversion Study may be eligible to enroll in the Part C 
Patient-Led Under Medical Supervision Cardioversion Study if 
their AF safely converted to SR due to study drug and they did 
not experience any difficulties or issues with inhalation (in the 
opinion of the investigator), serious AEs, or serious AESIs.  
 
The Patient-Led Under Medical Supervision Cardioversion Study 
will require all subjects to return to the clinic for training and 
pass an assessment on their ability to self-administer the study 
drug. Subjects will then return to the clinic within 48 hours of 
the onset of a recurrent episode of paroxysmal AF to self-
administer the study drug.  
 
Part B and Part C: 
Part B and the Part C Medically-Led Cardioversion Study also 
have an optional Handheld Echo (HHE) Sub-Study (only at select 
EU sites), where subjects who specifically consent will undergo 
an additional screening procedure using a portable hand-held 
ultrasound device to obtain an echocardiogram. Additional 
details on the HHE Sub-Study can be found in Appendix 6. 
 


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All Parts: 
Study procedures are performed as described in the Schedule of 
Assessments (Section 17.4). If by 90 minutes post dose, no 
conversion to SR is observed, the Investigator may offer the 
subject another appropriate therapy, as per institutional 
standard (with exceptions; refer to Section 5.4.2 B). Discharge 
of the subject is at the discretion of the treating physician but 
may not be scheduled prior to 90 minutes after initiation of 
dosing. 
 
An independent Data and Safety Monitoring Board (DSMB) is 
responsible for monitoring safety during the study. The Sponsor 
may discontinue a treatment dose cohort due to 
safety/tolerability concerns, change in the benefit/risk to the 
subject. 
 
Enrollment occurs on Day 1 and the start of the first inhalation 
is considered time zero (T0). 
 
Dosing regimen(s) 
Part A: 
Four dosing regimens were evaluated in Part A: 30 mg eTLD, 60 
mg eTLD, 90 mg eTLD, and 120 mg eTLD. 
 
Part B and Part C: 
One 'dose/inhale to conversion' regimen will be tested using 
FlecIH-103 inhalation solution: 
- 
120 mg eTLD (2 x 60 mg) repeat dose regimen (75 
mg/mL): a first 60 mg inhalation is administered using an 
AeroEclipse® II BAN. The second 60 mg inhalation is 
administered using the identical AeroEclipse® II BAN.  
 
Dosing in a 'dose/inhale to conversion' regimen shall continue 
according to the assigned regimen until the conversion of AF to 
SR is observed for ≥ 1 minute, or until the assigned dose is 
completed, whichever comes first. 
 
Study duration 
The study duration for Part A, Part B, and the Medically-Led 
Cardioversion Study of Part C lasts for a total of 5 days. In Part 
B, subjects are monitored for up to approximately 2 hours and 
23 minutes (for 45 minutes before dosing, up to 8 minutes 
during dosing, and for 90 minutes after dosing) on Day 1. 


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Subjects receive two outpatient telephone contacts, one on Day 
2 and one on Day 5. The telephone contact on Day 5 is the final 
study contact and marks the end-of-study (EOS) for each 
subject, unless they consent to participate in the Part C Patient-
Led Under Medical Supervision Cardioversion Study.  
 
The duration of the Part C Patient-Led Under Medical 
Supervision Cardioversion Study will continue through the Day 5 
telephone contact after a recurrent episode of AF is treated, or 
approximately 8 months after consent, whichever comes first.  
 
Indication 
Flecainide acetate inhalation solution is indicated for rapid 
cardioversion of recent onset atrial fibrillation (AF) in patients 
with symptomatic paroxysmal AF when the need for treatment 
has been established. Flecainide acetate inhalation solution 
shall only be used in the absence of any contraindication to 
flecainide. 
 
Investigational drug(s) 
FlecIH-101, FlecIH-102, and FlecIH-103 (flecainide acetate 
inhalation solution) 
 
Name of active ingredient 
 
Flecainide Acetate 
Dose(s) 
Part A: 
Four doses were evaluated in Part A: 30 mg eTLD, 60 mg eTLD, 
90 mg eTLD, and 120 mg eTLD. Each dose was administered 
using the hand-held inhaler device AeroEclipse® II BAN. 
 
Part B and Part C: 
FlecIH-103 (75 mg/mL): 
- 
120 mg (repeat dose regimen): 2 consecutive inhalations 
of 60 mg eTLD 
 
Each dose is administered using the hand-held inhaler device 
AeroEclipse® II BAN. 
 
Route of administration 
Oral inhalation 
 
Reference drug(s) 
Not applicable 
 
Part A Eligibility Criteria 
Refer to a previous version of the Protocol. 


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Part B and Part C Eligibility 
Criteria 
Subjects to be included in the study must meet the following 
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. 
 
 
 
 
 


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Subjects are NOT eligible to participate in this study if they meet 
ANY of the following exclusion criteria: 
General 
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. For 
subjects to meet eligibility criteria for Part B or the Part 
C Medically-Led Cardioversion Study C, at least 2 of the 3 
measurements of vital signs during screening (45, 30, 
and/or 15 minutes prior to dosing) must meet the stated 
criteria. For subjects to meet eligibility criteria for the 
Part C Patient-Led Under Medical Supervision 
Cardioversion Study, the measurement of vital signs 
taken within 10 minutes prior to dosing must meet the 
stated 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 (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. 
Relevant structural heart disease 
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% 
i) For subjects in the US, a standard diagnostic 
echocardiogram assessed ≤ 180 days prior to 
screening is required to ascertain eligibility. If 
none is available, the subject must undergo a 
standard diagnostic echocardiogram or a 
diagnostic echocardiogram using a portable 
ultrasound device (handheld echocardiogram 
[HHE]) during screening to confirm eligibility. 


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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 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.  
7) History of myocardial infarction (MI) within 3 months of 
screening 
8) Known uncorrected severe aortic or mitral valve 
stenosis. For subjects receiving an HHE assessment at 
screening (refer to exclusion criterion 5), any moderate 
or severe valvular disease noted during the HHE 
assessment is considered exclusionary. 
9) Hypertrophic cardiomyopathy with outflow tract 
obstruction. For subjects receiving an HHE assessment at 
screening (refer to exclusion criterion 5), any moderate 
or severe hypertrophy noted during the HHE assessment 
is considered exclusionary. 
Other cardiac conditions 
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) 


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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 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 
Concomitant conditions 
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. 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 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 


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asthma is well controlled with steroids and/or as-needed 
administration of a bronchodilator are eligible for the 
study. 
Concomitant and study 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, 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 
Other 
22) Subject is deemed unsuitable for the trial by the 
Investigator (including but not limited to: patients who 
are considered at high risk for stroke based on 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 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. 
23) Known drug or alcohol dependence within the past 12 
months as judged by the Investigator 
24) A body mass index > 40 kg/m2 
25) Legally incompetent to provide informed consent (IC) 
26) Previous treatment in this study (this does not apply to 
enrollment in the Part C Patient-Led Under Medical 
Supervision Cardioversion Study) or previous treatment 
with any other investigational drug within 30 days from 
screening or 5 half-lives of the drug, whichever is longer 


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27) Female of childbearing potential 
a) Who are not surgically sterile, or post-menopausal 
(defined as no menses for 2 years without an 
alternative cause), or 
b) For whom a negative pregnancy test is unavailable 
before study entry, or 
c) Who are pregnant or breast feeding at study entry 
28) 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) 
29) 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  
30) Respiratory rate of > 22 breaths per minute 
 
Study endpoint(s) 
PART A 
Feasibility was 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 
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 
 
Conversion of AF to SR and safety/tolerability were compared in 
an exploratory manner.  
 
Study endpoint(s) 
PART 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. For the definition of the 
endpoint conversion to SR refer to Section 10.2.1.1 B. 
 
Secondary efficacy endpoints include: 
- 
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 


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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. 
 
The secondary safety endpoint is the incidence of treatment 
emergent serious adverse events of interest for flecainide. 
 
Exploratory endpoints (HHE):  
- 
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 
 
The HHE data will be submitted to an independent reviewer to 
compare with the HHE assessments made by the site staff 
during the screening period; however, this independent review 
will not be used for the assessment of subject eligibility during 
screening. This independent review will only be used to explore 
if site staff made a successful assessment of subject eligibility 
using the HHE data obtained during screening. 
 


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Study Endpoint(s)  
Part C 
 
All endpoints in Part C are exploratory: 
- 
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 
 
Study centers 
Part A: 14 clinical sites in Europe  
Part B and Part C: approximately 20 clinical sites in Europe and 
North America 
 
Planned sample size 
Approximately 126 subjects with recent onset of symptomatic 
paroxysmal AF are planned to be enrolled in the study. This 
includes the 101 subjects treated in Part A (N = 10 evaluable 
subjects for 30 mg dose cohort; N = 22 evaluable subjects for 60 
mg dose cohort; N = 21 subjects for 90 mg dose cohort; N = 48 
subjects for 120 mg dose cohort) and the approximately 25 
subjects planned for Part B. In Part B, subjects who enroll but 
are not treated with study drug will not count towards the 
planned sample size.  Part C (EU only) does not have an 
enrollment target. However, enrollment will continue in the 
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the Sponsor to support rollover participation in the Part C 
Patient-Led Under Medical Supervision Cardioversion Study 
(refer to description above).   
 
All subjects enrolled and treated with study drug will be 
analyzed within the safety population.  For the modified 
intention-to-treat population (mITT), for any subject who was 
not in AF at the time of dosing and who does not complete 
inhalation of the full assigned dose will be replaced to keep the 
sample size needed.   
 
In Part B, the estimated sample size of 25 subjects for the 120 
mg dose cohort is based upon the evaluation of the following 
statistical hypotheses using an exact binomial test, 
 
     H0:  = 20%     versus     HA:  > 20%     ( = 0.05). 
 
Given the actual conversion rate for the Part A 120 mg dose 
cohort (FlecIH-103 inhalation solution) is 48%, a sample size of 
25 subjects has at least 92% power to reject the null hypothesis 
(H0) in favor of the alternative (HA) with a one-sided significance 
level of 0.05. The null hypothesis is rejected when at least 9 
subjects' AF converts to SR within 90 minutes after initiation of 
dosing.  
 
For example, with 25 subjects enrolled in Part B, if 9 of them 
have their AF converted to SR, the resulting conversion rate is 
36% with a 90% exact binomial confidence interval of [20.24%, 
54.39%]. If 9 or more subjects’ AF converts to SR, the lower 
bound of the 90% exact binomial confidence interval will be 
greater than 20.24%. When the lower bound of the 90% 
confidence interval for conversion rate is greater than 20%, 
there is sufficient support for the rejection of the null 
hypothesis in favor of the alternative.  
 
It is expected approximately 20 subjects will participate in the 
HHE Sub-Study in Europe (Part B and the Part C Medically-Led 
Cardioversion Study); however, the HHE Sub-Study does not 
have a minimum or maximum enrollment target. 
 
 


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Statistical analyses 
PART A: 
The main feasibility, efficacy and safety parameters were 
presented in a descriptive manner. Data on PK, PD and other 
assessments were presented in a similar manner.  
 
PART B: 
All (primary and secondary) efficacy endpoints are analyzed with 
the modified Intention-to-treat (mITT) population. The mITT 
population is defined as all enrolled subjects who were in AF at the 
time of dosing and completed the full assigned dose of study drug.  
 
The primary endpoint analyses of Part B will be based on Part B 
subjects alone. If the Part B primary endpoint analysis meets the 
pre-specified criteria for significance and is not substantially 
different from Part A 120 mg FlecIH-103, the two dose cohorts 
(120mg FlecIH-103 cohorts from Part A and Part B) will be 
combined for the overall analysis of Part B to provide a more 
precise estimate of efficacy, safety, and PK/PD.  
 
The primary efficacy analyses will compute the proportion of 
subjects whose AF converted to SR within 90 minutes after 
initiation of dosing. For Part B, the primary analysis will be based 
upon one-sided testing (i.e.,  > 20%) via an exact binomial test. 
One-sided testing is being undertaken based on the results from 
Part A with the same dose showing a conversion rate of 48%. A 
one-sided binomial exact test will be used to determine whether 
the null hypothesis of equality may be rejected in favor of a 
conversion rate of greater than a historical placebo rate of 
approximately 20%, a value higher than reported for placebo in 
the literature (16%)3 and in the more recent randomized, placebo-
controlled trials with vernakalant (approximately 5%)4.  
 
PART C: 
No formal hypothesis testing is planned for Part C. Summary 
statistics will be generated, including estimates of the endpoints 
with their associated 90% confidence intervals. 
 
All statistical analyses performed in the evaluation of the INSTANT 
Study data are described in the statistical analysis plan (SAP). 
 
 
 


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V. 
Table of contents 
I. 
CLINICAL STUDY TITLE PAGE ................................................................................................................ 1 
II. 
PROTOCOL APPROVAL PAGE ............................................................................................................... 2 
III. 
SIGNATURE PAGE PRINCIPAL INVESTIGATOR ....................................................................................... 3 
IV. PROTOCOL SYNOPSIS .......................................................................................................................... 4 
V. 
TABLE OF CONTENTS ......................................................................................................................... 19 
VI. LIST OF TABLES ................................................................................................................................. 24 
VII. LIST OF IN-TEXT FIGURES ................................................................................................................... 24 
VIII. LIST OF ABBREVIATIONS .................................................................................................................... 25 
IX. 
INTRODUCTION ................................................................................................................................ 26 
1 
INTRODUCTION ................................................................................................................................ 26 
1.1 FLECAINIDE ACETATE ........................................................................................................................ 27 
1.2 FLECAINIDE ACETATE INHALATION SOLUTION (FLECIH) ....................................................................... 29 
1.2.1 
Non-clinical studies ............................................................................................................................................... 29 
1.2.2 
Clinical experience ................................................................................................................................................ 31 
1.3 RATIONALE FOR THE STUDY .............................................................................................................. 34 
1.4 RATIONALE FOR DOSE SELECTION ...................................................................................................... 35 
1.5 BENEFIT/RISK ASSESSMENT ............................................................................................................... 36 
X. 
STUDY PROTOCOL (PART A) ............................................................................................................... 39 
XI. 
STUDY PROTOCOL (PART B) ............................................................................................................... 40 
2 
B - STUDY OBJECTIVES ....................................................................................................................... 40 
2.1 B – EFFICACY OBJECTIVE(S) ................................................................................................................ 40 
2.2 B - SAFETY OBJECTIVE(S).................................................................................................................... 40 
2.3 B – PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) OBJECTIVE(S) ........................................ 40 
2.4 B - EXPLORATORY OBJECTIVE: ........................................................................................................... 40 
3 
B - STUDY DESIGN ............................................................................................................................. 40 
4 
B - STUDY POPULATION..................................................................................................................... 42 
4.1 B - INCLUSION CRITERIA .................................................................................................................... 43 
4.2 B - EXCLUSION CRITERIA .................................................................................................................... 43 
4.3 B - SCREEN FAILURES ......................................................................................................................... 46 
5 
B – TREATMENT ................................................................................................................................ 47 
5.1 B - STUDY TREATMENTS .................................................................................................................... 47 
5.1.1 
B - Repeat dose regimen ...................................................................................................................................... 47 


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5.2 B - TREATMENT ASSIGNMENT ........................................................................................................... 47 
5.3 B - IDENTITY OF STUDY DRUG(S) ........................................................................................................ 47 
5.3.1 
B – Description ...................................................................................................................................................... 47 
5.3.2 
B - Labeling and packaging ................................................................................................................................... 48 
5.3.3 
B – Preparation ..................................................................................................................................................... 48 
5.3.4 
B – Administration ................................................................................................................................................ 48 
5.3.5 
B – Shipment, receipt and storage ....................................................................................................................... 50 
5.3.6 
B - Drug accountability ......................................................................................................................................... 50 
5.4 B – NON-STUDY THERAPY.................................................................................................................. 51 
5.4.1 
B - Prior and concomitant medication.................................................................................................................. 51 
5.4.2 
B - Post-dose regimen therapy and medication ................................................................................................... 52 
5.4.3 
B – Other recommendations ................................................................................................................................ 52 
5.5 B – DISCONTINUATION CRITERIA ....................................................................................................... 52 
6 
B - STUDY PROCEDURES .................................................................................................................... 53 
6.1 B – SCREENING PERIOD ..................................................................................................................... 54 
6.1.1 
B - Screening ......................................................................................................................................................... 54 
6.1.2 
B - Informed consent (IC) ...................................................................................................................................... 54 
6.1.2.1 
B - Pre-study screening IC (for select subjects) .................................................................................................... 54 
6.1.2.2 
B - Study IC (for all symptomatic subjects presenting with paroxysmal AF) ........................................................ 55 
6.1.2.3 
B - Handheld Echo Sub-Study IC ........................................................................................................................... 56 
6.1.2.4 
B – Optional Part C Patient-Led Under Medical Supervision Cardioversion Study IC .......................................... 56 
6.1.3 
B - AF-monitoring.................................................................................................................................................. 56 
6.1.4 
B – Allocation ........................................................................................................................................................ 57 
6.2 B – TREATMENT PERIOD .................................................................................................................... 58 
6.2.1 
B - Study treatment .............................................................................................................................................. 58 
6.2.1.1 
B - Subjects without conversion of AF to SR......................................................................................................... 59 
6.3 B – EXTENDED OBSERVATION PERIOD................................................................................................ 59 
6.3.1 
B - Discharge ......................................................................................................................................................... 60 
6.4 B - FOLLOW-UP PERIOD ..................................................................................................................... 60 
6.4.1 
B – Telephone assessment (Visit 1): Day 2 ........................................................................................................... 60 
6.4.2 
B – Telephone assessment (Visit 2): Day 5 ± 1 day .............................................................................................. 61 
6.4.3 
B – End-of-study (EOS) definition ......................................................................................................................... 61 
7 
B - EFFICACY ASSESSMENTS AND ENDPOINTS ..................................................................................... 61 
7.1 B – RHYTHM MONITORING ASSESSMENTS ......................................................................................... 61 
7.2 B – RHYTHM STATUS ASSESSMENTS .................................................................................................. 61 
7.3 B - AF-RELATED SYMPTOMS .............................................................................................................. 62 
7.4 B - TREATMENT SATISFACTION QUESTIONS........................................................................................ 62 
7.5 B - STUDY ENDPOINT(S)..................................................................................................................... 62 
7.5.1 
B - Primary endpoint ............................................................................................................................................. 62 
7.5.2 
B - Secondary endpoints ....................................................................................................................................... 62 
7.5.3 
B - Exploratory endpoints ..................................................................................................................................... 63 


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8 
B - OTHER ASSESSMENTS................................................................................................................... 63 
8.1 B - PHARMACOKINETIC (PK) ASSESSMENT(S) ...................................................................................... 63 
8.2 B - PHARMACODYNAMIC (PD) ASSESSMENT(S) .................................................................................. 64 
9 
B - SAFETY EVALUATION AND REPORTING ......................................................................................... 65 
9.1 B - ADVERSE EVENTS ......................................................................................................................... 65 
9.1.1 
B - Adverse event collection and reporting .......................................................................................................... 66 
9.1.2 
B - Events of special interest ................................................................................................................................ 67 
9.1.2.1 
B – AEs related to inhalation device ..................................................................................................................... 67 
9.1.2.2 
B - Pregnancies ..................................................................................................................................................... 67 
9.1.2.3 
B - AEs known to be related to other flecainide formulations (i.e., IV and oral) ................................................. 67 
9.1.2.4 
B – Serious Adverse Events of Special Interest (SAESI) ........................................................................................ 68 
9.1.3 
B - Notification to Regulatory authorities, Investigators and IRBs ....................................................................... 68 
9.2 B – CLINICAL LOCAL LABORATORY ASSESSMENTS ............................................................................... 68 
9.2.1 
B - Total blood volume.......................................................................................................................................... 70 
9.3 B - VITAL SIGNS ................................................................................................................................. 70 
9.4 B – OTHER ELECTROCARDIOGRAMS ................................................................................................... 70 
9.5 B - PHYSICAL EXAMINATION .............................................................................................................. 70 
9.6 B - HANDHELD ECHOCARDIOGRAM (HHE) .......................................................................................... 71 
10 
B - STATISTICAL METHODS ................................................................................................................ 71 
10.1 B - STUDY POPULATIONS ................................................................................................................... 71 
10.1.1 
B - Population of consented subjects ................................................................................................................... 71 
10.1.2 
B - Intention-to-treat population (ITT) ................................................................................................................. 72 
10.1.3 
B - Modified ITT population (mITT) ...................................................................................................................... 72 
10.1.4 
B - PK population .................................................................................................................................................. 72 
10.1.5 
B - Safety population ............................................................................................................................................ 72 
10.2 B – STATISTICAL ANALYSES ................................................................................................................ 72 
10.2.1 
B - Efficacy analyses .............................................................................................................................................. 72 
10.2.1.1 B - Statistical analysis of the primary efficacy endpoint ...................................................................................... 73 
10.2.1.2 B - Statistical analysis of proportion of subjects who convert within 90 minutes after initiation of dosing and 
have Cmax values ≥ 200ng/mL (e.g., 200, 300, 400, and 500 ng/mL) .................................................................... 73 
10.2.1.3 B - Statistical analysis of time-to-conversion to SR from initiation of dosing up to 90 minutes after initiation of 
dosing.................................................................................................................................................................... 74 
10.2.1.4 B - The proportion of subjects in SR on Day 2 ...................................................................................................... 74 
10.2.1.5 B - The proportion of subjects with reduced or no AF symptoms at 30 minutes post dose ............................... 74 
10.2.1.6 B - The proportion of subjects with reduced or no AF symptoms at 60 minutes post dose ............................... 74 
10.2.1.7 B - The proportion of subjects with reduced or no AF symptoms at 90 minutes post dose ............................... 75 
10.2.1.8 B - Descriptive statistics of proportion of conversion to SR within 90 minutes after initiation of dosing without 
AF recurrence requiring electrical or pharmacological cardioversion or rate control intervention up to 
discharge ............................................................................................................................................................... 75 
10.2.1.9 B - The proportion of subjects in SR on Day 5 ...................................................................................................... 75 
10.2.2 
B - Safety analyses ................................................................................................................................................ 75 
10.2.2.1 B - Clinical laboratory evaluation analyses ........................................................................................................... 76 
10.2.2.2 B - Vital signs analyses .......................................................................................................................................... 76 
10.2.2.3 B - Physical examination analyses ........................................................................................................................ 76 
10.2.3 
B - Pharmacokinetic / Pharmacodynamic analyses .............................................................................................. 76 


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10.3 B - SAMPLE SIZE DETERMINATION ..................................................................................................... 77 
XII. STUDY PROTOCOL (PART C - EU ONLY): MEDICALLY-LED CARDIOVERSION AND PATIENT-LED UNDER 
MEDICAL SUPERVISION CARDIOVERSION STUDIES .......................................................................................... 78 
2 
C - STUDY OBJECTIVES ....................................................................................................................... 78 
3 
C - STUDY DESIGN ............................................................................................................................. 78 
4 
C - STUDY POPULATION ..................................................................................................................... 80 
4.1 C - INCLUSION CRITERIA .................................................................................................................... 80 
4.2 C - EXCLUSION CRITERIA .................................................................................................................... 80 
4.3 C - SCREEN FAILURES ......................................................................................................................... 80 
5 
C - TREATMENT ................................................................................................................................. 80 
5.1 C - STUDY TREATMENTS .................................................................................................................... 80 
5.2 C - TREATMENT ASSIGNMENT............................................................................................................ 80 
5.3 C - IDENTITY OF STUDY DRUG(S) ........................................................................................................ 81 
5.4 C - NON-STUDY THERAPY .................................................................................................................. 81 
5.5 C - DISCONTINUATION CRITERIA ........................................................................................................ 81 
6 
C - STUDY PROCEDURES .................................................................................................................... 81 
6.1 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: CONSENTING ..................... 82 
6.2 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: TRAINING .......................... 82 
6.3 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: TREATMENT ...................... 83 
6.4 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: FOLLOW-UP ....................... 86 
7 
C - EFFICACY ASSESSMENTS AND ENDPOINTS ..................................................................................... 86 
7.1 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: RHYTHM MONITORING 
ASSESSMENTS ................................................................................................................................................ 86 
7.2 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: AF-RELATED SYMPTOMS .... 86 
7.3 C - STUDY ENDPOINT(S) ..................................................................................................................... 87 
8 
C - OTHER ASSESSMENTS ................................................................................................................... 87 
8.1 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: PK ASSESSMENT(S)............. 88 
8.2 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: PD ASSESSMENT(S) ............ 88 
9 
C - SAFETY EVALUATION AND REPORTING.......................................................................................... 89 
9.1 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: ADVERSE EVENTS ............... 89 
9.2 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: CLINICAL LOCAL LABORATORY 
ASSESSMENTS ................................................................................................................................................ 89 
9.2.1 
C - Patient-Led Under Medical Supervision Cardioversion Study: total blood volume ....................................... 90 
9.3 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: VITAL SIGNS ....................... 90 


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9.4 C - PATIENT-LED UNDER MEDICAL SUPERVISION CARDIOVERSION STUDY: PHYSICAL EXAMINATION .... 90 
10 
C - STATISTICAL METHODS ................................................................................................................. 90 
10.1 C - STUDY POPULATIONS ................................................................................................................... 90 
10.2 C - STATISTICAL ANALYSES ................................................................................................................. 90 
10.3 C - SAMPLE SIZE DETERMINATION ..................................................................................................... 91 
11 
DATA INTEGRITY AND QUALITY ASSURANCE ...................................................................................... 91 
11.1 MONITORING ................................................................................................................................... 91 
11.2 DATA COLLECTION ............................................................................................................................ 92 
11.3 DATA MANAGEMENT ........................................................................................................................ 93 
11.4 STUDY DOCUMENTATION AND STORAGE .......................................................................................... 93 
11.5 ARCHIVING ....................................................................................................................................... 94 
12 
FINANCING AND INSURANCE ............................................................................................................. 94 
12.1 FINANCING ....................................................................................................................................... 94 
12.2 REIMBURSEMENT, INDEMNITY, AND INSURANCE............................................................................... 95 
13 
PUBLICATION POLICY ........................................................................................................................ 95 
14 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION......................................................................... 95 
14.1 COMPLIANCE STATEMENT, ETHICS AND REGULATORY COMPLIANCE .................................................. 95 
14.2 CONFIDENTIALITY ............................................................................................................................. 96 
14.3 INFORMED CONSENT ........................................................................................................................ 96 
14.4 SUPPLY OF NEW INFORMATION AFFECTING STUDY CONDUCT ............................................................ 96 
14.5 REGULATORY COMPLIANCE ............................................................................................................... 97 
14.6 PROTOCOL AMENDMENTS ................................................................................................................ 97 
14.7 STUDY TERMINATION ....................................................................................................................... 97 
15 
REFERENCES ..................................................................................................................................... 99 
16 
PROTOCOL AMENDMENTS .............................................................................................................. 104 
17 
APPENDICES ................................................................................................................................... 105 
17.1 APPENDIX 1: DEFINITION OF TERMS ................................................................................................ 105 
17.2 APPENDIX 2: ADVERSE EVENTS: DEFINITIONS AND CLASSIFICATIONS OF AE ASSESSMENT ................. 106 
17.2.1 
Definitions........................................................................................................................................................... 106 
17.2.1.1 Adverse Events ................................................................................................................................................... 106 
17.2.1.2 Serious adverse event......................................................................................................................................... 106 
17.2.2 
Classifications for AE assessment ....................................................................................................................... 107 
17.2.2.1 Seriousness ......................................................................................................................................................... 107 
17.2.2.2 Intensity .............................................................................................................................................................. 107 
17.2.2.3 Causal relationship ............................................................................................................................................. 107 
17.2.2.4 Action taken regarding study drug(s) ................................................................................................................. 108 


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17.2.2.5 Other action taken for event .............................................................................................................................. 108 
17.2.2.6 Adverse event outcome ..................................................................................................................................... 108 
17.3 APPENDIX 3: STUDY ORGANIZATION ............................................................................................... 109 
17.3.1 
Data and Safety Monitoring Board (DSMB)........................................................................................................ 109 
17.3.2 
Executive Committee.......................................................................................................................................... 109 
17.3.3 
Administrative information ................................................................................................................................ 109 
17.3.3.1 Sponsor ............................................................................................................................................................... 109 
17.3.3.2 CRO ..................................................................................................................................................................... 110 
17.3.3.3 Data Management .............................................................................................................................................. 110 
17.3.3.4 Safety Management ........................................................................................................................................... 110 
17.4 APPENDIX 4: SCHEDULE OF ASSESSMENTS ....................................................................................... 111 
17.4.1 
PRE-STUDY SCREENING ...................................................................................................................................... 111 
17.4.2 
PART A: Schedule of Assessments ...................................................................................................................... 112 
17.4.3 
PART B and PART C Medically-Led Cardioversion Study: Schedule of Assessments.......................................... 113 
17.4.4 
PART C Patient-Led Under Medical Supervision Cardioversion Study: Schedule of Assessments .................... 114 
17.5 APPENDIX 6: HANDHELD ECHO (HHE) SUB-STUDY ............................................................................ 115 
17.5.1 
HHE Sub-Study design ........................................................................................................................................ 115 
17.5.2 
HHE Sub-Study population and eligibility criteria .............................................................................................. 115 
17.5.3 
HHE Sub-Study procedures................................................................................................................................. 116 
17.5.3.1 HHE Sub-Study Consenting ................................................................................................................................. 116 
17.5.3.2 HHE Sub-Study Evaluation .................................................................................................................................. 116 
17.5.4 
HHE Sub-Study assessments ............................................................................................................................... 116 
17.5.4.1 HHE Sub-Study Portable cardiac ultrasound ...................................................................................................... 116 
17.5.5 
HHE Sub-Study Other assessments .................................................................................................................... 117 
17.5.5.1 HHE Sub-Study Feasibility assessments.............................................................................................................. 117 
17.5.6 
HHE Sub-Study Schedule of Assessments .......................................................................................................... 117 
 
VI. 
List of tables 
Table 1 - Identity of investigational drug: FlecIH-103 ....................................................................................................................... 48 
Table 2 - Pharmacokinetic parameters to be calculated for plasma flecainide ............................................................................... 77 
Table 3 - Pre-Study Screening - Schedule of Assessments ............................................................................................................. 111 
Table 4 - PART B and PART C Medically-Led Cardioversion Study 120 mg FlecIH-103 (75 mg/mL) REPEAT DOSE REGIMEN - 
Schedule of Assessments ................................................................................................................................................................ 113 
Table 5 – PART C Patient-Led Under Medical Supervision Cardioversion Study 120 mg FlecIH-103 (75 mg/mL) REPEAT DOSE 
REGIMEN - Schedule of Assessments ............................................................................................................................................. 114 
Table 6 - HHE Sub-Study - Schedule of Assessments ...................................................................................................................... 117 
 
VII. 
List of in-text figures 
Figure 1. FLE-001 study: Single ascending inhaled flecainide doses ................................................................................................ 32 
Figure 2. Venous plasma concentration- time curve following flecainide IV (normalized to 30 mg dose) and oral IH ................... 33 
Figure 3. Study flow diagram Part B ................................................................................................................................................. 41 
Figure 4. Study assessments diagram Part B .................................................................................................................................... 42 
Figure 5. Schematic for Part C: 120 mg Dose.................................................................................................................................... 79 
Figure 6. Part C Study Design ............................................................................................................................................................ 79 
Figure 7. HHE Sub-Study Design ..................................................................................................................................................... 115 
 
 


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VIII. 
List of Abbreviations 
 
AE 
AECG 
AESI 
AF 
AHE 
BP 
CE 
Cmax 
CRF 
CRO 
d 
DSMB 
ECG 
eCRF 
EDTA 
e.g. 
EMA 
EOS 
et al. 
etc. 
EudraCT 
FAS 
FDA 
GCP 
GMP 
GP 
h 
HHE 
HR 
IB 
IC 
ICH 
IEC 
IRB 
ITT 
JTc 
LVEF 
MAP 
MedDRA 
min 
adverse event 
ambulatory ECG 
adverse event of special interest 
atrial fibrillation 
acute hypertensive episode 
blood pressure 
Conformite Europeene 
maximum serum concentration 
case report form 
contract research organization 
day(s) 
Data Safety Monitoring Board 
electrocardiogram 
electronic CRF 
ethylenediaminetetraacetic acid 
exempli gratia (for example) 
European Medicines Agency 
end-of-study 
et alia (and others) 
et cetera (and so on) 
European Clinical Trials Database 
full analysis set 
Food and Drug Administration 
Good Clinical Practice (refers to ICH) 
Good Manufacturing Practice 
General Practitioner 
hour(s) 
handheld echocardiogram 
hazard ratio 
Investigator's Brochure 
informed consent 
International Conference on Harmonisation  
independent ethics committee 
institutional review board 
intent-to-treat 
corrected JT interval 
left ventricular ejection fraction 
mean arterial pressure 
Medical Dictionary for Regulatory Activities 
minutes 
mITT 
MPI 
PD 
PDF 
PI 
PK 
PQ 
 
 
PR 
 
 
PT 
QA 
QoL 
QRS 
 
QT 
 
QTc 
 
QTcF 
 
RR 
SAE 
SAP 
SD 
SDV 
SID 
SOP 
SPC 
SpO2 
SR 
SUSAR 
 
TDP 
Tmax 
Tx 
VT 
modified ITT 
myocardial perfusion imaging 
pharmacodynamic 
Portable Document Format 
Principal Investigator 
pharmacokinetic 
on an ECG, the time between the beginning 
of the P wave and the beginning of the next 
QRS complex 
on an ECG, the time between the beginning 
of the P wave and the beginning of the next 
QRS complex (interchangeable with PQ) 
prothrombin time 
quality assurance 
quality of life 
on an ECG, a structure that corresponds to 
the depolarization of the ventricles 
on an ECG, the time between the start of the 
Q wave and the end of the T wave  
on an ECG, QT interval corrected for heart 
rate 
on an ECG, QT interval corrected for heart 
rate using Fridericia’s formula 
on an ECG, the time between QRS complexes 
serious adverse event 
Statistical Analysis Plan 
standard deviation 
source data verification 
subject identification   
Standard Operating Procedure 
Summary of Product Characteristics 
peripheral capillary oxygen saturation 
sinus rhythm 
suspected unexpected serious adverse 
reaction 
torsades de pointes 
time at which Cmax is observed 
time point at time X 
ventricular tachycardia 
 
 
 


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IX. 
Introduction 
1 Introduction 
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, with an 
estimated global prevalence of 33.5 million5, and is projected to affect 3 million people in the 
United States by 20206. Once a person reaches the age of 40 years, the lifetime risk of AF is 1 in 
45. In patients with AF, systemic thromboembolic events, hemodynamic instability, 
demand-induced ischemia, and ventricular arrhythmias contribute to a significant increase 
in morbidity, mortality and frequent hospitalizations.  
 
Atrial fibrillation is classified into four different subtypes based primarily on the duration of the 
AF episodes7-9. Paroxysmal AF terminates spontaneously or with intervention within 7 days; 
episodes may recur with variable frequency. Persistent AF is sustained longer than 7 days and 
requires cardioversion to restore sinus rhythm (SR). Long-standing persistent AF has a duration 
of more than 12 months. The term permanent AF is used when there has been a joint decision 
by the patient and clinician to give up on attempts to maintain normal SR; acceptance of AF 
represents a therapeutic approach on the part of the patient and clinician rather than an 
inherent pathophysiological attribute of the AF.  
 
The pathophysiology and mechanisms of AF are complex and multifactorial. Etiological factors 
associated with AF include hypertension, diabetes, heart failure, obesity, obstructive sleep 
apnea (major risk factor), coronary artery disease, ageing, and genetic predisposition. They 
contribute to a complex array of pathophysiological changes in the atrial myocardium, including 
stretch-induced atrial fibrosis, hypocontractility, fatty infiltration, inflammation, vascular 
remodeling, ischemia, ion channel dysfunction, and dysregulation of intracellular Ca2+ 
homeostasis. These changes enhance both ectopy and conduction disturbances, that increase 
the susceptibility of the atria to develop or maintain AF8. 
 
The management of AF depends on the type of AF, but the general objectives are to provide 
symptom relief, rate control (aimed at slowing the ventricular rate), and/or rhythm control 
(aimed at restoring SR), antithrombotic therapy (aimed at reducing risk of thromboembolic 
events, and treatment of the comorbidities. Due to its debilitating consequences, stroke 
prevention is critical. The choice of antithrombotic therapy is guided by risk factors for stroke, 
regardless of the presence or absence of symptoms or classification of AF. Currently, the 
CHA2DS2-VASc scoring system is used to determine both the need and the selection of 
anticoagulation strategies7, 8, 9. Selection of a primary therapeutic strategy of rhythm control or 
rate control is a multifactorial decision depending on the patient’s age, symptoms, and 
importance of maintaining SR.  
 


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Current therapies for rhythm control include antiarrhythmic drugs (AADs), electrical 
cardioversion (ECV), or invasive electrophysiological procedures (e.g., AF catheter ablation). The 
efficacy, safety, tolerability and contraindications of the current therapeutic options have been 
extensively described in numerous reviews10, 11 and in the relevant medical guidelines8, 9. With 
regard to the acute management of recent-onset AF, the current guideline recommendations 
are based on various factors that include the duration of the AF episode, the presence or 
absence of existent heart disease(s) such as ischemic heart disease, heart failure, left 
ventricular (LV) function, and the hemodynamic status of the patient12.  
 
For the acute management of AF, restoration of SR is a therapeutic choice in order to reduce 
symptoms, shorten hospitalization, and improve quality of life, with the long-term goal of 
preventing the detrimental effects of prolonged AF and avoiding subsequent hospitalization13-
17. Both ECV and pharmacological cardioversion (PCV) are considered safe in patients in whom 
the AF episode duration is known to be less than 48 hours, or who have been previously 
maintained on oral anticoagulant therapy for at least 3 weeks. Electrical cardioversion is most 
effective but requires sedation or anesthesia, with the associated requirements for specialized 
medical personnel and appropriate facilities, and patients must be in a fasting state8, 9, 14, 18. In 
general, ECV is reserved for patients who are hemodynamically unstable and/or refractory to 
PCV12. The decision to use PCV is based mainly on whether or not the patient has demonstrable 
(moderate or severe) underlying cardiac disease (e.g., ischemic heart disease, HF, valvular heart 
disease, cardiomyopathy), and on the status of the LV systolic function12. Currently available 
oral and intravenous (IV) AADs for PCV are limited by their delayed onset of action, slow 
metabolism, and potential to cause hypotension and/or proarrhythmia, all of which may 
require or prolong hospitalization8, 9, 13, 19, 20.  
 
Approximately 60% of patients presenting with recent-onset AF in the Emergency Department 
(ED) in the US are admitted to the hospital (~ 300,000 patients per year [2014])21. This 
represents a major burden (resource utilization and costs) to the US healthcare system and has 
a significant negative impact on patient quality of life. Furthermore, because of the lack of an 
available pharmacological agent that is safe, effective and rapid-acting (minutes), requires 
minimal set up time and skills to administer, and a short monitoring time post-administration, 
PCV is not attempted in many patients whose AF could be successfully converted to SR. Thus, a 
pharmacological agent with the aforementioned properties would represent an important 
advancement in the acute management of patients with symptomatic recent-onset of AF 
presenting in the ED, which would also markedly reduce healthcare utilization. 
1.1 Flecainide acetate 
Flecainide is a potent cardiac sodium channel blocker that belongs to the AAD Class Ic. 
Flecainide has been in use since the mid-1980s for the management of patients with ventricular 
and atrial tachyarrhythmias10. Over the last three decades, a large body of clinical data and 
experience has been gathered using flecainide acetate. This data has strongly established 


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flecainide’s efficacy and its safety profile10, 11. Both oral and IV flecainide are recommended by 
US and European Medical Society Guidelines as a first line therapy (class-1, level A) for PCV of 
recent-onset AF (< 48 hours' duration) in patients without structural heart disease8, 9, 12, 22, 
although oral flecainide is not approved by health authorities for this use. The adverse effects 
of IV flecainide (2 mg/kg delivered over 10 minutes) when used according to guidelines for 
acute cardioversion of recent-onset AF are for the most part limited to the cardiovascular 
system and include rapid atrial flutter with 1:1 atrioventricular (AV) conduction and wide 
QRS complex, hypotension, and bradycardia. 
 
Flecainide’s inhibition of peak (transient) sodium current (peak INa) is responsible for slowing of 
electrical impulse conduction through the myocardium and specialized conduction system. This 
action of flecainide in the heart is detectable on a 12-lead ECG as dose-dependent prolongation 
of the PR and QRS intervals23, 24. The prolongation of the QTc interval by flecainide is relatively 
small (or not observed) and is mainly a consequence of the increase in QRS interval duration10. 
Thus, flecainide causes a small, generally insignificant prolongation of the JTc interval, a 
measure of ventricular repolarization10.  
 
The mechanism underlying the anti-AF activity of class Ic agents has been extensively 
investigated using various experimental cardiac preparations and models of AF25-27. Some key 
electrophysiological effects of flecainide that are likely to contribute to its anti-AF activity are: 
(1) induction of post-repolarization refractoriness (greater prolongation of atrial refractory 
period than the action potential duration [APD])28, (2) decrease in excitability29, 30, (3) rate-
dependent prolongation of atrial refractoriness31, 32, and (4) suppression of spontaneous 
diastolic SR Ca+2 release33. 
 
Class Ic AADs (such as flecainide) are also well known to be arrhythmogenic properties. The 
same or similar ion channel and electrophysiological effects that explain the therapeutic effects 
of flecainide are considered to be responsible for its proarrhythmic activity. The inhibition by 
flecainide of peak INa is exacerbated in depolarized myocytes and at high frequencies of 
depolarization (i.e., fast heart rates). Consequently, inhibition of peak INa in diseased 
myocardium may cause marked rate-dependent slowing of conduction and facilitate the 
initiation of re-entrant wave fronts around lines of functional conduction block such as 
infarcted or fibrosed tissue, leading to life-threatening ventricular arrhythmias and sudden 
cardiac death. It is important to recognize that the proarrhythmic effects of flecainide have 
been observed primarily in patients with ischemic heart disease, depressed LV function 
(e.g., HF), electrolyte disturbances, congenital (genetic) and acquired diseases/conditions 
resulting in conduction abnormalities. The results of the Cardiac Arrhythmia Suppression Trial 
(CAST)34 demonstrated that flecainide, like other Class Ic AADS, caused serious malignant 
arrhythmias that led to a 3.6% (95% CI, 1.7 to 8.5) increase in risk of non-fatal cardiac arrest and 
death from arrhythmia compared to placebo. Due to this proarrhythmic potential, patients with 
depressed LV function, ventricular scar tissue and ischemic myocardium should not be treated 


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with flecainide. In addition, the negative inotropic effect of flecainide is greater in patients with 
LV dysfunction. Directly related to the proarrhythmic effects of flecainide caused by marked 
inhibition of peak INa, is the excessive widening of the QRS interval and/or slowing of the AV 
nodal conduction (PR prolongation or AV nodal block). These are important premonitory signs 
of the impending arrhythmogenic effects of flecainide. 
 
Flecainide undergoes renal elimination35 and CYP-mediated biotransformation. Hepatic 
oxidative metabolism via cytochrome CYP2D6 and CYP1A236 results in two major metabolites 
which display minimal/no cardiac activity. Both flecainide (~ 30%) and its major inactive 
metabolites are primarily excreted in the urine37, 38. Although the elimination half-life of a single 
dose of flecainide is likely to be increased in patients with severe renal and/or hepatic 
impairment, these conditions should not alter the initial Cmax and tissue distribution kinetics of 
flecainide and are not likely to affect the pharmacodynamics associated with acute inhalation 
use. 
1.2 Flecainide acetate inhalation solution (FlecIH) 
An inhaled version of flecainide acetate is being developed for the acute conversion of recent-
onset AF to SR in symptomatic patients without structural heart disease. The inhalation solution 
formulation for the 30 mg (35 mg/mL), 60 mg (35 mg/mL) and 90 mg (45 mg/mL) dose cohorts 
contained 90 mM acetic acid (FlecIH-101). To continue with dose escalation above the 90 mg 
dose cohort, e.g., 120 mg, the flecainide concentration in the inhalation solution was increased 
to 75 mg/mL by adding the excipient hydroxypropyl -cyclodextrin in an acetic acid 
formulation, without (FlecIH-102) or with the addition of sodium saccharin (FlecIH-103). The 
current investigational product is the FlecIH-103 inhalation solution. 
1.2.1 Non-clinical studies 
The following non-clinical pharmacology studies in dogs and pigs have been completed for 
inhaled flecainide; they are: 
- 
Pharmacokinetics (PK), pharmacodynamics (PD) and cardiovascular safety of 
intratracheal instillation of flecainide in pigs (study No: TRE-0022 and Study No. 
RPT-002) 
- 
PK and PD of intratracheal instillation of flecainide in dogs (study No. SPD16-013) 
- 
Cardiovascular Safety Pharmacology in dogs (Non-GLP study No. SPD12-003) 
 
The two pilot PK studies in pigs and dogs mentioned above indicate that intratracheal 
instillation of flecainide can yield plasma concentrations within or in excess of the therapeutic 
concentration range of 200–1000 ng/mL35. In addition, the concentrations of flecainide 
achieved following intratracheal instillation are comparable to those observed when flecainide 
is given by the IV route (2 mg/kg infused over 10 minutes) for rapid cardioversion of AF. 
 


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In line with literature data39, 40, a significant correlation between venous peak plasma 
concentrations of flecainide and the magnitude of the increases in QRS interval duration 
irrespective of the route of administration, either IV or intratracheal instillation, was observed. 
Moreover, there was a linear relationship between the peak plasma levels of flecainide and QRS 
interval durations pooled across the IV and intratracheal routes of administration with these 
two routes yielding equivalent relationships between peak plasma levels of flecainide and QRS 
interval durations. 
 
The increase in QRS interval following intratracheal instillation of flecainide indicates that the 
plasma levels of flecainide achieved following pulmonary delivery are sufficient to elicit the 
expected “signature” pharmacologic effect of flecainide, consistent with inhibition of peak INa. 
More importantly, flecainide administered by intratracheal instillation at single or cumulative 
doses of 0.75 or 1.0 mg/kg was effective in rapidly (< 147 seconds) converting AF to SR in dogs. 
Flecainide administered by IV at doses 0.75–1.25 mg/kg was also effective in converting AF to 
SR, whereas administration of placebo vehicle (intratracheal or IV) to dogs had no effect on AF. 
 
An additional non-clinical pharmacology study in pigs has been completed to evaluate the 
modified inhalation solution (FlecIH-102), containing hydroxypropyl -cyclodextrin as an 
excipient. This PK and PD study comparing FlecIH-101 and FlecIH-102 inhalation solutions 
following intravenous infusion or intratracheal instillation in pigs (study No. RPT-002) revealed 
the following: the plasma-concentration-time profile and PD effects (electrocardiographic and 
hemodynamic) were comparable for the FlecIH-101 and FlecIH-102 inhalation solutions 
following IV infusion or intratracheal instillation showing that the addition of the cyclodextrin to 
the inhalation solution had no effect on the systemic distribution or pharmacologic activity of 
flecainide. 
 
The following toxicology studies in rats and dogs have been completed for inhaled flecainide; 
they are: 
- 
Maximum Tolerated or Maximum Feasible Dose of Flecainide in Rats by Nose Only 
Inhalation. Non-GLP study No. FY16-027A; 
- 
Maximum Tolerated or Maximum Feasible Dose of Flecainide in Beagle Dogs by Face 
Mask Inhalation. Non-GLP study No. FY15-092A; 
- 
14-Day Repeated-dose Toxicity with 14-day Recovery and cardiovascular safety in 
Beagle Dogs via Face Mask Inhalation. GLP study No. FY15-092B and study No. 
FY19-020A; 
- 
14-day Nose Only Inhalation Toxicology Study in Rats with 14-day Recovery. GLP study 
No. FY16-027B, study No. FY19-019A, and study No. FY19-019B. 
 
The results of the preclinical toxicology screening showed that flecainide administered via the 
lungs did not result in proarrhythmia, cardiac depression or hemodynamic instability; that is, no 
safety issues were observed. The initial 14-day toxicity study in dogs established a  


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No-Observed-Adverse-Effect-Level (NOAEL) dose of 8.03 mg/kg/day (FY15-092B). The initial 14-
day rat inhalation toxicology study established a NOAEL dose of 28.7 mg/kg/day (FY16-027B).  
 
Additional toxicology studies in dogs and rats were completed for inhaled flecainide using the 
modified inhalation solution formulation containing hydroxypropyl -cyclodextrin (FlecIH-102), 
and using the inhalation solution formulation containing sodium saccharin (FlecIH-103). The 
results of the 14-day toxicity studies confirmed a NOAEL dose of approximately 9.87 mg/kg/day 
in dogs and of approximately 67.7 mg/kg/day in rats for FlecIH-102 (similar to that reported for 
FlecIH-101 in GLP study No. FY15-092B and FY16-027B, respectively) and provide a bridge to 
the non-clinical safety data obtained with the original acetic acid formulation. The additional 
excipient in the FlecIH-103 inhalation solution, sodium saccharin, was added to improve the 
sensory quality (organoleptic properties) of the inhalation solution. GLP study No. FY19-019B 
was conducted with the FlecIH-103 inhalation solution to bridge to the non-clinical safety data 
obtained with the FlecIH-101 and FlecIH-102 inhalation solutions and the results support its 
safety for clinical use. Sodium saccharin has been used previously in marketed inhalation 
solutions (see Investigator's Brochure [IB], Section 4.4.2.2.2). 
 
Additional details on the non-clinical studies conducted are available in Section 4 of the IB41.  
1.2.2 Clinical experience 
Two Phase 1 studies41 have been conducted in healthy volunteers to assess the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled flecainide, FLE-001 
(completed), and FLE-003 (completed).  FLE-001 was a single center study comprised of two 
parts: 1) a double-blind, randomized, placebo-controlled, three single ascending doses (20, 30 
and 60 mg estimated total lung dose [eTLD]) part; and 2) an open-label, two period IV flecainide 
(2mg/kg ≈ 150 mg) vs. IH flecainide (30 mg eTLD) cross-over part. FLE-003 was a single center 
study comprised of two parts: 1) a double-blind, randomized, placebo-controlled, two single 
ascending doses (75 and 90 mg eTLD) part; and 2) an open-label, cross-over cohort comparing 
two different compressed air flow rates (8 vs 5 L/min) for delivering the aerosolized dose (90 
mg eTLD). 
 
In FLE-001, a total of 40 subjects completed the study; in the ascending dose first part of the 
study, subjects received doses of 20 mg (8 subjects: 2 placebo and 6 IH flecainide), 40 mg (14 
subjects: 4 placebo and 10 IH flecainide), 60 mg (12 subjects: 3 placebo and 9 IH flecainide), and 
in the cross-over part, 6 subjects received 30 mg IH flecainide and 2 mg/kg (approx. 150 mg) IV 
flecainide infused over 10 minutes. 
 
The results of the FLE-001 ascending doses study demonstrated that inhalation doses of 
flecainide, in the range of 30 to 60 mg, are safe, well-tolerated and delivers flecainide into the 
systemic circulation, within 1 to 3 minutes after the completion of inhalation, in sufficient 


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amounts to elicit the expected electrophysiological effect of flecainide, such as prolongation of 
QRS interval (Figure 1).  
 
Figure 1. FLE-001 study: Single ascending inhaled flecainide doses 
 
Panel A: Mean plasma flecainide concentration vs. time for 20, 40 and 60 mg eTLD of flecainide from the post-hoc 
dataset. Values are Mean ± SD. 
Panel B: Relationship between peak venous plasma concentrations of flecainide (Cmax ) and the magnitude of 
maximal QRS prolongation. Data are from lead V4 of the 12-lead ECG recordings. Each data point represents the 
mean (± SEM) of the flecainide concentration (horizontal error bars) and QRS interval (vertical error bars).  
The data in both these plots includes only the post-hoc population which excludes 4 subjects in which Tmax was ≥ 15 
min. 
 
In both parts of the FLE-001 study, inhaled flecainide displayed a rapid distribution phase lasting 
≈10-15 minutes, with an estimated t1/2α of 3.5-4.2 minutes and elimination t1/2β of 9-12 hours. 
The distribution phase and elimination half-life were independent of the doses of inhaled 
flecainide whereas the Cmax and AUClast were dose-dependent. In the cross-over study, the 
distribution phase and elimination half-life were nearly identical for intravenous infusion and 
inhalation: 4.7±01.4 min and 10.0±1.8h for intravenous, and 4.3±1.5 min and 10.1±2.0h for 
inhalation. The relevancy of this finding is linked to the fact that flecainide given via IV at the 
approved dose of 2 mg/kg is an established agent for acute pharmacological cardioversion of 
recent onset AF (efficacious and safe dose). 
 
In the FLE-001 cross-over study, a within subject comparison of the PK, PD, safety and 
tolerability of 30 mg eTLD of flecainide given via oral inhalation was made with that of a 10 min 
IV infusion dose of 2 mg/kg of flecainide (≈ 150 mg). To directly compare the PK profiles of 
flecainide given via IV infusion and oral inhalation, the mean ± SD plasma flecainide 


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concentration vs time for the IV dose was normalized to 30 mg in order to match the 30 mg oral 
inhalation dose (Figure 2). The resulting concentration-time profile curves are near-identical, 
indicating comparable pharmacokinetics by these two routes of administration. The results of 
the cross-over comparison between IV and inhaled flecainide also clearly demonstrated that 
the reported adverse events were far fewer and less intense following inhalation of a lower 
dose of flecainide (30 mg eTLD) than the 10 min IV infusion of 2 mg/ml of flecainide. 
 
Figure 2. Venous plasma concentration- time curve following flecainide IV (normalized to 30 
mg dose) and oral IH 
 
 
Values are mean ± SD. Inset shows the first 70 minutes after start of dosing. The Least Square Mean Cmax value for 
the IV infusion was 143 ng/ml and that for the inhalation was 102 ng/ml. Note that the estimated bioavailability of 
flecainide given via IH is ≈75% compared to the 100% given via IV. 
 
The changes in heart rate (HR), arterial systemic blood pressure (BP), and pulmonary function 
test parameters associated with administration of flecainide or placebo were assessed. 
Transient (5 to 10 mins) increases in both HR and systolic and diastolic BPs were noted in 
subjects that were given inhaled flecainide and placebo. These changes were not dose-
dependent, and are, in part, due to the sympathetic reflex responses associated with postural 
changes (from semi-recumbent to seated) and are also, likely, due to the oral inhalation 
procedure.  
 
All standard lung spirometry measurements and peripheral oxygen saturations (pulse oximetry) 
values were normal before and after flecainide or placebo. No SAEs were reported and no 
subject had to interrupt the inhalation of flecainide acetate or placebo. The changes in vital 
signs (HR, BP, respiratory rate) and pulmonary function are described in detail in the IB (IB 
Section 5.2.1.2.3)41. 


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Therefore, inhaled flecainide at eTLD ≥ 30 mg was found to yield venous plasma flecainide 
concentrations and cause QRS interval prolongation within the range, albeit in the lower end of 
the range, reported to convert AF to SR by IV flecainide42-44. Based on the PK and PD of 
flecainide reported in the literature, inhaled flecainide at eTLDs ≥ 30 mg are considered likely to 
be effective in converting recent-onset AF to SR within minutes of administration; the 30 mg 
dose was used as the starting dose for the INSTANT study.  
 
The FLE-003 study consisted of two Parts. Part 1 of the study was a single-center, double-blind, 
randomized, placebo-controlled design. A total of 21 subjects were enrolled in Part 1 (of 2) with 
ascending eTLDs of 75 mg (6 subjects: 2 placebo and 4 IH flecainide) and 90 mg (15 subjects: 3 
placebo and 12 IH flecainide). A dose-dependent increase in plasma flecainide concentrations 
was observed for the 75 and 90 mg eTLDs, along with a transient (~ 3 minutes) increase in QRS 
and PR interval durations. Cmax values reported for the 75 mg and 90 mg doses were 301 ng/mL 
and 347 ng/mL, respectively; whereas, the mean maximum change in QRS interval were 
generally small and ranged up to 8 msec at the 90 mg eTLD. Part 2 was an exploratory, open-
label study, in which 6 subjects (5 from Part 1 and 1 naïve subject received 1 or 2 doses of 
inhaled flecainide. The main goal was to compare the PK of a 90 mg eTLD given to the same 
subjects at two compressed air flow rates. There were no significant differences in Cmax values 
following inhalation of the 90 mg dose using compressed air pressure of 8 L/min (340 ng/mL) or 
5 L/min (313 ng/mL) in the same 5 subjects, indicating no clear trend for effect of compressed 
air flow rate on Cmax (or any PK parameter). Overall, inhaled flecainide at eTLDs of 75 and 90 mg 
was safe and well tolerated. The most frequently reported adverse events were headache, 
oropharyngeal pain, and throat irritation; all adverse events were mild and resolved 
spontaneously, and no serious adverse events were reported. 
 
Additional information on the results of the Phase 1 studies conducted are provided in Section 
5 of the IB41. 
 
The results of the Phase 1 studies warrant further development of inhaled flecainide, i.e., justify 
a Phase 2 study in patients with recent-onset paroxysmal episodes of AF. The rationale and 
objectives for the development of this route of administration of flecainide are described 
below. 
1.3 Rationale for the study 
The aim of inhaled flecainide (in patients that have no contraindications for IV or oral 
flecainide) is the restoration of SR in symptomatic patients with recent onset AF (of < 48 hours) 
in a manner that is safe, rapid (in minutes) and convenient. Minimizing the time spent in AF is 
consistent with the concept that “sinus rhythm begets sinus rhythm” and may decrease the 
frequency of recurrences, and thereby slow/delay the progression of paroxysmal to persistent 
and/or permanent AF.   
 


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Part A - Initial data for inhaled flecainide suggest that cardioversion of subjects with recent 
onset of paroxysmal AF may be achieved within minutes with the possibility to eliminate the in-
hospital administration in the long term. Before embarking on further stages of the clinical 
development plan for inhaled flecainide, it was important to ascertain that flecainide, at the 
dose and regimens to be tested, is well tolerated and that the study is feasible. Therefore, Part 
A of the current study was devised as an open-label, dose-escalation investigation to evaluate 
the feasibility and tolerability of several inhalation regimens of inhaled flecainide. 
Although no conclusions about the effectiveness of inhaled flecainide can be drawn from the 
results of Part A, the aims of the study were to provide supportive data on the viability, 
acceptability and tolerability of the study design and procedures prior to proceeding into Part B 
to confirm the efficacy of the selected dose using an open-label study design. 
 
Part B is an open-label multi-center design to confirm the safety (including tolerability) and to 
provide a more precise estimate of efficacy of the optimal inhaled flecainide dose regimen 
determined from Part A. The planned dose is an eTLD of 120 mg given as two sequential 
inhalations (repeat regimen, 2 x 60 mg eTLD = 120 mg eTLD). Subjects will 'dose/inhale to 
conversion'; dosing in a 'dose/inhale to conversion' regimen continues according to the 
assigned regimen until the conversion of AF to SR is observed for ≥ 1 minute, or until the 
assigned dose is completed, whichever comes first. The study drug is administered to subjects 
with a recent onset of symptomatic AF without relevant structural heart disease.  
 
Part C (EU only) includes an open-label Patient-Led Under Medical Supervision Cardioversion 
Study, whereby subjects who specifically consent and whose AF episode was previously 
converted to SR following an oral inhalation of flecainide solution in Part A, Part B and/or a 
Medically-Led Cardioversion Study in Part C may be eligible to participate. Part C will serve as a 
feasibility study to assess the ability of subjects to independently assemble the nebulizer, 
dispense the study medication, and self-administer the study medication with minimal 
supervision during a recurrent episode of recent-onset AF.  
1.4 Rationale for dose selection 
A 14-day repeat dose inhaled toxicology program has been conducted in rats and dogs. The 
study showed that inhaled flecainide resulted in no new or unusual toxicology associated with 
inhalation of flecainide compared with the marketed IV and oral flecainide dosage forms. The 
NOAEL weight-based doses were in excess of the proposed Phase 2 clinical doses of 30 mg, 60 
mg, 90 mg, and 120 mg. The weight-based doses for inhaled flecainide assuming a 70 kg subject 
are also lower than the 2 mg/kg dose recommended for IV flecainide in the summary of product 
characteristics. The weight-based doses to be examined in this study are (assuming 70 kg 
subject): 0.43 mg/kg for 30 mg inhaled flecainide dose, 0.86 mg/kg for 60 mg inhaled flecainide 
dose, 1.29 mg/kg for 90 mg inhaled flecainide dose, and 1.71 mg/kg for 120 mg inhaled 
flecainide dose.  
 


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Based on the results of the FLE-001 and FLE-003 studies, the overall safety profile for doses of 
20, 30, 40, 60, 75, and 90 mg of inhaled flecainide solution was favorable; adverse events (AEs) 
were transient and mostly mild in severity. The most frequently reported AE was oropharyngeal 
discomfort, a common side effect of medications administered via inhalation. However, none of 
the subjects discontinued the inhalation.  
 
Doses of 30 mg (1 x 30 mg), 60 mg (2 x 30 mg), and 90 mg (2 x 45 mg) and 120 mg (2 x 60 mg) 
have been under evaluation in this study based on PK and PD data (QRS prolongation) from 
FLE-001 and FLE-003 showing that doses ≥ 30 mg had the potential to convert AF to SR. Part A 
concluded after enrolling 101 subjects, as follows: 10 subjects treated with 30 mg eTLD, 22 
subjects treated with 60 mg eTLD, 21 subjects treated with 90 mg eTLD, and 48 subjects treated 
with 120 mg (19 with FlecIH-102 and 29 with FlecIH-103. Enrollment in the 120 mg dose cohort 
was completed on 05Mar2020 and Part A was concluded. The rate of conversion from AF to SR 
observed to date for the dose cohorts is as follows: 30 mg, 1/10 (10%); 60 mg, 6/18 (33%; 2 
subjects were excluded from analysis as they were not in AF at time of dosing); and 90 mg, 7/21 
(33%); For the 120 mg dose, the conversion rate was 7/17 (41%) for the FlecIH-102 cohort (2 
subjects were excluded from efficacy analysis because they did not receive the full dose of 
study drug) and 13/27 (48%) for the FlecIH-103 cohort (2 subjects were excluded from the 
efficacy analysis because they did not receive the full dose of study drug).   
 
The majority of subjects had AEs that were mild in severity and the most commonly reported 
AEs were those associated with the inhalation route of administration, e.g., cough and throat 
irritation. All non-serious AEs of bradycardia and hypotension were minor, transient and 
resolved without drug treatment. A total of four subjects experienced serious AEs (SAEs) that 
were considered possibly related to study drug by the Investigator or Sponsor. The SAEs 
considered related to inhaled flecainide included the following: two cases of prolonged sinus 
pauses at the time of conversion of AF to SR (one mild and one moderate, as per the 
Investigators), one case of bradycardia (severe, as per the Investigator), and one case of atrial 
flutter with 1:1 conduction with fast ventricular response (severe, as per the Investigator). All 
SAEs were transient in nature, resolved without intervention, and had no sequelae. 
 
Based on the feasibility, safety, tolerability and efficacy results from Part A using the FlecIH-103 
inhalation solution, Part B and Part C of the study will use the 120 mg dose of flecainide to 
further evaluate the cardioversion of recent onset AF. 
1.5 Benefit/Risk assessment 
This is the first study investigating inhaled flecainide acetate for acute conversion of recent 
onset of paroxysmal AF to SR. Based on the data from Part A of the study, the doses of 
flecainide acetate inhalation solution (30 mg eTLD, 60 mg eTLD [2 x 30 mg eTLD], 90 mg eTLD [2 
x 45 mg eTLD], and 120 mg eTLD [2 x 60 mg eTLD]), were safe in 101 subjects. The 120 mg eTLD 
selected for Part B provides an acceptable benefit/risk in this population: 


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a) The potential cardiovascular risks of oral and IV flecainide are monitored closely in 
clinical studies of oral inhaled flecainide (AEs of special interest): ventricular 
tachycardia (VT), hypotension, bradycardia, sinus pause post conversion of AF to SR, 
and atrial flutter with 1:1 conduction with fast ventricular response (ventricular 
heart rate ≥ 200 bpm). 
i) Ventricular tachycardia (VT) is rare in subjects without structural heart disease, 
electrolyte disturbances and coronary artery disease. Ventricular proarrhythmia 
manifests either as monomorphic or polymorphic VT not only early but also late 
after the initiation of chronic therapy34. The incidence of VT in patients receiving 
flecainide for acute cardioversion of atrial fibrillation is less than 3%45. These 
potential risks have been mitigated by excluding subjects who have structural 
heart disease, myocardial ischemia, and LV systolic dysfunction, populations in 
which these adverse effects are more commonly encountered. 
ii) Due to a negative inotropic effect, flecainide is contraindicated in subjects with 
congestive heart failure and reduced LV ejection fraction (LVEF)46, 47. Therefore, 
these subjects have been excluded from the current study population. 
iii) Clinically significant slowing of electrical conduction have been reported with 
chronic oral flecainide therapy, including exacerbation/unmasking of conduction 
system disturbances, such as sinus node dysfunction (1.2%; i.e., sinus pause, 
sinus arrest or symptomatic bradycardia). Flecainide alone may cause 
bradycardia, second-degree AV block (0.5%) or third-degree AV block (0.4%).48 
Flecainide slows cardiac electrical conduction because it inhibits peak INa, which 
is the basis for the contraindication for its use in patients with conduction 
system disturbances. 
iv) Conversion of AF into atrial flutter, has been occasionally reported with 
flecainide, resulting in rapid ventricular rates (200 bpm) in cases of 1:1 
atrioventricular conduction49. Although the frequency of this proarrhythmic 
effect is low (3.5% - 5.0%) and its occurrence has been associated with 
conditions whereby sympathetic (adrenergic) activity is increased50, the potential 
risks have been mitigated by allowing concomitant use of drugs with 
atrioventricular nodal blockade properties, such as β-blockers, and calcium 
channel blockers, lowering the risk of rapid ventricular rate and atrial flutter.  
b) Other AADs used as part of the standard of care for pharmacological cardioversion 
(e.g., flecainide, propafenone, ibutilide, and dronedarone), have a similar pattern of 
expected cardiac adverse effects. 
c) The study is being conducted under cardiac monitoring in a hospital setting in order 
to safeguard subject safety. 
d) The potential benefits of subjects in need of treatment for recent onset 
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i) Between approximately 1.25- to 2.5-fold lower dose for inhaled flecainide, than 
the maximum doses for either oral (300 mg) or IV (~150 mg) flecainide. The 
rationale for the potential efficacy of a lower dose with the oral inhalation route 
of administration may be due to: 
(1)  Delivery to the site of action within minutes, given the proximity of the 
pulmonary venous circulation to the left atrium, and then to the coronary 
circulation without systemic circulation dilution; 
(2) Cmax being achieved rapidly without the requirement for steady state plasma 
concentration to be reached. 
ii) Rapid conversion of AF to SR, enabling a relatively short time period for medical 
monitoring/follow up. 
iii) The duration of elevated plasma flecainide concentrations > 200 ng/mL, and 
consequent pharmacological effects of orally inhaled flecainide, are significantly 
shorter (~15 min for 120 mg eTLD) than those of IV flecainide (~ 120 min for 
~150 mg dose). Therefore, the lower inhaled dose is expected to have fewer, 
milder, short-lived acute adverse effects and an improved overall safety profile. 
 
Overall, the population selected for this study is appropriate for evaluation of the efficacy and 
safety of flecainide acetate inhalation solution for rapid cardioversion of recent onset 
symptomatic AF in patients with paroxysmal AF with disabling symptoms when the need for 
treatment has been established. 
 
The available safety data for 30 mg, 60 mg, 90 mg, and 120 mg cohorts support the safety of 
treatment with the current dose of 120 mg eTLD (2 x 60 mg). A total of four SAEs that were 
considered possibly related to study drug by the Investigator or Sponsor have been reported; all 
were transient in nature, resolved without intervention, and had no sequelae (see Section 1.4, 
above). Based on the safety profile of inhaled flecainide observed in Part A, the Sponsor and 
DSMB have reviewed safety/tolerability, and determined that the 120 mg eTLD (2 x 60 mg) 
dose cohort is acceptable for continued use in Part B and Part C of the study. 
 


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X. 
Study protocol (PART A) 
 
Part A was an open-label, multicenter design and studied the feasibility of administration of 
inhaled flecainide in four dosing regimens (30, 60, 90, and 120 mg). Part A included a 
randomized phase. 
 
Part A was closed to enrollment on 05Mar2020, after a total of 101 subjects were treated with 
the study drug (10 with 30 mg, 22 with 60 mg, 21 with 90 mg, and 48 with 120 mg). The final 
dose in Part A (120 mg FlecIH-103) was selected as the dose to continue evaluating in Part B 
and Part C. 
 
In this protocol version, Part A procedures have been removed for clarity. Preliminary Part A 
data are summarized in the IB41.  
 
 


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XI. 
Study protocol (PART B) 
2 B - Study objectives 
2.1 B – Efficacy objective(s) 
The efficacy objective is to evaluate the conversion of AF to SR and symptom relief by flecainide 
acetate inhalation solution in subjects with recent onset of paroxysmal AF. 
2.2 B - Safety objective(s) 
The safety objective is to assess the safety and tolerability of flecainide acetate inhalation 
solution in subjects with recent onset of paroxysmal AF. 
2.3 B – Pharmacokinetic (PK) and pharmacodynamic (PD) objective(s) 
The PK and PD objectives in Part B include: 
• To evaluate the PK 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 
2.4 B - Exploratory objective: 
The exploratory objective in Part B is to explore the feasibility of implementing the use of a 
portable cardiac ultrasound to record a diagnostic echocardiogram at screening. This is 
applicable to all US sites, and to select EU sites participating in the optional HHE Sub-Study. 
3 B - Study design 
Part B is an open-label, multicenter design to confirm the safety (including tolerability) and 
efficacy of the optimal inhaled flecainide dose determined from Part A. Subjects are enrolled to 
receive a repeat dose regimen of 120 mg eTLD (2 x 60 mg) FlecIH-103 (N = approximately 25 
subjects). The dose regimen is described in Section 5.1 B and 5.3.4 B. 
 
The study design for Part B is described below in Figure 3. Subjects presenting with a 
symptomatic AF episode of recent onset (from 1 hour to 48 hours in duration) and without 
known relevant structural heart disease are candidates for the study. To qualify, subjects must 
also correspond to one of these categories: the first detected AF episode, a recurrent 
paroxysmal AF episode, or an episode post-cardiac ablation for paroxysmal AF. 
 
Additionally, select subjects who may not be eligible to participate until a future date (e.g., not 
currently experiencing a symptomatic episode of paroxysmal AF) may sign a pre-study 


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screening consent to determine their eligibility to participate in the study by performing 
screening assessments (refer to Section 6.1.2.1 B). 
 
Figure 3. Study flow diagram Part B  
 
 
After written IC has been obtained for Part B, the subject is connected to cardiac telemetry and 
study ECG devices to evaluate the stability of AF during for at least 45 minutes prior to dosing 
(subject must remain predominantly in AF to be eligible for treatment with the study drug and 
must be in AF immediately prior to dosing).  
 
The subject’s right to early terminate inhalation of study drug, for whatever reason, shall not be 
infringed upon.  
 
Enrollment (study drug allocation) occurs on Day 1 (day of dosing) and the start of the first 
inhalation is time zero (T0). 
 
An overview of study assessments is shown in Figure 4. Vital signs, triplicate 12-lead ECGs, and 
blood samples for PK analysis are collected at multiple serial time points just before, during, 
and after the inhalation regimen, and at the time of conversion of AF to SR as detailed in the 
Schedule of Assessments. AECG (12-lead Holter) data are collected from 45 minutes pre-dose 
until 90 minutes post dose in order to identify the time of conversion of AF to SR and to 
monitor the safety of the study subjects. Time to discharge of the subject is left to the 
discretion of the treating physician but may not be scheduled prior to 90 minutes post dose (a 
— (minus) 10-minute window is allowed). 
 
If conversion of AF to SR does not occur within 90 minutes post dose, the Investigator may offer 
another appropriate therapy, as per institutional standard, except for IV ibutilide, 
procainamide, or sotalol which are not allowed. See Section 5.4.2 B for specific requirements.  
 
All subjects have a Day 2 (+1 day) and a Day 5 (± 1 day) telephone assessment (Visit 1 and Visit 
2, respectively). ECG recordings are also obtained by the subject on Day 2 and Day 5 using an 
Event Recorder. All enrolled subjects are followed for 5 days and every effort shall be made to 
maintain the scheduled follow-up of the subject. End-of-study activities are completed for all 
enrolled subjects who received study drug. Study follow-up is only terminated at the explicit 
INSTANT Study 
PART B
N =  approx. 25
FlecIH-103 (2x60 mg)
Repeat dose
120 mg


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request of the subject. The overall duration of subject participation from screening through 
follow-up is 5 days. 
 
Figure 4. Study assessments diagram Part B 
 
 
 
The study organization is described in Section 17.3. An independent DSMB periodically reviews 
pertinent study data to protect the safety of the subjects participating in the study.  
 
Part B and the Part C Medically-Led Cardioversion Study also include an optional sub-study 
(only at select EU sites): a Handheld Echo (HHE) Sub-Study, where subjects who consent will 
undergo an additional screening procedure that is a diagnostic echocardiogram using a portable 
HHE device. Details on the HHE Sub-Study can be found in Section 17.5. 
 
Upon completion of Day 1 in Part B, EU 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) are potentially eligible to consent to participate in the Part C 
Patient-Led Under Medical Supervision Cardioversion Study. 
4 B - Study population 
In Part B, approximately 20 sites will participate to enroll approximately 25 subjects who have 
met all of the inclusion and none of the exclusion criteria as described under Sections 4.1 B and 
4.2 B below. 


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4.1 B - Inclusion criteria 
Subjects to be included in the study must meet the following 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. 
4.2 B - Exclusion criteria  
Subjects are NOT eligible to participate in this study if they meet ANY of the following exclusion 
criteria: 
 
General 
1) Subject < 18 or > 85 years of age 
2) Hemodynamic and/or cardiac instability, with systolic blood pressure < 100 mmHg or > 
150 mmHg, or ventricular heart rate < 80 bpm or > 160 bpm. For subjects to meet 
eligibility criteria for Part B or the Part C Medically-Led Cardioversion Study, at least 2 of 
the 3 measurements of vital signs during screening (45, 30, and/or 15 minutes prior to 
dosing) must meet the stated criteria. For subjects to meet eligibility criteria for the Part 
C Patient-Led Under Medical Supervision Cardioversion Study, the measurement of vital 
signs taken within 10 minutes prior to dosing must meet the stated criteria. 


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3) Current AF episode has been 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. 
 
Relevant structural heart disease 
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% 
i) For patients in the US, 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. 
ii) For patients in the EU who are participating in the optional HHE Sub-Study, the 
patient 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 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. 
7) History of myocardial infarction (MI) within 3 months of screening 
8) Known uncorrected severe aortic or mitral valve stenosis. For subjects receiving an HHE 
assessment at screening (refer to exclusion criterion 5), any moderate or severe valvular 
disease noted during the HHE assessment is considered exclusionary. 
9) Hypertrophic cardiomyopathy with outflow tract obstruction. For subjects receiving an 
HHE assessment at screening (refer to exclusion criterion 5), any moderate or severe 
hypertrophy noted during the HHE assessment is considered exclusionary. 
 
Other cardiac conditions 
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 
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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 patients >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 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 
 
Concomitant conditions 
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. 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 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. 
 
Concomitant and study 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, ritonavir, some antihistamines) or CYP 2D6 inducers (e.g. 
phenytoin, phenobarbital, carbamazepine) 


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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 
 
Other 
22) Subject is deemed unsuitable for the trial by the Investigator (including but not limited 
to: patients who are considered at high risk for stroke based on 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 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. 
23) Known drug or alcohol dependence within the past 12 months as judged by the 
Investigator 
24) A body mass index > 40 kg/m2 
25) Legally incompetent to provide informed consent (IC) 
26) Previous treatment in this study (this does not apply to enrollment in the Part C Patient-
Led Under Medical Supervision Cardioversion Study) or previous 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 
a) Who are not surgically sterile, or post-menopausal (defined as no menses for 2 years 
without an alternative cause), or 
b) For whom a negative pregnancy test is unavailable before study entry, or 
c) Who are pregnant or breast feeding at study entry 
28) 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) 
29) 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 
30) Respiratory rate of > 22 breaths per minute 
4.3 B - Screen failures  
Subjects are pre-screened based on the information available from the institutional standard of 
care. For subjects who appear to be candidates for the study based on this available 
information, IC signature and other study-specific screening procedures take place prior to 
enrollment. A subject who withdraws IC before enrollment or who fails to meet 


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inclusion/exclusion criteria before enrollment is defined as a screen failure. No further clinical 
follow-up is performed for screen failed subjects unless they are re-screened and enrolled. 
 
Subjects who are enrolled but who do not receive study drug (e.g., due to spontaneous 
conversion of their AF to SR prior to dosing) are considered early terminations; refer to Section 
5.5 B. 
5 B – Treatment 
5.1 B - Study treatments 
Study treatment in Part B consists of a 120 mg eTLD (2 x 60 mg) FlecIH-103 inhalation solution 
repeat dose regimen. Specific instructions for the administration of study treatments are 
provided to the sites in the Instructions for Use (IFU). Also refer to Section 5.3.4 B for more 
treatment guidelines. 
5.1.1 B - Repeat dose regimen 
'Dose/inhale to conversion’: 
2 x 60 mg eTLD (FlecIH-103) for 120 mg eTLD (75 mg/mL concentration) 
 
Dosing in a 'dose/inhale to conversion' regimen continues until the conversion of AF to SR is 
observed for ≥ 1 minute, or until the assigned dose is completed, whichever comes first. 
5.2 B - Treatment assignment 
After the IC has been signed, the investigational site enters the subject in the eCRF to obtain a 
unique subject identification number (SID) (if not already obtained during pre-study screening). 
Subjects may be enrolled at the end of the AF monitoring period provided they meet all the 
inclusion criteria and none of the exclusion criteria (note, AF monitoring must continue for at 
least 45 minutes prior to dosing, regardless of enrollment time).  
 
Subjects are assigned to a 120 mg eTLD (2 x 60 mg) FlecIH-103 repeat dose regimen (N = 
approximately 25 subjects).  
5.3 B - Identity of study drug(s) 
5.3.1 B – Description 
Study drug is supplied as a 4.7 mL of sterile FlecIH-103 (75 mg/mL flecainide acetate) in a 6-mL 
clear glass vial, with a grey rubber stopper, and sealed with an aluminum crimp. 


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5.3.2 B - Labeling and packaging 
FlecIH-103 is labeled according to the requirements of local regulatory guidelines. Label text is 
approved according to the Sponsor’s procedures. A description of FlecIH-103 is given in Table 1 
below. 
 
A system of numbering in accordance with all requirements of Good Manufacturing Practice 
(GMP) is used, ensuring that each dose of FlecIH-103 can be traced back to the respective bulk 
batch of the ingredients. Lists linking all numbering levels are maintained by the Sponsor. A 
complete record of batch numbers and expiry dates of FlecIH-103 as well as the labels is 
maintained in the Sponsor’s study file. 
 
Table 1 - Identity of investigational drug: FlecIH-103 
 
75 mg/mL concentration 
Active ingredient or INN  
Flecainide acetate 
CAS No. 
54143-56-5 
Material name 
FlecIH-103 (flecainide acetate inhalation solution) 
Dosage(s) 
120 mg: 2 x 60 mg eTLD 
Color of the vial 
Clear 
Composition 
Active ingredient: Flecainide acetate 
 
Excipients: water for injection, Glacial Acetic Acid, hydroxypropyl 
-cyclodextrin, Sodium Saccharin, and Sodium Hydroxide 
Concentration 
75 mg/mL 
Type of packaging 
Glass vial 
Content 
1 sealed vial of 4.7 mL 
 
5.3.3 B – Preparation 
The FlecIH-103 is supplied in glass vials. The clinical site will prepare the dose to be 
administered by withdrawing the required volume of the study drug from the vial(s) using a 
syringe with needle and then dispensing the study drug into the nebulizer cup(s). In order to 
maintain sterility, the study drug must be administered within 4 hours of dispensation into the 
nebulizer cup. Detailed instructions for dose preparation are outlined in the Pharmacy Manual.  
5.3.4 B – Administration 
Subjects will be dosed with 120 mg eTLD (2 x 60 mg) FlecIH-103 (75 mg/mL) inhalation solution: 
2 inhalations of 3.5 minutes each, separated by a 1-minute break ('dose/inhale to conversion').  
Dosing in a 'dose/inhale to conversion' regimen continues until the conversion of AF to SR is 
observed for ≥ 1 minute, or until the full dose is completed, whichever comes first. 
 
For the administration of study drug, the following procedures are to be performed: 


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1. The subject must be seated in an upright position in a chair or adjustable bed from 
approximately 30 minutes prior to the start of inhalation up to completion of dosing, 
at which point subjects may return to a semi-recumbent position. A height-
adjustable table must be placed in front of the subject (e.g., overbed table on 
casters), whereby the subject can rest his/her arms during the inhalation regimen. 
The set up at the site will allow for subject to remain in this upright sitting position 
while connected to the cardiac monitoring system and while blood samples are 
collected during the self-administration of the inhalation solution.  
NOTE: Subjects may be placed in a semi-recumbent, supine, or other position as 
needed for an adverse event, at the discretion of the investigator. These occurrences 
will not constitute a protocol deviation. 
2. The subject is given instructions from study personnel on how to inhale the study 
drug according to the IFU.  
3. The subject is required to use a nose clip to seal off their nostrils during inhalation, 
unless the subject refuses. 
4. The subject may practice the inhalation procedure (without flecainide) prior to 
starting the inhalation of study drug. 
5. The inhaler must be connected to medical compressed air that is set at a steady flow 
rate of 5 L/min.  
6. The subject shall be informed prior to the start of the inhalation about the potential 
to experience throat discomfort, bad taste, and the impact of the sensation caused 
by the vapors being inhaled.  
7. If not contraindicated, a topical oral anesthetic (e.g., containing lidocaine or phenol) 
spray (e.g., Medica, Chloraseptic) or lozenge (e.g., Trachitol, Cepacol) may be used by 
the subject to prophylactically mitigate the discomfort or pain associated with the 
inhalation and thereby improve the tolerability. 
8. The subject inhales the study drug using a fully assembled AeroEclipse® II BAN 
provided by the study nurse. 
9. Site staff shall closely observe the subject during inhalation to ensure that the 
subject only inhales and exhales through the mouth. 
10. Once the inhalation rhythm is established, the subject should not remove the 
mouthpiece of the inhaler from the mouth during the entire inhalation time. If the 
subject removes the mouthpiece of the inhaler from their mouth for any 
reason/cause (e.g., cough, excessive saliva, etc.) and the inhalation is interrupted for 
> 30 seconds, then the inhalation time may be extended by the duration of the 
interruption if conversion of AF to SR is not achieved during inhalation. During the 
entire inhalation procedure, the nurses shall remain vigilant and ready to assist the 
subjects to successfully complete each inhalation period.  
11. Once conversion of AF to SR is observed on telemetry, the time of the observation 
should be recorded as the time of conversion; however, the subject must continue 
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for ≥ 1 minute, the subject should continue dosing according to the assigned regimen 
and conversion to SR will not be reported. 
12. The subject’s right to early terminate inhalation of study drug, for whatever 
reason/cause, shall not be infringed upon. 
13. If a subject experiences difficulty in following the instructions for the inhalation 
procedure, this must be recorded in the eCRF along with the reason.  
14. If an unexpected event is observed during the inhalation procedure, this 
event/observation must be recorded in the eCRF (e.g., liquid dripping from the 
inhaler, fugitive aerosol, etc.). 
 
Additional instructions for the inhalation of the study drug are provided to the sites in the IFU.   
5.3.5 B – Shipment, receipt and storage 
When a drug shipment is received, the Investigator or designee must check the amount and 
condition of the drug, check for appropriate local language on the label, check the drug 
expiration date, and provide confirmation of receipt of the study drug. Problems with drug 
shipments must be reported to the site Monitor as soon as possible. 
 
Drug supplies are stored at the investigational site in accordance with GCP and GMP and must 
be stored in a secure, limited-access storage area protected from light and under the 
recommended storage conditions. All drug supplies shall be stored at 15°C to 25°C (59°F to 
77°F) as measured by a min/max thermometer. Excursions to 2°C to 40°C (36°F to 104°F) 
shorter than a week in duration are permitted. Excursions to 30°C at the site are allowed in 
accordance with USP <659> guidance. Temperature measurement shall be recorded daily on a 
temperature log, excluding weekends and holidays. The Sponsor must be notified as soon as 
possible in the event of any temperature excursion, with the exception of those permitted as 
described above. The site-relevant elements of special storage conditions, complete batch 
numbers, and expiry dates are available in the Investigator site file. 
5.3.6 B - Drug accountability 
Inhalation of study drug is performed under Principal Investigator (PI) or designee supervision.  
Pertinent information and data on the administration of study drug shall be captured by the 
site staff in the eCRF. All materials supplied, namely study drug and hand-held inhaler device 
(AeroEclipse® II BAN), are intended for use in this study only and shall not be used for any other 
purpose. 
 
The PI or designated trained site staff are responsible for assuring the retrieval of all study 
supplies needed for the subjects. The pharmacy dispenses the study drug and the Investigator 
oversees the subject’s inhalation and ensures the study drug is only administered according to 
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Study drug administration is documented in the relevant module of the eCRF and other study 
drug records. The PI at the site is responsible for oversight of the investigational product 
accountability, reconciliation and record maintenance at the investigational site. In accordance 
with all applicable regulatory requirements, the PI and/or designated trained staff at each site 
must maintain investigational product accountability records throughout the course of the 
study. The amount of investigational product received, administered to study subjects and 
unused must be documented in study records. Following drug accountability and reconciliation 
by the Monitor, destruction (if any) of study drugs must be properly documented according to 
the Sponsor’s specified procedures. Re-supply of study drug is made upon request to the 
investigational product supply vendor. The drug accountability process is described in further 
detail separately in the Pharmacy Manual. Written instructions on medication destruction are 
made available to the clinical sites as applicable. 
5.4 B – Non-study therapy 
5.4.1 B - Prior and concomitant medication 
Prior medications that the subject has taken within 30 days of enrollment and the subject’s 
alcohol use are recorded in the eCRF. Medications taken by the subject prior to enrollment or 
at any time during the study, including adjunct therapy or medical devices, are regarded as 
prior and/or concomitant medications/treatments and must be documented on the 
appropriate pages of the eCRF throughout the study and until the final contact with the subject, 
i.e., EOS.  
 
If the subject experiences an AE, information on concomitant medications taken within the past 
30 days needs to be evaluated when considering causal relationship (Section 17.2.2.3). 
 
The concomitant use of Class II and Class IV AADs, i.e. beta-blockers and calcium channel 
blockers is allowed throughout the study. 
 
Concomitant use of the following therapies is not allowed: 
- 
Treatment with Class I and any Class III AADs within 1 week before enrollment (except 
Amiodarone, which is not allowed within 12 weeks before enrollment); 
- 
Concomitant pharmacological or electrical cardioversion up to 90 minutes post 
completion of dosing; refer to Section 5.4.2 B; 
- 
Concomitant treatment with sotalol, procainamide or ibutilide is not allowed 
throughout the study; 
- 
Concomitant systemic treatment with drugs that are strong inhibitors of CYP2D6 (e.g., 
antidepressants, neuroleptics, propranolol, ritonavir, some antihistamines) or CYP 2D6 
inducers (e.g., phenytoin, phenobarbital, carbamazepine); 
- 
Investigational drugs (other than the study treatment regimen) 
- 
Bronchodilators from time of consent to start of inhalation of the study drug 


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5.4.2 B - Post-dose regimen therapy and medication 
The Investigator may offer an alternative treatment after 90 minutes post dose, within the 
institutional standard of care and in accordance with Section 5.4.1 B above, to subjects without 
conversion of AF to SR. The choice of the treatment is guided by subject-specific factors and 
subject preferences and is left at the discretion of the treating physician and to subject’s 
approval with the exception of sotalol, procainamide or ibutilide, which are not allowed 
throughout the study. Alternate therapy in accordance with the guidelines above may be given 
as early 60 minutes pose dose only if deemed medically necessary by the investigator not to 
wait until 90 minutes post dose; however, IV flecainide and propafenone may not be 
administered until at least 90 minutes post dose. 
5.4.3 B – Other recommendations 
Exercise: Subjects shall refrain from strenuous activity for the duration of the study (i.e., until 
completion of Day 5 assessments [EOS]). 
 
Caffeine and alcohol: Subjects are instructed to abstain from caffeine and alcohol for the 
duration of the study (i.e., until completion of Day 5 assessments [EOS]). 
 
Fasting: After providing IC, subjects should remain fasting in order to facilitate anesthesia care, 
if deemed necessary if no conversion to SR occurs within 90 minutes post dose. This is 
particularly relevant for sites that may consider performing an electrical cardioversion, as per 
their institutional standard of care. 
5.5 B – Discontinuation Criteria 
Subjects who are enrolled but who do not receive study drug (e.g., due to spontaneous 
conversion of their AF to SR prior to dosing) are considered early terminations. The subjects 
may be replaced and can re-screen for the study.  
 
At any time during the study and without giving reasons, a subject may decline completion of 
the assigned study treatment. Study treatment may also be discontinued at the discretion of 
the Investigator as deemed appropriate for safety and/or if the subject’s medical condition 
contraindicates further study treatment. 
 
Follow-up and data collection continue until EOS for all enrolled subjects who received study 
drug, unless the subject explicitly withdraws consent for further clinical follow-up and data 
collection. If a subject withdraws consent for further collection of study data, their data up to 
that point are evaluated, and the reason for the termination is recorded in the eCRF. If 
termination of treatment or of clinical follow-up is a result of an AE or death, the AE must be 
recorded in the eCRF, including any changes in concomitant medications. 
 


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For subjects who cannot be located for their follow-up contacts, every reasonable effort must 
be made to make contact. The subject is considered “lost to follow-up” when contact with the 
subject has been lost without completing Day 5, and every attempt to contact has failed. Final 
documentation regarding all attempts to contact the subject shall be documented in the 
subject source records. All premature terminations of either study treatment or of clinical 
follow-up are tabulated and reported. 
 
A subject’s decision to withdraw from the study and/or to disallow further clinical follow-up is 
acceptable for any reason, without prejudice or detriment to their medical care, and the 
subject will not suffer any disadvantage as a result. 
 
An excessive rate of subjects who withdraw consent or subjects lost-to-follow-up could render 
the study difficult to interpret. Hence, unnecessary withdrawal of subjects shall be avoided. 
Should a subject withdraw or be withdrawn, every effort must be made to contact the subject 
for a final follow up. 
 
The Sponsor has the right to terminate the study, any part of the study, or the HHE Sub-Study 
at any time. In this event, the investigator(s) and relevant authorities will be informed of the 
reason for study termination. 
6 B - Study procedures 
The study is divided into the following periods: screening, treatment, extended observation, 
and follow-up. Subjects with an episode of recent onset, symptomatic AF (either their first 
episode, a recurrent episode of paroxysmal AF, or an episode post-ablation for paroxysmal AF) 
that requires acute conversion of AF to SR, without known relevant structural heart disease, 
and without contraindications to flecainide, are evaluated for potential participation in this 
study (included in screening). Additionally, select subjects who are not currently experiencing 
an episode of recent onset, symptomatic AF may sign a pre-study screening consent to 
determine their eligibility to participate in the study in the future (a recurrent episode of AF) by 
performing screening assessments (refer to Section 6.1.2.1 B).  
 
Part B and the Part C Medically-Led Cardioversion Study also contain an optional Handheld 
Echo Sub-Study (only at select EU sites). Subjects who consent will have an additional screening 
procedure and will be evaluated with a portable ultrasound device to obtain an HHE. More 
details on the Handheld Echo Sub-Study can be found in Section 17.5. 
 
All medications used in the study and the hand-held inhaler device are provided by the 
Sponsor. Details on drug accountability are provided in Section 5.3.6 B. 
 
 
 


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Windows for PK blood draws and vital signs assessments 
Where PK blood draws and vital signs assessments coincide at scheduled time points, PK blood 
draws are prioritized and must occur at the protocol-specified time point (with the exception of 
the 60 minutes post dose time point, which may be collected within a ± 5-minute window, and 
the 90 minutes post dose time point, which may be collected within a ± 10-minute window). 
Vital signs shall be collected as close as possible to the scheduled time point after the PK blood 
draw is completed. As vital signs assessments coincide with PK blood draws, any deviations 
from the protocol-required time points for vital signs will not be recorded as protocol 
deviations. Any missed vital signs assessments will be recorded as protocol deviations. 
 
Discharge window 
Discharge is left to the discretion of the Investigator, but may not occur before 90 minutes post 
dose, with a -10-minute window allowed. Because discharge may occur, at the earliest, at 80 
minutes post dose due to the window, all 90-minute post dose study assessments also have a 
±10-minute window (may be performed between 80 and 100 minutes post dose, inclusive). 
 
For the Schedule of Assessments please refer to Appendix 4. 
6.1 B – Screening period 
6.1.1 B - Screening 
The Investigator or designee identifies patients who may be potential candidates for the study 
by reviewing: 
- 
Recent history of paroxysmal AF; 
- 
Other targeted medical/surgical history; 
- 
Medication history over the past 30 days, including prescription drugs and alcohol use; 
- 
Other inclusion and exclusion criteria assessable by routinely available clinical 
information. 
 
This review is based on clinical information routinely available at the time of screening. 
6.1.2 B - Informed consent (IC) 
6.1.2.1 B - Pre-study screening IC (for select subjects) 
Subjects who: 
- 
are prescribed a pill-in-the-pocket regimen (flecainide or propafenone) for 
paroxysmal AF, or 
- 
are within 3 months of undergoing ablation for paroxysmal AF but who are not 
currently experiencing an episode of recent-onset paroxysmal AF, or 


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- 
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 sign a pre-screening consent to determine their eligibility to participate in the study by 
performing selected screening assessments. The selected assessments include a review of 
medical history to confirm that the subject does not meet certain exclusion criteria. The subject 
will also receive training and practice with the inhaler without any study drug. The subject may 
withdraw or be withdrawn from pre-study screening at any time. 
 
The care of these pre-study screening subjects should be as per institutional standard of care. 
During the pre-study screening, to be eligible, subjects cannot be treated with Class I or Class III 
AADs within the last week, or with amiodarone in the last 12 weeks, as per the protocol (refer 
to Section 5.4.1 B). 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. 
 
The subject may use their own or a site-provided personal cardiac monitoring device to self-
monitor for recurrence of AF as per institutional standard of care and if permitted by local 
regulations. Site staff is encouraged to contact the subject approximately monthly to review the 
subject's status. AEs will not be collected for pre-study screening subjects. If the subject returns 
to clinic for a visit with the Investigator (related or unrelated to the study), repeat training and 
practice with the inhaler should be performed if possible.  
 
When the subject presents with recent-onset (≥ 1 to ≤ 48 hours) symptomatic AF, they may sign 
the IC for Part B and complete all remaining screening assessments (e.g., laboratory tests, AF 
monitoring, etc.) to determine eligibility criteria prior to study enrollment on Day 1. Only after 
confirming that they fulfill all the inclusion and exclusion criteria, may the subject be enrolled in 
the study to receive study drug. 
6.1.2.2 B - Study IC (for all symptomatic subjects presenting with paroxysmal AF) 
Signature of IC is always preceded by subject’s qualification during screening which is based on 
clinical information routinely available. Only after the IC is signed does the subject undergo any 
study-specific procedures. Informed consent for Part B may only be obtained after the subject 
presents with symptomatic AF. 


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6.1.2.3 B - Handheld Echo Sub-Study IC  
Only at select EU sites, subjects may consent to an optional Handheld Echo Sub-Study during 
screening on Day 1 after consenting to participate in Part B or the Part C Medically-Led 
Cardioversion Study. Refer to Section 17.5 for details on the Sub-Study. 
6.1.2.4 B – Optional Part C Patient-Led Under Medical Supervision Cardioversion 
Study IC 
Subjects in EU whose AF is converted to SR within 90 minutes of inhalation of study drug 
without an alternative therapy in Part B and who did not experience difficulties or issues with 
inhalation (in the opinion of the investigator), serious AE(s) or serious AESIs may be eligible for 
participation in the Part C Patient-Led Under Medical Supervision Cardioversion Study. Eligible 
subjects may consent to the study after successful conversion of AF to SR during Part B.  
6.1.3 B - AF-monitoring 
The AF-monitoring period is part of screening. The following procedures are performed by the 
Investigator or trained and qualified study staff after IC for the study has been obtained to 
determine subject eligibility for enrollment: 
o A physical exam including auscultation of the heart and of the lungs is performed 
and height, weight, and temperature are recorded; 
o A diagnostic echocardiogram is obtained using a handheld portable ultrasound 
device if:  
 (US subjects only) the subject does not have results from a standard 
diagnostic echocardiogram (including LVEF) within 180 days prior to 
screening 
 (EU subjects only) the subject has consented to the HHE Sub-Study; 
o An IV catheter/cannula for blood sample draws is placed (please refer to detailed 
instructions of sample collection in the Laboratory Manual); 
o Blood samples are drawn for clinical local laboratory assessment including: 
hematology panel, comprehensive metabolic panel, coagulation panel and a serum 
pregnancy test for women of childbearing potential (a urine pregnancy test may be 
collected instead of serum; see details under Section 9.2 B). A blood draw for 
assessment of potassium must always be drawn after informed consent and prior 
to enrollment; however, if results are available for any or all other parameters 
from a blood draw prior to screening (up to 24 hours prior to IC), there is no need 
for a new blood draw for those parameters; 
o A single source for the time of all assessments shall be utilized for each patient. For 
example, if telemetry is used, all assessments for that patient must be recorded 
from the same telemetry unit. All times shall be reported in a 24-hour format. 
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match the date and time of the device used for capturing the time of all 
assessments, for each subject;  
o A baseline remote ECG event recording is obtained prior to connecting the subject 
to the AECG (12-lead Holter); 
o The subject is connected to site cardiac telemetry and study AECG (12-lead Holter) 
approximately 45 minutes prior to the planned start of study drug administration, 
if not already connected; 
o The subject is seated in an upright position approximately 15 minutes prior to the 
start of inhalation and after the 30-minute pre-dose time point assessments are 
completed (refer to Section 5.3.4 B);  
NOTE: For the medication to be effectively delivered into the lungs, the subject 
must be seated in an upright position;  
NOTE: When subject changes their position from seated to semi-recumbent or vice 
versa, the subject must be allowed time to stabilize in the new position for about 
10 minutes for PD assessments; 
o Vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate 
(breaths/min) and oxygen saturation) are collected from telemetry at 45 (semi-
recumbent), 30 (semi-recumbent), and 15 (seated upright) minutes prior to the 
start of study drug.  
 For vital signs where 3 measurements are required during screening, at 
least 2 of the 3 assessments during screening must be within the eligibility 
requirements. Additionally, these criteria shall be rechecked at T0 for 
confirmation of eligibility prior to dosing. If the T0 assessment is not within 
eligibility requirements, subject is not eligible to receive the study drug and 
will be early terminated. 
 
Triplicate 12-lead ECG readings are extracted from the AECG (12-lead Holter) recording by the 
ECG Core Laboratory for the 45-, 30-, and 15-minute pre-dose time points after receipt of the 
data. 
 
Adverse events and concomitant medications are continually assessed and recorded from time 
of IC through EOS. 
6.1.4 B – Allocation 
Refer to Section 5.2 B for a description of the treatment assignment process. 
 
While the study drug is being retrieved, the Investigator or designee shall train the subject in 
the use of the inhaler (AeroEclipse II BAN) as described in the IFU. The subject shall remain 
seated in an upright position in a chair or adjustable bed with a height-adjustable table on 
wheels in front (e.g., overbed table on casters). 


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6.2 B – Treatment period 
The Treatment Period comprises the time from T0 (start of the first inhalation) to 60 minutes 
post dose. 
6.2.1 B - Study treatment 
Before dosing 
The subject must be predominantly in AF (i.e., no other arrhythmias [e.g., VT, atrial flutter] and 
no conversion to SR ≥ 1 minute) during the 45-minute AF monitoring period. Once this is 
confirmed and just before the subject is ready to initiate the inhalation of the study drug (T0), 
the following baseline measurements are performed: 
o a PK blood sample is drawn (this may be drawn up to 45 minutes prior to initiation 
of study drug after enrollment); 
o vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate 
[breaths/min] and oxygen saturation) are collected from telemetry; 
 If the T0 vital signs assessment is not within eligibility requirements, subject 
is not eligible to receive the study drug and will be early terminated. 
o The subject's AF-related symptoms are recorded; 
 
Triplicate 12-lead ECG readings are also extracted from the AECG (12-lead Holter) recording by 
the ECG Core Laboratory after receipt of the data. 
 
The Investigator or designee prepares the inhaler. 
 
After completion of the baseline measurements as described above, the Investigator verifies 
whether the subject is still in AF. Study inhalation is not started in subjects who have 
spontaneously converted to SR or are in a heart rhythm other than AF.  
 
During dosing 
Subjects will 'dose/inhale to conversion'. 
 
The following procedures are performed during the 1-minute break in between inhalations: 
o a PK blood sample is drawn; 
o Vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate 
(breaths/min) and oxygen saturation) are collected from telemetry; 
o Triplicate 12-lead ECG readings are extracted from the AECG (12-lead Holter) 
recording by the ECG Core Laboratory after receipt of the data. 
 
Used inhalers are disposed according to local hospital procedures. 
 


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The Investigator may terminate the subject's inhalation of study drug earlier in the event of any 
clinically significant arrhythmias (e.g., bradycardia, frequent PVCs, non-sustained VT, or 
sustained VT or ventricular fibrillation [VF]) or other life-threatening or serious adverse 
reactions (e.g., hypotension). The subject may also stop the inhalation of study drug early as 
defined under Section 5.5 B. 
 
No other pharmacological or electrical cardioversion may be attempted until at least 90 
minutes post dose. Alternate therapy may be given as early 60 minutes pose dose only if 
deemed medically necessary by the investigator not to wait until 90 minutes post dose; 
however, IV flecainide and propafenone may not be administered until at least 90 minutes post 
dose. An exception to the above guidance is in case of an SAE, that requires an immediate 
treatment as per the discretion of the Investigator.  Subjects remain on rhythm monitoring (i.e., 
cardiac telemetry and study AECG [12-lead Holter]) during dosing and for the entire duration of 
Day 1, including the observation period. 
 
After dosing 
After administration of the study drug regimen is complete, the following procedures are 
performed: 
o a PK blood sample is drawn;  
o vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate 
(breaths/min) and oxygen saturation) are collected from telemetry; 
o Triplicate 12-lead ECG readings are extracted from the AECG (12-lead Holter) 
recording by the ECG Core Laboratory after receipt of the data. 
 
The procedures above are performed at: TX (1, 3, 10, and 30 minutes post dose) and at 
conversion to SR. 
 
The subject may return to a semi-recumbent position after completion of dosing. 
 
The subject’s AF-related symptoms at 30 minutes post dose are recorded. 
6.2.1.1 B - Subjects without conversion of AF to SR 
The Investigator may offer an alternative treatment, within the standard of care, to subjects 
without conversion of AF to SR, in accordance with Section 5.4.2 B.  
6.3 B – Extended observation period 
The extended observation period starts at 60 minutes post dose and lasts until 90 minutes post 
dose. During this period, subjects remain connected to rhythm monitoring (i.e., cardiac 
telemetry and study AECG [12-lead Holter]). 
 


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After administration of the study drug regimen is complete, vital signs (heart rate, systolic and 
diastolic blood pressure, respiratory rate (breaths/min) and oxygen saturation) are collected 
from telemetry at 60 and 90 minutes post dose. 
 
Triplicate 12-lead ECG readings are extracted from the AECG (12-lead Holter) recording by the 
ECG Core Laboratory for the time points above after receipt of the data. 
 
A PK blood sample is drawn at 60 and 90 minutes post dose. 
 
A comprehensive metabolic panel blood sample is drawn for the clinical local laboratory 
assessment at 90 minutes post dose. 
 
The subject’s AF-related symptoms are recorded at 60 and 90 minutes post dose. 
 
After 90 minutes post dose and prior to discharge, subjects whose AF converted to SR due to 
the study drug (converted within 90 minutes post dose without any alternative treatment) will 
be asked questions about their treatment satisfaction (refer to Section 7.4 B). 
6.3.1 B - Discharge 
Discharge is left to the discretion of the treating physician 90 minutes post dose (— (minus) 10-
minute window). At discharge a plan for the Day 2 and Day 5 follow-up study contacts is made 
with the subject. 
 
Once the study AECG (12-lead Holter) has been disconnected, a single reading using the remote 
ECG Event Recorder is performed. Before discharge, the Investigator trains each subject in the 
use of the remote ECG Event Recorder as described in Section 7.2 B. 
 
The subject’s primary care provider (PCP) is informed of the subject’s participation in the trial 
by means of a letter from the Investigator. Information is included on the subject's treatment 
regimen as well as on specific clinical assessments (i.e., medical contacts for AF-related 
complaints) that must come to the attention of the investigational study center until EOS. 
6.4 B - Follow-up period 
6.4.1 B – Telephone assessment (Visit 1): Day 2 
The following procedures are completed during a pre-scheduled Day 2 telephone contact: 
o Review of concomitant medications/treatments; 
o Assessment of AEs; 
o Assessment of AF-status (any recurrence); 
o Assessment of the status of the subject’s AF symptoms; 
o Reminder to the subject to collect a remote ECG recording. 


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6.4.2 B – Telephone assessment (Visit 2): Day 5 ± 1 day 
Day 5 is the final subject contact and marks the EOS for Part B and may be completed within a ± 
1 day window. The following procedures are completed during a pre-scheduled Day 5 
telephone contact.  
o Review of concomitant medications/treatments; 
o Assessment of AEs; 
o Assessment of AF-status (any recurrence); 
o Assessment of the status of the subject’s AF symptoms; 
o Reminder to the subject to collect a remote ECG recording; 
o Instruction of the subject to return the remote ECG device to the site using the 
courier service or return instructions provided. 
6.4.3 B – End-of-study (EOS) definition 
All subjects in Part B have a final visit (telephone contact) planned at approximately 4 days after 
enrollment (Day 5 = EOS). For EU subjects continuing into the Part C Patient-Led Under Medical 
Supervision Cardioversion Study, EOS occurs on Day 5 following treatment of a recurrent 
episode of AF, or 8 months following informed consent for the Patient-Led Under Medical 
Supervision Cardioversion Study, whichever comes first. 
7 B - Efficacy assessments and endpoints 
7.1 B – Rhythm monitoring assessments 
Subjects are connected to the AECG system (12-lead Holter) after signature of IC is obtained 
and at least 45 minutes prior to dosing until 90 minutes post dose. Remote ECG Event 
Recordings are performed according to the Schedule of Assessments. Anonymized ECG 
recordings are analyzed centrally by the ECG Core Laboratory. Further detail may be found in 
separate instructions provided. 
7.2 B – Rhythm status assessments 
Remote ECG event recordings are performed according to the ECG Core Laboratory acquisition 
manual and following the study Schedule of Assessments. 
 
- 
Recording #1: at the start of AF monitoring period before the AECG system is connected; 
- 
Recording #2: at the end of the extended observation period after the AECG system is 
disconnected; 
- 
Recording #3: on Day 2 (+1 day) at home (e.g., during the follow-up telephone 
assessment [Visit 1]); 
- 
Recording #4: on Day 5 (± 1 day) at home (e.g., during the follow-up telephone 
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The site staff will train each subject in the use of the remote ECG Event Recorder according to 
separate instructions provided.  
7.3 B - AF-related symptoms 
Before enrollment, subjects are queried about the absence or presence of each of the following 
AF-related symptoms: 
- 
Palpitations, i.e., sensation of a racing, uncomfortable, irregular heartbeat or a flip-
flopping in your chest 
- 
Lightheadedness or dizziness 
- 
Shortness of breath or dyspnea 
- 
Chest discomfort 
 
At 30, 60, and 90 minutes post dose, subjects are again queried about each of these individual 
symptoms in terms of “no symptoms, improved, unchanged or worsened” as compared to 
baseline.  
 
During the Day 2 and Day 5 telephone assessments, the subject is again queried on the status of 
each of these individual AF symptoms as compared to baseline.  
7.4 B - Treatment satisfaction questions 
After 90 minutes post dose and prior to discharge, subjects whose AF converted to SR due to 
study drug (i.e., converted within 90 minutes post dose without any alternative treatment) are 
asked the following questions regarding their treatment satisfaction: 
o If offered, would you take the study treatment again in the future? 
o On a scale of 1 to 10 (1 being very dissatisfied and 10 being very satisfied), how 
satisfied were you with the study treatment? 
7.5 B - Study endpoint(s) 
7.5.1 B - Primary endpoint 
The primary efficacy endpoint is the proportion of subjects whose AF converted to SR by 
inhaled flecainide within 90 minutes after initiation of dosing. Conversion of AF to SR is defined 
as the presence of SR lasting for at least 1 minute.  
7.5.2 B - Secondary endpoints 
The secondary efficacy endpoints are: 
• 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 
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• 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 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 study drug and 
completion of study drug. 
 
The secondary safety endpoint is the incidence of treatment emergent serious adverse events 
of interest for flecainide 
7.5.3 B - Exploratory endpoints 
The exploratory endpoints (for the HHE) are:  
• 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 
 
The HHE data will be submitted to an independent reviewer to compare with the HHE 
assessments made by the site staff during the screening period; however, this independent 
review will not be used for the assessment of subject eligibility during screening. This 
independent review will only be used to explore if site staff made a successful assessment of 
subject eligibility using the HHE data obtained during screening. 
8 B - Other assessments 
8.1 B - Pharmacokinetic (PK) assessment(s) 
Whole blood samples of about 4.0 mL are collected for measurement of plasma concentrations 
of flecainide acetate components as specified in the Schedule of Assessments (Section 17.4). 
Dense sampling occurs only over a 90-minute period on Day 1 (day of dosing). 
 
 
 


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Sample collection times are as follows: 
1. Pre-dose inhalation: TPre (any time up to 45 minutes prior to dosing and after treatment 
assignment) 
2. During dose regimen administration: Tbetween admin (in the 1-minute break in between 
inhalations), if applicable 
3. At the time of conversion to SR: TSR.  A PK sample shall be taken at SR regardless of method 
of conversion.  If conversion is, for example, by ECV, the PK sample should be taken at the 
earliest time feasible. 
4. After administration of the study drug regimen is complete: Tx (1, 3, 10, 30, 60 and 90 
minutes post dose).   
 
When time points coincide for blood draw and vital signs assessments, procedures should be 
performed in said order. 
 
Instructions for the collection, processing, storage and shipping of biological samples are 
provided in the Laboratory Manual. 
 
Plasma samples are assayed by a validated LC/MS/MS method, which is specific for the 
determination of flecainide acetate components and used to evaluate the PK parameters.  
 
No genetic analyses are to be performed on these plasma/whole blood samples.  
 
Subject confidentiality is maintained at all times. 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) are informed of any 
safety issues that require alteration of the safety monitoring scheme or amendment of the IC. 
8.2 B - Pharmacodynamic (PD) assessment(s) 
To evaluate the electrocardiographic effects of inhaled flecainide under oral inhalation dosing 
regimens in subjects with recent onset of paroxysmal AF, which are detectable on 12-lead ECG 
recordings mainly by assessing the following PD variables: PR, QRS, and QT intervals. 
 
ECGs are reviewed by an independent ECG Core Laboratory. Triplicate ECGs will be extracted 
from the recorded AECG (Holter) data transmitted by the site to the ECG Core Laboratory 
according to the Schedule of Assessments (Section 17.4). 12-lead ECGs will be extracted at or 
after each specified time point (up to 5 minutes after the specified time point or up to the next 
scheduled time point, whichever comes first).  The triplicate 12-lead ECG extractions are over-
read on the same lead by the same ECG Core Laboratory reader. 
 
Extraction time points for ECG recordings under both regimens are as follows: 
1. Pre-dose inhalation: TPre - at -45, -30 and -15 minutes 
2. Just before the start of inhalation:  TAdmin  


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3. During dose regimen administration:  Tbetween admin (in the 1-minute break in between 
inhalations) 
4. At the time of conversion to SR: TSR 
5. After administration of study drug regimen is complete: Tx (1, 3, 10, 30, 60, and 90 minutes 
post dose) 
 
Details of the ECG Core Laboratory analyses are included in the Core Laboratory analysis plan. 
At a minimum, the following ECG parameters are determined for each ECG recording: 
- 
Heart rate (HR) 
- 
RR interval 
- 
PR interval 
- 
QRS duration 
- 
QTcF duration 
- 
JTc duration (QTc-QRS) 
 
ECGs extracted from the 12-lead Holter are provided to Investigators for filing in the subject's 
source records. Any original ECG recordings obtained at the site must also be stored in the 
subject’s source records. 
9 B - Safety evaluation and reporting 
9.1 B - Adverse events  
Refer to the definitions for AEs and SAEs in Section 17.2.1. The clinical safety of inhaled 
flecainide is evaluated by the frequency of treatment emergent AEs and SAEs. Treatment 
emergent SAEs (TESAE) are those SAEs defined as following dose administration.  
 
Safety and tolerability of inhaled flecainide is further evaluated by collection of the following 
measurements performed according to the Schedule of Assessments (Section 17.4): 
- 
Monitoring of AEs, SAEs and AEs/SAEs of special interest (AESIs/SAESIs) 
- 
Physical examinations 
- 
Vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate and oxygen 
saturation) 
- 
Routine ECGs or 10-second printouts of telemetry rhythm strip performed for safety 
purposes are printed and reviewed on-site 
- 
Continuous telemetry 
- 
Pulmonary function by lung auscultation and oxygen saturation 
- 
Clinical local laboratory assessment (including hematology, comprehensive metabolic 
and coagulation panel) 
 
Recurrent AF will not be considered an AE as it is an expected event in this patient population. 
Recurrence of AF will be captured in a separate eCRF.  


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9.1.1 B - Adverse event collection and reporting 
All AEs occurring after signature of the study IC and until the EOS are recorded in the eCRF 
according to the definitions and classifications described under Section 17.2.1. All AEs must be 
recorded and reported, including AEs that occur during the administration of other drugs. Even 
if the subject has not yet received the study drug, untoward medical occurrences shall be 
treated as AEs. After the EOS contact, there is no requirement to actively collect AEs, including 
deaths. 
 
All laboratory results and vital signs are to be evaluated by the Investigator for clinical 
significance. Isolated abnormal laboratory results or vital signs findings that are not part of a 
diagnosis and are considered clinically significant shall be reported as AEs. Medical conditions 
(including laboratory values/vital signs that are out of range) that were diagnosed or known to 
exist prior to IC are recorded as medical history. 
 
Adverse events may be directly observed, reported spontaneously by the subject, or reported 
by the subjects after being questioned by study staff. Holter, ECG and Event Recorder reports 
may also be used as source to identify AEs. Subjects shall be questioned in a general way, 
without asking about the occurrence of any specific symptoms. The Investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 17.2.1. The Investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature. 
 
All SAEs recorded on the AE eCRF page, that meet seriousness criteria (see Section 17.2.1.2) or 
that meet the criteria for AESI (serious or non-serious; see Section 9.1.2 B) must be reported 
within 24 hours of the Investigator’s awareness. If all the required information is not available, 
the information which is available is to be recorded without delay (within 24 hours), and the 
outstanding data recorded as soon as available thereafter. Responses to queries related to the 
reported SAE or AESI must be provided as soon as possible. 
 
In case of an occurrence of an AE, the Investigator must ensure appropriate medical treatment 
and shall decide whether to discontinue or interrupt the study drug, as applicable. 
 
For each SAE, a separate assessment for expectedness, seriousness, and causal relationship to 
study drug is performed by the Sponsor in addition to the assessment from the Investigator. 
 
The Investigator is responsible for continuous monitoring of all SAEs (whether or not related to 
study drug) until resolution or until the event is considered chronic and/or stable by the 
Investigator and/or other physician who has the responsibility for the subject’s medical care. 
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as new significant information becomes available and within 24 hours of the Investigator's 
awareness of the event.  
 
For all EU subjects who consent to the Part C Patient-Led Under Medical Supervision 
Cardioversion Study, AEs will continue to be collected until the subject withdraws or is 
withdrawn, or until EOS (Day 5 after treatment for a recurrent episode of AF or 8 months after 
signing informed consent for the Part C Patient-Led Under Medical Supervision Cardioversion 
Study, whichever comes first). 
9.1.2 B - Events of special interest 
The following AESIs (even if classified as non-serious) will be reported within 24 hours of the 
Investigator’s awareness by recording them on the AE page of the eCRF. 
9.1.2.1 B – AEs related to inhalation device 
Events related to the inhalation device (AeroEclipse® II BAN) are considered AESI. All AEs 
related to inhalation device are followed to conclusion to determine their outcome. Inhalation 
devices associated with AESIs are to be retained and returned to the Sponsor for further 
evaluation as appropriate. 
9.1.2.2 B - Pregnancies 
Any female study subject or female partner of a study subject that becomes pregnant while 
participating in this study must be reported within 24 hours of the Investigator’s awareness. All 
pregnancies must be followed to conclusion to determine their outcome. This information is 
important for both drug safety and public health concerns. The Investigator shall contact the 
Medical Monitor to discuss subject management.  
9.1.2.3 B - AEs known to be related to other flecainide formulations (i.e., IV and oral) 
The following events are known to be related to other formulations of flecainide (i.e., IV and 
oral) and are considered AESI if they occur after the initiation of study drug. These events will 
be monitored closely and will be followed to conclusion to determine their outcome. 
- 
Hypotension: an acute hypotensive episode (AHE) is a sudden drop in BP resulting in a 
BP < 90/60 mmHg (MAP < 70 mmHg) that lasts for at least 5 minutes and is based on 
multiple sequential readings (≥ 3). MAP is calculated as 1/3 (SBP – DBP) + DBP.  
- 
Ventricular tachycardia ≥ 3 beats 
- 
Bradycardia: an ECG-derived rate < 50 bpm  for ≥ 1 minute  
- 
Sinus pause post conversion of AF to SR: an ECG-derived pause > 3 seconds  
- 
Atrial flutter with 1:1 conduction with fast ventricular response (ventricular heart rate ≥ 
200 bpm) 


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9.1.2.4 B – Serious Adverse Events of Special Interest (SAESI)  
The following potential SAESIs are defined for study purposes: 
- 
Hypotension, with symptoms/signs of clinical instability (i.e., severe chest pain/dyspnea 
or altered mental status), and requiring a vasopressor or inotropic agent 
- 
Ventricular tachycardia, sustained (> 30 seconds or requiring intervention before that 
time) VT, TdP, or VF 
- 
Bradycardia, with symptoms/signs of clinical instability (i.e., severe chest pain/dyspnea, 
altered mental status or hypotension), and requiring pacing or a chronotropic agent 
- 
Sinus pauses post conversion of AF to SR, causing syncope, or requiring pacing or CPR 
- 
Atrial flutter with 1:1 conduction with fast ventricular response (ventricular heart rate ≥ 
200 bpm), and requiring intervention (DC cardioversion) for termination, or an IV AV 
nodal blocking agent (β-blocker or Ca2+-channel blocker) to slow the ventricular rate 
- 
Any arrhythmia with symptoms/signs of clinical instability (i.e., severe chest 
pain/dyspnea, altered mental status or hypotension), and requiring DC cardioversion, 
defibrillation, pacing, or a vasopressor, inotropic or chronotropic agent 
9.1.3 B - Notification to Regulatory authorities, Investigators and IRBs 
Detailed SAE processing, distribution and reporting is provided in the Safety Management Plan. 
Sponsor and/or CRO(s) inform Investigators, IRBs/IECs and regulatory authorities of any 
Suspected Unexpected Serious Adverse Event Reactions (SUSARs) occurring in the study or 
other Sponsor studies of the investigational product, as appropriate per local reporting 
requirements.  
9.2 B – Clinical local laboratory assessments 
Blood samples for determination of the hematology panel, the comprehensive metabolic panel 
and the coagulation panel are taken at the times indicated below and in the Schedule of 
Assessments. No fasting is required.  
 
Sample collection times are as follows: 
- 
During screening, approximately 45 minutes preceding initiation of study drug. Note, a 
blood draw for assessment of potassium must always be drawn after informed consent 
and prior to enrollment; however, if results are available for any or all other parameters 
from a blood draw prior to screening (up to 24 hours prior to IC), there is no need for a 
new blood draw for those parameters.  
- 
At 90 minutes post dose 
 
The following laboratory safety variables are measured and analyzed at the local laboratory: 
 


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Hematology panel: performed at screening and may include some or all of the following 
parameters (use the site's standard hematology panel, also known as complete blood count 
with differential): 
- 
Red blood cell (RBC) count 
- 
Hemoglobin 
- 
Hematocrit 
- 
Mean corpuscular volume (MCV) 
- 
Mean corpuscular hemoglobin (MCH) 
- 
Mean corpuscular hemoglobin concentration (MCHC) 
- 
Red cell distribution width (RDW) 
- 
White blood cell (WBC) count 
- 
Neutrophils 
- 
Lymphocytes 
- 
Monocytes 
- 
Eosinophils 
- 
Basophils 
- 
Platelet count 
- 
Mean platelet volume (MPV) 
 
Comprehensive metabolic panel (CMP): performed at screening and at 90 minutes post dose 
and may include some or all of the following parameters (use the site's standard 
comprehensive metabolic panel): 
- 
Glucose and calcium 
- 
Kidney function tests (serum creatinine*, to derive the estimated creatinine clearance 
[mL/min/1.73m2], and blood urea nitrogen [BUN]) 
- 
Proteins (total protein and albumin)  
- 
Electrolytes (potassium*, sodium, chloride, bicarbonate)  
- 
Liver function tests (total bilirubin [TBL], conjugated bilirubin [e.g., if TBL is elevated], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline 
phosphatase [ALP]) 
* = parameter is required for evaluation of eligibility and must be collected at screening 
 
Coagulation panel: performed at screening and includes at least of the following parameters 
(use the site's standard coagulation panel): 
- 
Partial thromboplastin time (PTT) 
- 
Prothrombin time (PT) 
- 
Thrombin time (TT) 
- 
Fibrinogen 
 
Pregnancy: female subjects of childbearing potential that undergo screening after IC signature 
need to have either a serum or urine pregnancy test. 


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Laboratory reports are filed with the source documents. The Investigator must review the 
laboratory reports, document this review, and record any clinically significant abnormal 
laboratory results occurring during the study as adverse events. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the subject's condition. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in subject’s management or are considered 
clinically significant by the Investigator, then the results must be recorded in the eCRF. 
9.2.1 B - Total blood volume 
Blood samples for PK analysis (Section 8.1 B) and for laboratory safety assessments (Section 9.2 
B) are collected for each subject periodically on Day 1, resulting in the following total blood 
volume, in mL, per subject per assessment type: 
- 
Pharmacokinetic assessments (a maximum of 9 samples of 4.0 mL) 
36.0 mL 
- 
Clinical local laboratory assessment (screening) 
 
 
 
12.5 mL 
- 
Clinical local laboratory assessment (discharge) 
 
 
 
  7.0 mL 
 
 
 
 
 
 
 
 
 
 
Total    55.5 mL 
 
The total blood volume of 55.5 mL corresponds to approximately 3.75 tablespoons. 
9.3 B - Vital signs 
Heart rate, systolic and diastolic BP, respiratory rate (breaths/min), oxygen saturation (SpO2), 
and body temperature are recorded from the cardiac telemetry monitoring according to the 
Schedule of Assessments (Section 17.4). Body temperature is only recorded at screening.  
 
When time points coincide for blood draws and vital signs assessment, blood draws will be 
performed prior to vital signs assessments. 
9.4 B – Other electrocardiograms 
Other original routine ECGs obtained at the site or printouts of the telemetry rhythm strip 
performed according to local clinical practice are stored in the subject’s medical record as 
source documentation. 
9.5 B - Physical examination 
A physical examination is performed by medically qualified individuals. The targeted 
examination includes general appearance, cardiovascular, respiratory (including lung 
auscultation), abdomen (liver and spleen) and neurological evaluations. Results are recorded as 
normal or abnormal per evaluation with a listing of abnormalities in the eCRF. Height, weight 
and derived BMI are also measured and recorded in the eCRF at screening. 


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9.6 B - Handheld echocardiogram (HHE) 
To evaluate the subject's eligibility during screening (e.g., LVEF, valvular disease, structural 
heart disease), a diagnostic echocardiogram with a Sponsor-provided handheld portable 
ultrasound device will be required at screening for US subjects if the subject does not have 
results from a standard diagnostic echocardiogram (including LVEF) within the 6 months prior 
to screening. For information on the HHE Sub-Study available to EU subjects, refer to Section 
17.5. 
 
The following data will be recorded from the HHE in the eCRF: 
• Date and time HHE is administered 
• Who performed the HHE (e.g., professional title or study role) 
• Date and time HHE report/results became available 
• Who analyzed the echocardiogram obtained (e.g., professional title or study role) 
• The following assessments will be recorded: 
o LV size 
o LVEF  
o LV hypertrophy 
o Valvular disease 
o Other clinically significant findings 
 
The HHE data will be submitted to an independent reviewer to compare with the HHE 
assessments made by the site staff during the screening period; however, this independent 
review will not be used for the assessment of Part B subject eligibility during screening. This 
independent review will only be used to explore if site staff made a successful assessment of 
subject eligibility using the HHE data obtained during screening. 
10 B - Statistical methods 
Statistical analyses for Part B will apply to all Part B subjects, including those EU subjects 
participating in the Handheld Echo Sub-Study (refer to Appendix 6). Data from the HHE Sub-
Study are collected on a subset of the Safety Population for Part B and the Part C Medically-Led 
Cardioversion Study.  The analysis for the additional echocardiogram data measured will be 
separate from the safety analyses of all Part B subjects and Part C subjects in the Medically-Led 
Cardioversion Study. 
10.1 B - Study populations 
10.1.1 B - Population of consented subjects 
The population of consented subjects includes all subjects who signed the informed consent 
form. 


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10.1.2 B - Intention-to-treat population (ITT) 
The intention-to-treat (ITT) population includes all subjects that were enrolled.  Compared to the 
population of consented subjects, the ITT population excludes subjects who are not enrolled.  The 
population does include subjects who were enrolled when re-entering the study for a new episode 
of AF. 
10.1.3 B - Modified ITT population (mITT) 
The modified ITT population includes all enrolled subjects who received the full assigned dose of 
study drug and were in AF at the time of start of the inhalation of the study drug. Subjects whose AF 
converted to SR prior to completion of the assigned full dose of study drug will also be included in 
the mITT population. 
10.1.4 B - PK population 
The PK population includes all enrolled subjects who received the full assigned dose of study drug 
irrespective of whether the subject was in AF or not at the initiation of dosing. Compared to the 
Safety population the PK population excludes subjects who did not receive the full assigned dose of 
study drug. 
10.1.5 B - Safety population 
The Safety population includes all enrolled subjects who started the inhalation of study drug, 
whether the subject was in AF or not and whether the subject received the full assigned dose of 
study drug or not.  Compared to the ITT population, the Safety population excludes subjects who 
are enrolled but did not start of the inhalation of study drug.  
10.2 B – Statistical analyses 
The primary endpoint analyses of Part B will be based on Part B subjects alone. If the Part B primary 
endpoint analysis meets the pre-specified criteria for significance and is not substantially different 
from Part A 120 mg FlecIH-103, the two dose cohorts (120mg FlecIH-103 cohorts from Part A and 
Part B) will be combined for the overall analysis of Part B to provide a more precise estimate of 
efficacy, safety, and PK/PD.    
 
This protocol provides general aspects of the statistical methods. Specific details are outlined in the 
Statistical Analysis Plan (SAP). 
10.2.1 B - Efficacy analyses 
Modified ITT population 
The mITT population will be used to evaluate all primary and secondary efficacy endpoints.  
 
Statistical analyses of secondary efficacy endpoints 
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10.2.1.1 
B - Statistical analysis of the primary efficacy endpoint 
The endpoint of conversion to SR is defined as the presence of SR, derived from the AECG, 
lasting for at least 1 minute. The first conversion to SR that lasts for at least 1 minute is referred 
to as the index conversion. Any conversion not lasting for at least 1 minute is not considered an 
index conversion. 
 
The conversion rate (%) of recent onset of AF to SR, within 3 hours, ranges from 2 – 14% 
spontaneously22 and with placebo51, 52 approximately  16%3. In more recent studies such as 
those with vernakalant, the reported placebo conversion rate was ~5%4. For this study, we have 
selected a somewhat higher placebo conversion rate of 20%. In order to statistically evaluate 
whether the proportion of subjects whose AF converted to SR by inhaled flecainide within 90 
minutes after initiation of dosing is > 20%, the following hypotheses are evaluated at a one-
sided significance level of 0.05: 
 
H0 :   = 20% 
 
The one-sided alternative hypothesis is: 
 
HA :   >  
 
The null hypothesis is tested with the use of an exact binomial test. A 90% Clopper-Pearson 
confidence interval is computed for the proportion of subjects who met the primary endpoint. 
If the lower bound of the 90% confidence interval is > 20% then the null hypothesis is rejected 
in favor of the alternative, i.e. there is sufficient evidence to conclude the percentage of 
subjects AF converting to SR is > 20%. 
10.2.1.2 
B - Statistical analysis of proportion of subjects who convert within 90 
minutes after initiation of dosing and have Cmax values ≥ 200ng/mL (e.g., 200, 
300, 400, and 500 ng/mL) 
This endpoint is defined as the number of subjects who meet the endpoint criteria, divided by 
the total number of subjects included in the analysis. The estimate for the conversion rate and 
its associated 95% Clopper-Pearson CIs will be derived.  
 
For the purpose of this study, Cmax is defined as the peak plasma level of flecainide prior to 
administration of any alternative pharmacological agent (e.g., oral flecainide). 


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10.2.1.3 
B - Statistical analysis of time-to-conversion to SR from initiation of 
dosing up to 90 minutes after initiation of dosing 
The cumulative incidence function for the time to conversion from initiation of study drug up to 
90 minutes after initiation of dosing will be determined via Kaplan-Meier methods as described 
in the SAP. 
10.2.1.4 
B - The proportion of subjects in SR on Day 2 
The rhythm status used for the evaluation of this secondary efficacy endpoint is derived from 
the remote ECG Event Recorder, in which the subject’s heart rhythm is recorded. A subject is 
considered in SR on Day 2 if the remote ECG recording at the intended time shows SR. The 
variable is set to missing if no evaluable remote ECG recording is available for analysis. 
 
The proportion is estimated by the number of subjects in SR on Day 2, divided by the total 
number of subjects with available data. The estimate for the proportion and its associated 95% 
Clopper-Pearson CI will be derived. 
10.2.1.5 
B - The proportion of subjects with reduced or no AF symptoms at 30 
minutes post dose  
A subject is considered to have reduced or no AF symptoms at 30 minutes post dose based 
upon patient-reported outcomes (reported as either 'no symptoms' or 'improved'). 
 
The evolution of symptoms (no symptoms, improved, unchanged or worsened) is a categorical 
variable that will be summarized by the frequency and proportion of subjects within each 
category. The estimate for the proportion and its associated 95% Clopper-Pearson CI will be 
derived. 
10.2.1.6 
B - The proportion of subjects with reduced or no AF symptoms at 60 
minutes post dose  
A subject is considered to have reduced or no AF symptoms at 60 minutes post dose based on 
patient-reported outcomes (reported as either 'no symptoms' or 'improved'). 
 
The evolution of symptoms (no symptoms, improved, unchanged or worsened) is a categorical 
variable that will be summarized by the frequency and proportion of subjects within each 
category. The estimate for the proportion and its associated 95% Clopper-Pearson CI will be 
derived. 


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10.2.1.7 
B - The proportion of subjects with reduced or no AF symptoms at 90 
minutes post dose  
A subject is considered to have reduced or no AF symptoms at 90 minutes post dose based on 
patient-reported outcomes (reported as either 'no symptoms' or 'improved'). 
 
The evolution of symptoms (no symptoms, improved, unchanged or worsened) is a categorical 
variable that will be summarized by the frequency and proportion of subjects within each 
category. The estimate for the proportion and its associated 95% Clopper-Pearson CI will be 
derived. 
10.2.1.8 
B - Descriptive statistics of proportion of conversion to SR within 90 
minutes after initiation of dosing without AF recurrence requiring electrical or 
pharmacological cardioversion or rate control intervention up to discharge 
This endpoint is derived from the primary efficacy endpoint at 90 minutes after initiation of 
dosing. The endpoint is met if the subject's AF converts to SR within 90 minutes after initiation 
of dosing without an alternative therapy and without subsequent AF recurrence up to discharge 
requiring additional intervention, either by electrical or pharmacological cardioversion or by 
rate control treatments. 
 
The proportion of subjects that convert to SR without AF recurrence is estimated as the number 
of subjects who meet the endpoint, divided by the total number of mITT subjects. The estimate 
for the proportion and its associated 95% Clopper-Pearson CI will be derived. 
10.2.1.9 
B - The proportion of subjects in SR on Day 5 
The rhythm status used for the evaluation of this secondary efficacy endpoint is derived from 
the remote ECG Event Recorder, in which the subject’s heart rhythm is recorded. A subject is 
considered in SR on Day 5 if the remote ECG recording at the intended time shows SR. The 
variable is set to missing if no evaluable remote ECG recording is available for analysis. 
 
The proportion is estimated by the number of subjects in SR on Day 5, divided by the total 
number of subjects with available data. The estimate of the proportion and its associated 95% 
Clopper-Pearson CI will be derived. 
10.2.2 B - Safety analyses 
The safety of inhaled flecainide is evaluated by collection of the following measurements 
performed according to the schedule of study assessments: 
- 
Monitoring of AEs, SAEs, AESIs, and SAESIs; 
- 
Physical examinations; 


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- 
Vital signs (heart rate, systolic and diastolic blood pressure, respiratory rate and oxygen 
saturation); 
- 
Routine ECGs or 10-second printouts of the telemetry rhythm strip performed for safety 
purposes are printed and reviewed on-site; 
- 
Continuous telemetry; 
- 
Pulmonary function by lung auscultation and oxygen saturation; 
- 
Clinical local laboratory assessment (incl. hematology, comprehensive metabolic and 
coagulation panel). 
 
Safety analyses will be performed and the results summarized in the safety population. The 
verbatim terms used in the eCRF by Investigators to identify AEs are coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) by System Organ Class (SOC) and Preferred Term. 
All reported AEs with onset during the treatment phase or that were already present but 
worsened either in intensity or frequency following the treatment (i.e., TEAEs) are included in 
the analysis. The incidence and percentage of subjects with at least 1 occurrence of a Preferred 
Term are included, according to the most severe grade using a 3-point scale (mild, moderate, 
severe). The number of events per Preferred Term is summarized. Causality (relationship to 
study treatment) is summarized separately. The incidence and frequency of TEAEs (including 
TESAEs and AESI) are summarized according to SOC and Preferred Terms. Durations of events 
are determined and included in listings, along with the action taken and outcome. 
10.2.2.1 
B - Clinical laboratory evaluation analyses 
Laboratory data are summarized by type of laboratory test. Reference ranges and clinically 
significant abnormal results are depicted in the summary of clinical local laboratory data, as 
described in the SAP. Descriptive statistics are used for each laboratory parameter at screening 
(Day 1) and at discharge. 
10.2.2.2 
B - Vital signs analyses 
Vital signs measurements and their change from baseline are summarized for the safety 
population at each scheduled time point using descriptive statistics. Time course of the changes 
is summarized in tables and also represented graphically. 
10.2.2.3 
B - Physical examination analyses 
Physical examination findings are summarized at screening and presented in subject listings. 
10.2.3 B - Pharmacokinetic / Pharmacodynamic analyses 
Table 2 describes the PK parameters to be calculated for plasma flecainide concentrations. The 
PK analysis is performed in all enrolled subjects who inhaled the full assigned dose (PK 
population).  
 


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Table 2 - Pharmacokinetic parameters to be calculated for plasma flecainide 
AUC0-10: 
The area under the plasma concentration versus time curve from the start 
of dosing (time zero, T0) to 10 minutes after initiation of dosing 
AUC0–90: 
The area under the plasma concentration versus time curve from the start 
of dosing (time zero, T0) to 90 minutes after initiation of dosing 
Cmax: 
The peak (maximum) plasma concentration prior to the start time of any 
alternate pharmacological therapy, is to be obtained directly from the 
plasma concentration time profile 
tmax: 
The time to Cmax (from the time of end of dosing) is obtained. If tmax is 
reached prior to the end of dosing, a negative value will be reported. 
t½ distribution: 
The distributive half-life is calculated by the equation t½ = ln(2)/kdist 
 
The effects of inhaled flecainide on the following ECG intervals is measured: 
• 
Heart rate (HR) 
• 
RR interval 
• 
PR interval 
• 
QRS duration 
• 
QTcF duration 
• 
JTc duration (QTc-QRS)
 
PK and PD data are analyzed in an exploratory manner and summarized descriptively. Time course 
of the changes is summarized in tables and also graphically represented. Details are given in a 
PK/PD analysis plan. The results of these analyses are presented in a separate report. 
10.3 B - Sample size determination 
In Part B, the estimated sample size of 25 mITT subjects for the 120 mg dose cohort is based upon 
the evaluation of the following statistical hypotheses using an exact binomial test, 
H0:  = 20%     versus     HA:  > 20%     ( = 0.05). 
 
Given the actual conversion rate for the Part A 120 mg dose cohort is 44%, a sample size of 25 
subjects has 84% power to reject the null hypothesis (H0) in favor of the alternative (HA) with a one-
sided significance level of 0.05. The null hypothesis is rejected when at least 9 subjects’ AF converts 
to SR within 60 minutes after initiation of dosing.  
 
If 9 subjects’ AF converts to SR, the resulting conversion rate is 36% with a 90% exact binomial 
confidence interval of [20.24%, 54.39%]. If 9 or more subjects’ AF converts to SR, the lower bound 
of the 90% exact binomial confidence interval will be greater than 20.24%. When the lower bound 
of the 90% confidence interval for conversion rate is greater than 20%, there is sufficient support 
for the rejection of the null hypothesis in favor of the alternative. 
 
It is expected approximately 20 subjects will participate in the Handheld Echo Sub-Study in Part B 
and the Part C Medically-Led Cardioversion Study; however, the Sub-Study does not have a 
minimum or maximum enrollment target. 
 


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XII. 
Study protocol (Part C - EU only): Medically-Led Cardioversion and 
Patient-Led Under Medical Supervision Cardioversion Studies 
2 C - Study objectives 
All Part C objectives are exploratory: 
• 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 
3 C - Study design 
Part C is conducted in Europe only. Part C comprises two distinct studies, a Medically-Led 
Cardioversion Study (procedures are identical to those in Part B) and a Patient-Led Under 
Medical Supervision Cardioversion Study (procedures include the subject self-preparing and 
self-administering the study drug under medical supervision in the clinic). 
 
Subjects with recent-onset AF who have not been previously treated with flecainide acetate 
inhalation solution will first be enrolled into the Medically-Led Cardioversion Study to 
determine eligibility for rollover participation in the Patient-Led Under Medical Supervision 
Cardioversion Study. 
 
Subjects who first participate in the Medically-Led Cardioversion Study whose AF converts to SR 
with flecainide acetate inhalation solution and who did not experience any serious AE(s), 
serious AESIs, or difficulties or issues with inhalation (in the opinion of the investigator) are 
then eligible for the Patient-Led Under Medical Supervision Cardioversion Study.  
 
Subjects from Part A and Part B who already had a previous AF episode converted to SR with 
flecainide acetate inhalation solution and who did not experience any serious AE(s), serious 
AESIs, or difficulties or issues with inhalation (in the opinion of the investigator) are also eligible 
for the Patient-Led Under Medical Supervision Cardioversion Study. These subjects do not need 
to participate in the Part C Medically-Led Cardioversion Study prior to proceeding into the 
Patient-Led Under Medical Supervision Cardioversion Study.  
 
The schematic for subject flow into Part C is described in  
 
Figure 5. 
 


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Figure 5. Schematic for Part C: 120 mg Dose 
 
 
 
For both studies in Part C, subjects receive a repeat dose regimen of 120 mg eTLD (2 x 60 mg) 
FlecIH-103 inhalation solution. The dose regimen is described in Section 5.1 B.  The study design for 
Part C is described in Figure 6.  
 
The Patient-Led Under Medical Supervision Cardioversion Study requires subjects to return to the 
clinic for training, pass an assessment of their ability to self-administer the study drug, and then 
return to the clinic within 48 hours of the onset of symptoms when they experience a recurrent 
episode of paroxysmal AF to self-administer the study drug. Subjects may return and self-administer 
study drug for one recurrent episode of AF. 
 
Figure 6. Part C Study Design 
INSTANT Study
PART C 
FlecIH-103
Medically-Led
FlecIH-103
Patient-Led Under 
Medical Supervision
INSTANT 
Study
PART A
INSTANT 
Study
PART B
Patients whose AF safely converted to SR with study drug in Part A, Part B, or 
the Medically-Led Cardioversion Study in Part C are eligible to consent to the 
Part C Patient-Led Under Medical Supervision Cardioversion Study. 


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4 C - Study population 
Part C does not have an enrollment target; enrollment will continue in the Part C Medically-Led 
Cardioversion Study at the discretion of the Sponsor to support rollover participation in the Part 
C Patient-Led Under Medical Supervision Cardioversion Study. 
 
Subjects to be included in the Patient-Led Under Medical Supervision Cardioversion Study must be 
re-checked for eligibility according to the same criteria in Part B (Section 4.1 B and 4.2 B) prior 
to each treatment of a recurrent AF episode with the study drug.  Safety labs and a symptom-
driven physical examination may be performed at the discretion of the PI (e.g., due to changes 
in recent medical history); except for those required to confirm the subject's eligibility, which 
must be performed.  
 
If a subject is not eligible, they may be treated as per institutional standard of care and return 
again if the future for a different recurrent episode of AF. 
4.1 C - Inclusion criteria 
Subjects to be included in Part C must meet the same inclusion criteria as described in Section 
4.1 B.  
4.2 C - Exclusion criteria  
Subjects are NOT eligible to participate in Part C if they meet ANY of the exclusion criteria 
described in Section 4.2 B. 
Patient with AF 
treated with 
FlecIH*
Patient not 
eligible for 
study
Successful
Cardioversion 
due to FlecIH
No 
Conversion
Patient returns 
for training on 
assembly/self-
administration
Patient returns to 
the clinic with AF 
to self-administer 
FlecIH under 
supervision
Patient Completes 
Training Successfully
Patient not 
eligible for 
study
Patient Fails to Demonstrate 
Ability to Assemble and 
Self- Administer FlecIH
Up to 8 months
Training Phase
Recurrent Episode of AF
To take place in the clinic
in a setting to mimic 
the home environment
Continued training at 
regular intervals until 
recurrent episodes of 
AF occur
Part A, Part B, or 
Part C Medically-Led
Part C Patient-Led Under Medical Supervision
*Potentially eligible patients from Part A, Part B, and the Medically-Led Cardioversion Study in Part C may provide Informed Consent 
for the Part C Patient-Led Under Medical Supervision Cardioversion Study. 


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4.3 C - Screen failures  
Refer to Section 4.3 B. 
5 C - Treatment 
5.1 C - Study treatments 
Refer to Section 5.1 B. 
5.2 C - Treatment assignment 
After the consent form has been signed, the investigational site enters the eCRF to obtain a 
unique subject identification number (SID) for that subject (if not previously obtained). Subjects 
may be enrolled provided they meet all the inclusion criteria and none of the exclusion criteria.  
 
Subjects are assigned to a 120 mg eTLD (2 x 60 mg) FlecIH-103 repeat dose regimen in both 
studies in Part C.  
5.3 C - Identity of study drug(s) 
Refer to Section 5.3 B. 
5.4 C - Non-study therapy 
Refer to Section 5.4 B. 
5.5 C - Discontinuation criteria 
Refer to Section 5.5 B. 
6 C - Study procedures 
For the Part C Medically-Led Cardioversion Study, the study procedures are identical to Part B. 
Refer to Section 6 B for more information. 
 
The Part C Patient-Led Under Medical Supervision Cardioversion Study is divided into consenting, 
training, treatment, and follow-up periods, as described in the following sections.  
 
Windows for PK blood draws and vital signs assessments 
Where PK blood draws and vital signs assessments coincide at scheduled time points, PK blood 
draws are prioritized and must occur at the protocol-specified time point (with the exception of 
the 60 minutes post dose time point, which may be collected within a ± 5-minute window, and 
the 90 minutes post dose time point, which may be collected within a ± 10-minute window). 
Vital signs should be collected as close as possible to the scheduled time point after PK blood 


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draw is completed. As vital sign assessments coincide with PK blood draws, any deviations from 
the protocol-required time points for vital signs will not be recorded as protocol deviations. Any 
missed vital signs assessments will be recorded as protocol deviations. 
 
Discharge window 
Discharge is left to the discretion of the Investigator, but may not occur before 90 minutes post 
dose, with a -10-minute window allowed. Because discharge may occur, at the earliest, at 80 
minutes post dose due to the window, all 90-minute post dose study assessments also have a 
±10-minute window (may be performed between 80 and 100 minutes post dose, inclusive). 
 
For the Schedule of Assessments please refer to Appendix 4. 
 
 
 
6.1 C - Patient-Led Under Medical Supervision Cardioversion Study: consenting 
Consent for the Part C Patient-Led Under Medical Supervision Cardioversion Study may occur in 
the following ways:   
- 
Potentially eligible subjects from Part A will need to return to the clinic to provide 
consent and train on the assembly of the device and self-administration of study drug as 
soon as possible.   
- 
Potentially eligible subjects from Part B may consent to the Part C Patient-Led Under 
Medical Supervision Cardioversion Study prior to or after discharge and complete the 
training on the assembly of the device and self-administration of study drug as soon as 
possible.   
- 
Potentially eligible subjects from the Part C Medically-Led Cardioversion Study may 
consent to the Patient-Led Under Medical Supervision Cardioversion Study prior to 
discharge (or return to the clinic within approximately two weeks) and complete the 
training on the assembly of the device and on self-administration of study drug.  
6.2 C - Patient-Led Under Medical Supervision Cardioversion Study: training 
Once consented to the Patient-Led Under Medical Supervision Cardioversion Study, a training visit 
will be conducted by study personnel in accordance with the Patient-Led Training Procedure 
(site-facing document only), which describes step-by-step what the subject will be responsible 
for performing. The subject will be provided a Patient IFU document to follow during training 
and the self-administration procedure. 
 
Subjects who successfully complete the training as determined by their ability to complete the 
procedures with minimal assistance, will be 'certified' and considered eligible to continue 
participation. A subject who does not successfully complete the procedures may be eligible 


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with additional training unless deemed unable or unfit to participate by the study personnel. 
Subject will continue to be re-trained on a regular basis (approximately monthly). 
 
During the training visit, the following procedures will be performed: 
o Study personnel will demonstrate all applicable steps to the subject, in accordance 
with the Patient-Led Training Procedure.  
o The subject will practice all applicable steps and ask questions as needed. Note: 
study drug may NOT be used during inhalation practice/training. 
o Study personnel will answer all of the subject's questions, ensuring the subject has 
a clear understanding of all applicable steps. 
o The subject will perform the required steps unassisted in order to become 
'certified' for self-administration. If the subject has difficulty in understanding or 
performing the required steps, they may receive further assistance from the study 
personnel, and try once again to repeat the required steps unassisted. Certification 
should be noted in the subject's source records. No formal certificate will be 
provided to the subject. 
o The subject may be deemed unable or unfit to participate by the study personnel if 
certification is not possible after up to 3 attempts. If this is the case, the subject 
will be early terminated from Part C. 
o Once certified, the subject is given a nebulizer to take home to independently 
practice with the device to learn to assemble it and inhale. 
o Study personnel informs the subject that they must return to the clinic for 
refresher training at least every 3 months, to avoid early termination from the 
study. The refresher training may also be completed by telemedicine visit or video 
conference (e.g., Facetime, Skype), if the site and subject have the capability. Study 
personnel should schedule a return training visit prior to the subject leaving the 
clinic.  
o Study personnel provides the subject with a training video and instructs the subject 
to watch the video approximately monthly as a refresher. Subjects without access 
to a computer may return to the site monthly to view the training video if 
necessary, or do so via a telemedicine visit or video conference, if the site and 
subject have the capability. 
o The study personnel instruct the subject to contact the clinic for return instructions 
as soon as they feel symptoms of a recurrence of paroxysmal AF. Subjects must 
return to the clinic and self-administer study drug within 48 hours of the onset of 
symptoms. If the subject cannot reach the study personnel, they should take the 
steps to care for themselves as they would normally if they were not participating 
in this study (e.g., proceed to emergency care or their regular doctor).  
 
Study personnel will contact the subject approximately monthly to check for adverse events 
and concomitant medications and confirm if subject has viewed the training video. 


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6.3 C - Patient-Led Under Medical Supervision Cardioversion Study: treatment 
After completion of training and becoming certified for patient-led self-administration of study 
drug, all eligible subjects may return to the clinic for a recurrence of symptomatic paroxysmal 
AF within 48 hours of the onset of symptoms. Subjects will independently dispense the dose 
into the nebulizer, reassemble the nebulizer, and self-administer the study drug in the clinic 
under observation of study personnel. For additional details refer to the IFU. Subjects will self-
administer 120 mg eTLD (2 x 60 mg) FlecIH-103 according to the same dosing regimen in Part B 
(Section 5.1 B).  
 
Subjects return for patient-led self-administration of study drug for a single recurrent 
episode(s) of paroxysmal AF within 8 months of signing consent. End of study coincides with 
Day 5 after the subject's treatment visit, or 8 months after signing consent, whichever comes 
first.  
Before dosing 
The following procedures will be performed prior to dosing: 
o The eligibility criteria for Part C are identical to Part B and must be checked and 
confirmed prior to dosing. 
o Blood samples are to be drawn per Investigator discretion to confirm the subject’s 
eligibility at approximately 30 minutes prior dosing, in accordance with the 
requirements in Section 9.2 C.  
o A standard 12-lead ECG (using site’s own equipment) is recorded to confirm that 
the subject’s heart rhythm is AF and remains in AF for at least 30 minutes prior to 
dosing. Once the recording of the ECG is completed and the presence of AF is 
confirmed, this 12-lead ECG may be disconnected. 
o A baseline PK blood sample is drawn prior to dosing. 
o A symptom-driven physical exam is performed prior to dosing, if deemed necessary 
by the Investigator. 
o The subject is connected to the telemetry system and to the AECG (Holter) 
approximately 30 minutes prior to dosing (after being disconnected from the 
standard 12-lead ECG).  
o A single source for the time of all assessments shall be utilized for each patient. For 
example, if telemetry is used, all assessments for that patient must be recorded 
from the same telemetry unit. All times shall be reported in a 24-hour format. 
NOTE: The date and time displayed on study Holter monitor AECG must be set to 
match the date and time of the device used for capturing the time of all 
assessments, for each subject. 
o An IV catheter/cannula is placed for blood sample draws. 
o Pre-dose vital signs (heart rate, systolic/diastolic blood pressure, respiratory rate 
[breaths/min], oxygen saturation, and body temperature) are recorded. 
approximately 30 minutes prior to dosing.  


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NOTE: When time points for drawing blood samples and recording of vital signs 
coincide, assessments should be performed in said order. 
o The subject's weight is recorded (for calculation of creatinine clearance)  
o Pre-dose vital signs (excluding body temperature) are recorded again within 10 
minutes prior to dosing. 
o The subject's AF-related symptoms are recorded prior to dosing. 
o The subject is offered the opportunity to review once again the steps for 
dispensing the study drug, assembly of the nebulizer, and the instructions for self-
administration of study drug. This review of the steps will be done along with the 
study personnel; any remaining questions prior to the start of the inhalation can be 
addressed by the study nurse. 
 
After completion of the baseline measurements as described above, the Investigator verifies 
whether the subject is still in AF. Inhalation of study drug should not start in subjects whose AF 
has spontaneously converted to SR, or who are in a heart rhythm other than AF. 
 
During dosing 
Once the subject confirms they are ready, the subject will dispense the study medication into 
the nebulizer, reassemble the nebulizer and self-administer the study drug according to the 
steps outlined in the Patient IFU. 
 
The following procedures will be performed during dosing: 
o The study personnel will use a stopwatch to monitor the dosing and will advise the 
subject when to stop inhaling at the time of completion or when their AF converts 
to SR, whichever comes first. 
o A PK sample will be collected when the subject's AF converts to SR (if applicable). 
 
Notwithstanding any difficulty that the subject experiences with the preparation of the 
nebulizer or with the self-administration/inhalation of study drug, they should make every 
attempt to perform the procedure without assistance. If needed, the subject can be referred 
back to the Patient IFU. If the subject is unable to prepare the device and self-administer the 
study drug without assistance, the study personnel may assist but this must be documented in 
the eCRF. 
 
The Investigator may stop the inhalation of the study drug early in the event of a S(AE) such as 
ventricular arrhythmias (frequent PVCs, non-sustained VT, or sustained VT or VF) or any other 
life-threatening or serious adverse events.  
 
No other pharmacological or electrical cardioversion may be attempted until at least 90 
minutes post dose. Alternate therapy may be given as early 60 minutes pose dose only if 
deemed medically necessary by the investigator not to wait until 90 minutes post dose; 


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however, IV flecainide and propafenone may not be administered until at least 90 minutes post 
dose. Subjects will remain on rhythm monitoring (i.e., cardiac telemetry and study AECG 
[Holter]) until at least 90 minutes post dose. 
 
After dosing 
The following procedures are performed after dosing: 
o A PK sample is collected at 3 minutes post dose.  
NOTE: A PK sample must also be collected when conversion of AF to SR occurs (if 
applicable). If time of conversion is approximately within 1 minute before or after 
the 3 minutes post dose PK sample, only 1 sample needs to be collected. 
o The subject's vital signs are recorded at 1, 3, 10, 30, 60 and 90 minutes post dose. 
o The subject's AF-related symptoms are recorded at 30, 60 and 90 minutes post 
dose. 
o The AECG (Holter) is removed at 90 minutes post dose. 
 
The timing of subject’s discharge is left to the discretion of the treating physician but may only 
occur at or after 90 minutes (a -10 minute window is allowed) post dose. At discharge, a plan 
for follow up study contacts on Days 2 and 5 is made with the subject. 
6.4  C - Patient-Led Under Medical Supervision Cardioversion Study: follow-up 
Study personnel will contact the subject on Day 2 (+ 1 day) and Day 5 (± 1 day) following self-
administration of study drug to assess concomitant medications, adverse events, and subject's 
AF-related symptoms status.  
 
End of study coincides with Day 5 after the subject's treatment visit, or 8 months after signing 
consent, whichever comes first. 
7 C - Efficacy assessments and endpoints 
The efficacy assessments in the Part C Medically-Led Cardioversion Study are identical to those 
in Part B. Refer to Section 7 B for more information.  
 
The assessments in the Part C Patient-Led Under Medical Supervision Cardioversion Study and the 
endpoints for Part C are described in the following sections. 
7.1 C - Patient-Led Under Medical Supervision Cardioversion Study: rhythm 
monitoring assessments 
Subjects are connected to the AECG (Holter) on Day 1 approximately 30 minutes prior to dosing 
after the site has confirmed the diagnosis of AF using the standard 12-lead ECG (using site’s 
own equipment). The subject will remain connected to the AECG until at least 90 minutes post 
dose. 


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Anonymized AECG recordings are analyzed centrally by a Core Laboratory. Further detail may 
be found in the separate instructions provided. 
7.2 C - Patient-Led Under Medical Supervision Cardioversion Study: AF-related 
symptoms 
Prior to self-administration of the study drug on Day 1, subjects are queried about the presence 
or absence of each of the following AF-related symptoms: 
 
- 
Palpitations, i.e. sensation of a racing, uncomfortable, irregular heartbeat or a flip-
flopping in your chest 
- 
Lightheadedness or dizziness 
- 
Shortness of breath or dyspnea 
- 
Chest discomfort 
 
At the following time points after dosing, subjects are again queried about each of these 
symptoms in terms of "no symptoms, improved, unchanged or worsened" as compared to 
baseline: 
- 
30, 60 and 90 minutes post dose on Day 1 
- 
On Day 2 (+ 1 day) 
- 
On Day 5 (± 1 day) 
7.3 C - Study endpoint(s) 
All endpoints in Part C are exploratory: 
- 
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 


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- 
Time from HHE administration to availability of HHE report/results 
8 C - Other assessments 
Pharmacokinetic and pharmacodynamic assessments in the Medically-Led Cardioversion Study 
of Part C are identical to Part B. Refer to Section 8 B for more information. 
 
Other assessments, including PK and PD assessments, in the Part C Patient-Led Under Medical 
Supervision Cardioversion Study are described in the following sections. 
8.1 C - Patient-Led Under Medical Supervision Cardioversion Study: PK 
assessment(s) 
Up to 3 whole blood samples of about 4.0 mL each are collected for measurement of plasma 
concentration of flecainide acetate: prior to dosing, 3 minutes post dose, and at time of 
conversion of AF to SR (if applicable). Instructions for the collection, processing and shipping of 
biological samples are provided in the Laboratory Manual. 
 
Plasma samples are assayed by a validated LC/MS/MS method as in Part B. Samples collected 
for analysis of flecainide plasma concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
 
No genetic analyses will be performed on these plasma/whole blood samples. 
8.2 C - Patient-Led Under Medical Supervision Cardioversion Study: PD 
assessment(s) 
To evaluate the electrocardiographic effects of inhaled flecainide under oral inhalation dosing 
regimens in subjects with recent onset of paroxysmal AF, which are detectable on 12-lead ECG 
recordings mainly by assessing the following PD variables: PR, QRS, and QT intervals. 
 
An independent central review of ECGs is conducted. The ECG recordings will be extracted in 
triplicate according to the Schedule of Assessments (Section 17.4) from the recorded AECG data 
by the ECG Core Laboratory after receiving the data. 12-lead ECGs will be extracted at or after 
each specified time point within up to 5 minutes or up to the next scheduled time point, 
whichever comes first.  
 
Triplicate 12-lead ECG readings are collected at pre-defined collection time points for a given 
subject and are over-read on the same lead by the same ECG Core Laboratory reader. 
 
Extraction times for ECG recordings under both regimens are as follows: 
1. Pre-dose inhalation – TPre - at -30 and -15 minutes 


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2. Just before the start of inhalation – TAdmin  
3. During dose regimen administration – Tbetween admin (in the 1-minute break in between 
inhalations) 
4. At the time of conversion to SR – TSR 
5. After administration of study drug regimen is complete – Tx (1, 3, 10, 30, 60, and 90 minutes 
post dose) 
 
Details of the Core Laboratory analyses are included in the Core Laboratory analysis plan but at 
least the following ECG parameters are determined: 
 
- 
Heart rate (HR) 
- 
RR interval 
- 
PR interval 
- 
QRS duration 
- 
QTcF duration 
- 
JTc duration (QTc-QRS) 
 
ECGs extracted from the 12-lead Holter are provided to Investigators for filing in the subjects' 
source records. Any original ECG recordings obtained at the site must also be stored in the 
subject’s source records. 
9 C - Safety evaluation and reporting  
Safety evaluation and reporting in the Part C Medically-Led Cardioversion Study are identical to 
Part B. Refer to Section 9 B for more information. 
 
Safety evaluation and reporting in the Part C Patient-Led Under Medical Supervision 
Cardioversion Study are described in the following sections. 
9.1 C - Patient-Led Under Medical Supervision Cardioversion Study: adverse 
events 
Adverse events for subjects participating in the study will be captured from time of consent 
until EOS. End of study coincides with Day 5 after the subject's treatment visit, or 8 months 
after signing consent, whichever comes first. All AEs, SAEs, and AESIs will be captured and 
reported in accordance with Section 9.1 B.  
 
Recurrent atrial fibrillation will not be considered as an adverse event as it is an expected event 
in this patient population. AF recurrence will be captured in a separate eCRF.  


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9.2 C - Patient-Led Under Medical Supervision Cardioversion Study: clinical 
local laboratory assessments 
Blood samples as described in Part B may be obtained on Day 1 prior to self-administration of 
the study drug per the discretion of the treating physician. The following laboratory 
assessments are required to confirm eligibility: 
- 
serum creatinine 
- 
serum potassium 
- 
serum or urine pregnancy test (only for female subjects of child-bearing potential) 
 
A blood draw for assessment of potassium must always be drawn on Day 1 prior to self-
administration of study drug; however, if results are available for any or all other parameters 
from a blood draw up to 24 hours prior to Day 1, there is no need for a new blood draw for 
those parameters. 
 
If laboratory values from non-protocol specified laboratory assessments performed at the site's 
local laboratory are considered clinically significant by the Investigator (e.g., AE or SAE), then 
the results must be recorded in the eCRF. 
9.2.1 C - Patient-Led Under Medical Supervision Cardioversion Study: total blood 
volume  
Blood samples in the Patient-Led Under Medical Supervision Cardioversion Study result in a total 
maximum estimated blood volume of 15.0 mL per subject: 
- 
PK assessments (up to 3 samples of 4.0 mL each) 
 
 
12.0 mL 
- 
Clinical local laboratory assessments on Day 1 
 
   
  3.0 mL 
 
 
 
 
 
 
 
 
 
Total   15.0 mL 
 
The total blood volume of 15.0 mL corresponds to approximately 1 tablespoon. 
9.3 C - Patient-Led Under Medical Supervision Cardioversion Study: vital signs  
Weight must be recorded on Day 1 prior to self-administration of the study drug to confirm 
creatinine clearance eligibility.  
 
Heart rate, systolic and diastolic blood pressure, respiratory rate (breaths/min), oxygen 
saturation and body temperature are recorded on Day 1 approximately 30 minutes prior to self-
administration of the study drug. Vital signs (excluding body temperature) are recorded again 
within 10 minutes prior to dosing. Finally, vital signs are recorded after dosing at 1, 3, 10, 30, 60 
and 90 minutes post dose. 


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9.4 C - Patient-Led Under Medical Supervision Cardioversion Study: physical 
examination  
A symptom-driven physical examination may be performed prior to self-administration of study 
drug per Investigator discretion to confirm eligibility.  
10 C - Statistical methods 
10.1 C - Study populations 
Refer to Section 0 B. 
10.2 C - Statistical analyses 
No formal hypothesis testing is planned for Part C. Summary statistics will be generated, 
including estimates of the endpoints with their associated 90% confidence intervals. 
 
All statistical analyses performed in the evaluation of the INSTANT Study data are described in 
the statistical analysis plan (SAP). 
10.3 C - Sample size determination 
Part C (EU only) does not have an enrollment target; enrollment will continue in the Part C 
Medically-Led Cardioversion Study at the discretion of the Sponsor to support rollover 
participation in the Part C Patient-Led Under Medical Supervision Cardioversion Study. 
11 Data integrity and quality assurance 
The Investigator shall allow study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data/documents. Direct access includes 
permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
 
In accordance with ICH GCP and regulatory requirements, this study may be selected for audit 
by the Sponsor or by its designated representatives. Inspection of site facilities (e.g., pharmacy, 
drug storage areas, laboratories) and review of study related records will occur in order to 
evaluate the study conduct and compliance with the protocol, ICH GCP, and applicable 
regulatory requirements. The Investigator will be informed of the audit outcome. 
 
In addition, inspections by regulatory health authority representatives and IRB(s)/IEC(s) are 
possible. The Investigator shall notify the Sponsor immediately of any such inspection. 
 
The Investigator (and Institution, if applicable) agrees to allow the auditor or inspector direct 
access to all relevant documents and allocate his/her time and the time of his/her staff to the 


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auditor/inspector to discuss findings and any issues. Audits and inspections may occur at any 
time during or after completion of the study. 
11.1 Monitoring 
In accordance with ICH GCP, applicable regulations, and Sponsor/CRO’s procedures, monitors 
provide training of the protocol, the study requirements, and the investigator's and site staff's  
responsibilities to satisfy regulatory, ethical, and Sponsor’s requirements prior to the site being 
activated for screening. When reviewing data collection procedures, the discussion also 
includes identification and documentation of source data. 
 
The Monitor performs on-site monitoring visits throughout the study, according to a 
Monitoring Manual, to verify adherence to the protocol; authenticity, completeness, accuracy, 
and consistency of the data; that the rights and well-being of human subjects are protected; 
and adherence to ICH GCP and local regulations on the conduct of clinical research. In certain 
circumstances (e.g., due to the COVID-19 pandemic), remote monitoring will be performed to 
the extent possible by local and site regulations. 
 
The Monitor is responsible for inspecting the case report forms and ensuring completeness of 
the study essential documents by site staff. The Monitor shall have access to subject medical 
records and other study-related records needed to verify entries on the case report forms. 
Monitoring visits (including site visit calls), are conducted in accordance with the Monitoring 
Manual. The Monitor communicates and documents deviations from the protocol, SOPs, ICH 
GCP and applicable regulations to the Investigator and ensures that appropriate action 
designed to prevent recurrence of the detected deviations is taken. The Investigator and study 
site personnel agree to cooperate with the Monitor to ensure that any issues detected in the 
course of the monitoring visits are documented and addressed. 
11.2 Data collection 
The data collection tool for this study is a validated electronic data capture (EDC) system, 
MARVIN. Data required according to this protocol are recorded by Investigator or designee into 
the internet based EDC, which CRO licenses from XClinical. MARVIN is validated by XClinical and 
CRO for use in clinical studies. MARVIN allows for the application of software logic to provide 
data entry screens and data checks to ensure the completeness and accuracy of the data 
entered by the site personnel. CRO applies further logic checks to ensure data are complete and 
reflect the clinical data requirements of the study. Data queries resulting from these checks are 
resolved by the site personnel. 
 
ALL access to MARVIN is regulated through a password-protected security system that is part of 
the MARVIN software. All relevant study personnel (Sponsor, site, CRO or other) seeking access 
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are maintained. All personnel with access to MARVIN are supported by a Service Desk, which is 
staffed with trained personnel to answer questions and ensure access is maintained such that 
data entry can proceed in a timely manner. 
 
Electronic CRF completion guidelines are provided to and reviewed with study personnel 
(including but not limited to Sub-/Co-Investigators, Data Managers and Study Nurses) before 
the start of the study. Completion of the eCRF is kept up-to-date to enable the Monitor to 
review the subject’s status throughout the study. For this purpose, all eCRF data entry must be 
completed within the agreed timeframe of the subject’s visit/contact. The specific 
requirements for AE collection and reporting are detailed in Section 9.1 B. The eCRF is 
completed, reviewed and signed (electronically) by the Investigator. Data entries made in the 
eCRF are supported by source documents maintained for all subjects enrolled in this study at 
the site. The site must implement processes to ensure availability of all required source 
documentation. 
 
Written instructions are provided for collection, preparation, and shipment of plasma samples. 
 
The Investigator or designee must also complete a subject pre-screening log, which lists all 
subjects who were seen to determine eligibility for inclusion in the study including the reason 
for failure of pre-screening. 
 
Data recorded from screen failures 
Data for subjects that have signed IC but were not enrolled into the study (i.e., screen failures) 
are recorded. At a minimum, the following data shall be recorded in the eCRF: 
- 
Demographic information (SID number; year of birth/age; sex) 
- 
Date/time of IC 
- 
Reason for failure of screening 
- 
Date of last visit/contact 
 
If a subject is deemed a screen failure, all AEs experienced during the screening period are 
documented and reported as described in Section 9.1 B. 
11.3 Data management 
Clinical data management is performed according to applicable Sponsor/CRO standards and 
data cleaning procedures. This applies for data recorded in the eCRF as well as data from other 
sources (e.g., laboratory, ECG, AECG). For data coding (i.e., AEs and concomitant medications), 
internationally recognized and accepted dictionaries are used. 


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11.4 Study documentation and storage 
The Investigator maintains an authorized signature log of appropriately qualified personnel to 
whom he/she has delegated study duties. All personnel authorized to make entries and/or 
corrections on eCRFs are included on the authorized signature log. 
 
Source documents are original documents, data, and records from which the subject’s eCRF 
data are obtained. These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
 
The Investigator is responsible for maintaining a comprehensive and centralized filing system 
(Investigator Site File [ISF]) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Sponsor and/or applicable regulatory 
authorities. Essential documents include: 
- 
Subject files containing ICs and supporting copies of source documentation as used for 
eCRF completion. In addition, all original source documents supporting entries in the 
eCRF must be maintained and be readily available. 
- 
Study files containing the protocol with all amendments, the IB (all relevant editions), 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the IRB/IEC and Sponsor. 
- 
Records related to the study drug, including acknowledgment of receipt at site, 
accountability records with final reconciliation, and applicable correspondence. 
 
Essential clinical trial documents (including case report forms) other than subject's medical files 
must be kept for at least 15 years after completion or discontinuation of the trial. Subject's 
medical files shall be retained in accordance with applicable legislation and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. It is the 
responsibility of the Sponsor to inform the Investigator as to when the clinical trial documents 
no longer need to be retained. 
 
No study document may be destroyed without prior written agreement between Sponsor and 
the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify Sponsor in writing of the new responsible 
person and/or the new location. 
11.5 Archiving 
Essential documents are archived in a way that ensures that they can be made readily available 
upon authorities’ request. 
 
Records of subjects, source documents, monitoring visit logs, data correction forms, CRFs, 
inventory of study product, regulatory documents (e.g., protocol and amendments, IRB/IEC 


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correspondence and approvals, approved and signed ICs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence 
pertaining to the study must be kept in appropriate study files at the site.  Source documents 
include all recordings and observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study.  These records are 
retained in a secure file for the period required by the institution or site policy.  Prior to transfer 
or destruction of these records, the Sponsor must be notified in writing and be given the 
opportunity to further store such records. 
12 Financing and insurance 
12.1 Financing 
Before the initiation of the study, the Investigator and/or Institution signs a clinical study 
agreement with the Sponsor (or with its authorized representative). 
12.2 Reimbursement, Indemnity, and insurance 
The Sponsor maintains clinical trial insurance coverage for study subjects in the event of trial-
related injuries, in accordance with the applicable laws and regulations of the country in which 
the study is performed. Also, according to the applicable regulatory requirement(s), the 
Sponsor provides insurance or indemnity (legal and financial coverage) to the 
Investigator/Institution against claims arising from the trial, except for claims that arise from 
malpractice and/or negligence.  
 
Reimbursement, indemnity and insurance is addressed in a separate agreement according to 
the terms agreed upon by the parties. 
13 Publication policy 
The Sponsor fulfils its obligations regarding the public disclosure of study results according to 
applicable laws and regulations. Furthermore, the Sponsor recognizes the right of the 
Investigator to publish the results upon completion of the study. The Investigator shall seek to 
obtain written consent of the Sponsor on any manuscript publication ahead of its submission. 
For this purpose, the Investigator must send a draft of the manuscript to the Sponsor. The 
Sponsor will review and provide feedback on the manuscript content to the Investigator in 
order to reach a mutual final manuscript. 
 
The Sponsor has made information on the study protocol publicly available on the internet at 
www.clinicaltrials.gov. 


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14 Ethics and study administrative information 
14.1 Compliance statement, Ethics and regulatory compliance 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigator uphold 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the Declaration of 
Helsinki. This study will be conducted in compliance with the protocol and in keeping with 
applicable local law(s) and regulation(s). 
 
Documented approval from appropriate IRBs/IECs is obtained for all participating sites before 
start of the study, according to GCP, local laws, regulations and organizations.   
 
Strict adherence to all specifications of this protocol is required for all aspects of study conduct; 
the Investigator may not modify or alter the procedures described in this protocol. 
Modifications to the study protocol may not be implemented by either the Sponsor or the 
investigator without prior approval of a protocol amendment by the IRB/IEC. However, the 
Investigator or the Sponsor may implement a deviation from or a change of the protocol to 
eliminate an immediate hazard(s) to the trial subjects without prior IRB/IEC approval. As soon 
as possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment shall be submitted to the IRB/IEC.  Any deviations from the 
protocol must be explained and documented by the Investigator. 
14.2 Confidentiality 
All records identifying the subject shall be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, not be made publicly available. The Investigator must 
ensure that the subject’s anonymity is maintained. Only the subject number is recorded in the 
eCRF, and if the subject name appears on any other document (e.g., ECG), it must be 
anonymized before a copy of the document is supplied to the Sponsor or its representatives. 
Study findings stored on a computer are stored in accordance with local data protection laws. 
As part of the IC process, subjects are informed in writing that representatives of the Sponsor, 
IRB/IEC, or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection is handled in strictest 
confidence and in accordance with local data protection laws. If the results of the study are 
published, the subject’s identity remains confidential. The Investigator maintains a list of 
subjects to enable subject identification if required. 
14.3 Informed consent 
Before any study-specific procedures take place, it is the Investigator’s responsibility to obtain 
voluntarily-given informed consent, in writing, from the subject after adequate explanation of 
the aims, methods, anticipated benefits, and potential risks of the study. Subjects must have 


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the opportunity to ask questions, receive satisfactory answers to their inquiries, and have 
adequate time to decide whether or not to participate in the study. The Investigator shall 
explain that written approval of the IRB/IEC has been obtained to conduct the study. The 
written IC will be prepared in the local language(s) of the potential subject population. Each 
subject shall be provided a copy of their signed and dated IC. 
14.4 Supply of new information affecting study conduct 
The Sponsor will inform all Investigators involved in the clinical study, IRBs/IECs, and regulatory 
authorities of any new information that may adversely impact the safety of subjects or the 
conduct of the study, and when needed, amends the protocol and/or subject IC. The 
Investigator shall immediately inform the subject whenever new information becomes available 
that may be relevant to the subject’s consent or that may influence the subject’s willingness to 
continue participation in the study. The communication will be documented in the subject's 
medical records, including whether the subject is willing to remain in the study or not. 
 
If the subject IC is revised, it must be re-approved by the IRB/IEC. The Investigator shall obtain 
written IC from the subject to continue participation with the approved revised IC, even if the 
subjects is already informed of any changes verbally. The Investigator or designee and the 
subject shall sign and date the approved revised IC, and a copy of the signed and dated IC shall 
be provided to the subject. 
14.5 Regulatory compliance 
The study protocol, IB, subject information and subject consent form, subject card or written 
instructions to be given to the subject, available safety information, subject recruitment 
procedures, and information about payments and compensation available to the subject shall 
be submitted to the IRB/IEC for ethical review and approval according to local regulations, prior 
to site activation for screening. The written approval should identify all documents reviewed by 
name and version. 
Changes in the conduct of the study or planned analysis are documented in a protocol 
amendment and/or the SAP. 
 
All subsequent substantial protocol amendments and changes to the IC are submitted to the 
IRB/IEC for approval. The Investigator shall notify the IRB/IEC of deviations from the protocol, 
SAEs occurring at the site, and other AE reports received from Sponsor/CRO, in accordance with 
local requirements. 
 
As required by local regulations, the Sponsor or designee ensures all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, prior to site activation for 
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documents happen only after the appropriate notification of or approval by the relevant 
regulatory bodies. 
14.6 Protocol Amendments 
Any amendments to the study protocol as the study progresses are communicated to the 
Investigator by the Sponsor. All protocol amendments must be submitted to the site IRB/IEC for 
review and approval prior to implementation at the site, unless immediate implementation of 
the change is necessary for subject safety.   
14.7 Study termination 
The Sponsor has the right to terminate this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to if 
the benefit-risk ratio becomes unacceptable owing to, for example, 
- 
Safety findings from this study (e.g., SAEs) 
- 
The DSMB has the responsibility for recommending early termination of the study to the 
Executive Committee and the Sponsor, which has ultimate authority/responsibility for 
making the decision. The criteria that the DSMB follows to determine whether/when to 
recommend termination of the study is detailed in DSMB charter (separate document). 
 
The Investigator has the right to close his/her center at any time. 
 
For any of the above closures, the following applies: 
- 
Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing. 
- 
All affected institutions (e.g., IRB(s)/IEC(s); competent authority(ies); study center; head 
of study center) must be informed as applicable according to local law. 
- 
All study materials (except documentation that has to remain stored at site) must be 
returned to the Sponsor. The Investigator retains all other documents until notification 
is given by the Sponsor for destruction. 
- 
In the event of a partial study closure, ongoing subjects, including those in any post-
study follow-up, must be taken care of in an ethical manner. 
 
Details for individual subject's premature termination and withdrawals from the study are 
found in Sections 5.5 A, 5.5 B, and 5.5 C. 
 


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15 References 
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Markey GC, Salter N and Ryan J. Intravenous Flecainide for Emergency Department 
Management of Acute Atrial Fibrillation. J Emerg Med. 2018;54:320-327. 
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Shen MJ, Choi EK, Tan AY, Lin SF, Fishbein MC, Chen LS and Chen PS. Neural mechanisms 
of atrial arrhythmias. Nat Rev Cardiol. 2011;9:30-9. 
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January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., Conti JB, Ellinor 
PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, 
Yancy CW and American College of Cardiology/American Heart Association Task Force 
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fibrillation: a report of the American College of Cardiology/American Heart Association 
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Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, 
Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, 
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McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, 
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Andrikopoulos GK, Pastromas S and Tzeis S. Flecainide: Current status and perspectives 
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Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof 
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Kowey PR, Marinchak RA, Rials SJ and Filart RA. Acute treatment of atrial fibrillation. Am 
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Wakai A and O'Neill JO. Emergency management of atrial fibrillation. Postgrad Med J. 
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Martinez-Marcos FJ, Garcia-Garmendia JL, Ortega-Carpio A, Fernandez-Gomez JM, 
Santos JM and Camacho C. Comparison of intravenous flecainide, propafenone, and 
amiodarone for conversion of acute atrial fibrillation to sinus rhythm. Am J Cardiol. 
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Coll-Vinent B, Fuenzalida C, Garcia A, Martin A and Miro O. Management of acute atrial 
fibrillation in the emergency department: a systematic review of recent studies. Eur J 
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Chen S, Dong Y, Fan J and Yin Y. Rate vs. rhythm control in patients with atrial 
fibrillation--an updated meta-analysis of 10 randomized controlled trials. Int J Cardiol. 
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Li H, Easley A, Barrington W and Windle J. Evaluation and management of atrial 
fibrillation in the emergency department. Emerg Med Clin North Am. 1998;16:389-403. 
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Hohnloser SH, Dorian P, Straub M, Beckmann K and Kowey P. Safety and efficacy of 
intravenously administered tedisamil for rapid conversion of recent-onset atrial 
fibrillation or atrial flutter. J Am Coll Cardiol. 2004;44:99-104. 
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Kochiadakis GE, Igoumenidis NE, Hamilos ME, Marketou ME, Chlouverakis GI and Vardas 
PE. A comparative study of the efficacy and safety of procainamide versus propafenone 
versus amiodarone for the conversion of recent-onset atrial fibrillation. Am J Cardiol. 
2007;99:1721-5. 
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Rozen G, Hosseini SM, Kaadan MI, Biton Y, Heist EK, Vangel M, Mansour MC and Ruskin 
JN. Emergency Department Visits for Atrial Fibrillation in the United States: Trends in 
Admission Rates and Economic Burden From 2007 to 2014. J Am Heart Assoc. 2018;7. 
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Savelieva I, Graydon R and Camm AJ. Pharmacological cardioversion of atrial fibrillation 
with vernakalant: evidence in support of the ESC Guidelines. Europace. 2014;16:162-73. 
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Holmes B and Heel RC. Flecainide. A preliminary review of its pharmacodynamic 
properties and therapeutic efficacy. Drugs. 1985;29:1-33. 
24. 
Roden DM and Woosley RL. Drug therapy. Flecainide. N Engl J Med. 1986;315:36-41. 


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25. 
Wang Z, Page P and Nattel S. Mechanism of flecainide's antiarrhythmic action in 
experimental atrial fibrillation. Circ Res. 1992;71:271-87. 
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Wijffels MC, Dorland R, Mast F and Allessie MA. Widening of the excitable gap during 
pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, 
hydroquinidine, flecainide, and d-sotalol. Circulation. 2000;102:260-7. 
27. 
Shinagawa K, Mitamura H, Takeshita A, Sato T, Kanki H, Takatsuki S and Ogawa S. 
Determination of refractory periods and conduction velocity during atrial fibrillation 
using atrial capture in dogs: direct assessment of the wavelength and its modulation by 
a sodium channel blocker, pilsicainide. J Am Coll Cardiol. 2000;35:246-53. 
28. 
Kirchhof P, Engelen M, Franz MR, Ribbing M, Wasmer K, Breithardt G, Haverkamp W and 
Eckardt L. Electrophysiological effects of flecainide and sotalol in the human atrium 
during persistent atrial fibrillation. Basic Res Cardiol. 2005;100:112-21. 
29. 
Arnsdorf MF and Sawicki GJ. Flecainide and the electrophysiologic matrix: the effects of 
flecainide acetate on the determinants of cardiac excitability in sheep Purkinje fibers. J 
Cardiovasc Electrophysiol. 1996;7:1172-82. 
30. 
Varro A, Bodi I, Jednakovits A and Rabloczky G. Frequency-dependent effects of class I, 
III and IV antiarrhythmic drugs on the conduction and excitability in rabbit ventricular 
muscle. Arch Int Pharmacodyn Ther. 1988;292:157-65. 
31. 
Wang ZG, Pelletier LC, Talajic M and Nattel S. Effects of flecainide and quinidine on 
human atrial action potentials. Role of rate-dependence and comparison with guinea 
pig, rabbit, and dog tissues. Circulation. 1990;82:274-83. 
32. 
O'Hara G, Villemaire C, Talajic M and Nattel S. Effects of flecainide on the rate 
dependence of atrial refractoriness, atrial repolarization and atrioventricular node 
conduction in anesthetized dogs. J Am Coll Cardiol. 1992;19:1335-42. 
33. 
Voigt N, Heijman J, Wang Q, Chiang DY, Li N, Karck M, Wehrens XHT, Nattel S and 
Dobrev D. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients 
with paroxysmal atrial fibrillation. Circulation. 2014;129:145-156. 
34. 
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, 
Baker A, Friedman L, Greene HL and et al. Mortality and morbidity in patients receiving 
encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J 
Med. 1991;324:781-8. 
35. 
Conard GJ and Ober RE. Metabolism of flecainide. Am J Cardiol. 1984;53:41B-51B. 
36. 
Funck-Brentano C, Becquemont L, Kroemer HK, Buhl K, Knebel NG, Eichelbaum M and 
Jaillon P. Variable disposition kinetics and electrocardiographic effects of flecainide 
during repeated dosing in humans: contribution of genetic factors, dose-dependent 
clearance, and interaction with amiodarone. Clin Pharmacol Ther. 1994;55:256-69. 
37. 
McQuinn RL, Quarfoth GJ, Johnson JD, Banitt EH, Pathre SV, Chang SF, Ober RE and 
Conard GJ. Biotransformation and elimination of 14C-flecainide acetate in humans. Drug 
Metab Dispos. 1984;12:414-20. 


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38. 
Conard GJ, Carlson GL, Frost JW, Ober RE, Leon AS and Hunninghake DB. Plasma 
concentrations of flecainide acetate, a new antiarrhythmic agent, in humans. Clin Ther. 
1984;6:643-52. 
39. 
Duff HJ, Roden DM, Maffucci RJ, Vesper BS, Conard GJ, Higgins SB, Oates JA, Smith RF 
and Woosley RL. Suppression of resistant ventricular arrhythmias by twice daily dosing 
with flecainide. Am J Cardiol. 1981;48:1133-40. 
40. 
Sallstrom J, Al-Saffar A and Pehrson R. Pharmacokinetic-pharmacodynamic modeling of 
QRS-prolongation by flecainide: heart rate-dependent effects during sinus rhythm in 
conscious telemetered dogs. J Pharmacol Toxicol Methods. 2014;69:24-9. 
41. 
InCardaTherapeutics. Investigators Brochure. Flecainide acetate inhalation solution (a 
Class ic antiarrhythmic agent) and the aeroeclipse II breath actuated nebulizer (BAN). 
Draft version, 29 Sep 2017. 2017;draft version. 
42. 
Crijns HJ, van Wijk LM, van Gilst WH, Kingma JH, van Gelder IC and Lie KI. Acute 
conversion of atrial fibrillation to sinus rhythm: clinical efficacy of flecainide acetate. 
Comparison of two regimens. Eur Heart J. 1988;9:634-8. 
43. 
Suttorp MJ, Kingma JH, Jessurun ER, Lie AHL, van Hemel NM and Lie KI. The value of 
class IC antiarrhythmic drugs for acute conversion of paroxysmal atrial fibrillation or 
flutter to sinus rhythm. J Am Coll Cardiol. 1990;16:1722-7. 
44. 
Donovan KD, Power BM, Hockings BE, Dobb GJ and Lee KY. Intravenous flecainide versus 
amiodarone for recent-onset atrial fibrillation. Am J Cardiol. 1995;75:693-7. 
45. 
McNamara RL, Tamariz LJ, Segal JB and Bass EB. Management of atrial fibrillation: 
review of the evidence for the role of pharmacologic therapy, electrical cardioversion, 
and echocardiography. Ann Intern Med. 2003;139:1018-33. 
46. 
de Paola AA, Horowitz LN, Morganroth J, Senior S, Spielman SR, Greenspan AM and Kay 
HR. Influence of left ventricular dysfunction on flecainide therapy. J Am Coll Cardiol. 
1987;9:163-8. 
47. 
Josephson MA, Kaul S, Hopkins J, Kvam D and Singh BN. Hemodynamic effects of 
intravenous flecainide relative to the level of ventricular function in patients with 
coronary artery disease. Am Heart J. 1985;109:41-5. 
48. 
US Prescribing Information , Flecainide Acetate Tablets: 50, 100 and 150 mg. Aurobindo 
Pharma Ltd, East Windsor, NJ, USA; December 2017. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14e89448-3a18-42e3-8537-
2589be1ef94e. 
49. 
Nabar A, Rodriguez LM, Timmermans C, Smeets JL and Wellens HJ. Radiofrequency 
ablation of "class IC atrial flutter" in patients with resistant atrial fibrillation. Am J 
Cardiol. 1999;83:785-7, A10. 
50. 
Falk RH. Proarrhythmia in patients treated for atrial fibrillation or flutter. Ann Intern 
Med. 1992;117:141-50. 
51. 
Van Gelder IC, Tuinenburg AE, Schoonderwoerd BS, Tieleman RG and Crijns HJ. 
Pharmacologic versus direct-current electrical cardioversion of atrial flutter and 
fibrillation. Am J Cardiol. 1999;84:147R-151R. 


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52. 
Fresco C and Proclemer A. Clinical challenge. II. Management of recent onset atrial 
fibrillation. PAFIT-2 Investigators. Eur Heart J. 1996;17 Suppl C:41-7. 
53. 
Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Guyton RA, O'Gara PT, 
Ruiz CE, Skubas NJ, Sorajja P, Sundt TM, 3rd, Thomas JD and American College of 
Cardiology/American Heart Association Task Force on Practice G. 2014 AHA/ACC 
guideline for the management of patients with valvular heart disease: executive 
summary: a report of the American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2438-88. 
54. 
Dolgin M FA, Gorlin R, Levin RI. New York Heart Association. Criteria Committee. . 
Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. . 9th 
ed. Boston, MA: Lippincott Williams and Wilkins. March 1, 1994. 
 
 


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16 Protocol Amendments 
Refer to separate Summary of Changes document. 
 


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17 Appendices 
17.1 Appendix 1: Definition of terms 
Abnormal liver function is defined as chronic hepatic disease (e.g., cirrhosis) or biochemical 
evidence of significant hepatic derangement (e.g., bilirubin > 2 times the ULN, in association with 
aspartate aminotransferase/alanine transferase/alkaline phosphatase > 3 times the upper limit of 
normal, and so forth). 
Abnormal renal function is defined as chronic dialysis, renal transplantation, or serum creatinine ≥ 
200 mol/L (≥ 2.26 mg/dL). 
Aortic or mitral stenosis typically refers to a narrowing, stiffening or obstruction of flow at the level 
of the native aortic or mitral valve. The earlier released AHA/ACC heart disease guidelines53 define 
the stages for stenosis. 
Body mass index (BMI) is defined as the body mass divided by the square of the body height, and is 
expressed in units of kg/m2. 
Chronic kidney disease is defined as either kidney damage or glomerular filtration rate (GFR) < 60 
mL/min/1.73 m2 for ≥ 3 months. Kidney damage is defined as pathologic abnormalities or markers 
of damage, including abnormalities in blood or urine test or imaging studies. All individuals with an 
estimated GFR < 30 mL/min/1.73 m2 are classified as having severe renal impairment. 
Heart failure (HF) classification according to the New York Heart Association (NYHA) Functional 
Classification places subjects in one of four categories based on how much they are limited during 
physical activity.54 
Class 
Subject Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on physical activity without discomfort. Symptoms of heart failure at rest. If 
any physical activity is undertaken, discomfort increases. 
 
Paroxysmal AF (PAF), also termed intermittent AF, is defined as an episode of AF that terminates 
spontaneously or with intervention in less than seven days8, 9. 
The QT interval corrected for heart rate (QTc) is estimated according to the Fridericia’s formula1,  
QTcF =
QT
√RRinterval in sec
3
 
 
, and where the RR interval is equal to (60 / HR) and HR is the heart rate in beats per minute. 
Sick sinus syndrome is an ECG diagnosis suggesting sinus node disease. It may be manifested by 
sinus bradycardia, sinus tachycardia, ectopic atrial rhythm, or sinus pauses, alone or in 
combination. 
 
 


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17.2 Appendix 2: Adverse Events: Definitions and classifications of AE 
assessment 
17.2.1 Definitions 
17.2.1.1 
Adverse Events 
In the context of a clinical study, an AE is any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  
 
For the purposes of this study, a recurrence of AF will not be considered as an AE. Atrial 
fibrillation recurrence will be collected in a specific, designated eCRF.  
17.2.1.2 
Serious adverse event 
An SAE (experience) or reaction is any untoward medical occurrence that, at any dose: 
a) results in death. 
b) is life-threatening.  
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe. 
c) requires inpatient hospitalization or prolongation of existing hospitalization.  
NOTE: A hospitalization or prolongation of hospitalization is not regarded as an SAE 
if at least one of the following exceptions is met: 
o The admission results in a hospital stay of less than 24 hours 
o The admission is not associated with an AE (e.g., social hospitalization for 
purposes of respite care). 
However, invasive treatment during any hospitalization may fulfill the criterion of 
‘medically important’ (see below) and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes 
precedence. 
d) results in persistent or significant disability/incapacity. 
e) is a congenital anomaly/birth defect. 
f) is any other medically important condition (see below). 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 


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immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
 
NOTE: A procedure is not an AE or SAE, but the reason for the procedure may be an AE or SAE. 
Treatment requiring hospitalizations for pre-existing conditions which do not worsen in severity 
are not SAEs. 
17.2.2 Classifications for AE assessment 
The following classifications are made by the Investigator, who is a qualified physician, based on 
all available information at the time of completion of the eCRF. 
17.2.2.1 
Seriousness 
The seriousness of each AE must be determined according to definitions provided under 
Section 17.2. 
17.2.2.2 
Intensity 
The intensity of an AE is graded as follows: 
a) Mild: 
 
Discomfort noted, but no disruption of normal daily activity. 
b) Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
c) Severe: 
Inability to work or perform normal daily activity. 
17.2.2.3 
Causal relationship 
Causality is assessed separately for each individual AE and detailed in the eCRF. The assessment 
shall be made based on the available information and can be updated as new information 
becomes available. The assessment is based on whether there is “reasonable causal 
relationship” to the medicinal product in question: 
a) Related: 
- 
The AE follows a reasonable temporal sequence from the assigned regimen 
administration and cannot be reasonably explained by the subject’s clinical 
state or other factors (e.g., disease under study, concurrent diseases, and 
concomitant medications). 
- 
The AE follows a reasonable temporal sequence from the assigned regimen 
administration and is a known reaction to any of the study drug under study 
or its chemical group or is predicted by known pharmacology. 


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b) Not Related: 
- 
The AE does not follow a reasonable sequence from the assigned regimen 
administration or can be reasonably explained by the subject’s clinical state 
or other factors (e.g., disease under study, concurrent diseases, and 
concomitant medications). 
17.2.2.4 
Action taken regarding study drug(s) 
Any action taken on study treatment to resolve the AE is documented in the eCRF as follows: 
a) Dose Not Changed: No change in study drug dosage is made. 
b) Drug Withdrawn: The study drug is permanently stopped. 
c) Dose Reduced: The dosage of study drug is reduced. 
d) Drug Interrupted: The study drug is temporarily stopped. 
e) Dose Increased: The dosage of study drug is increased. 
f) Not applicable: Study drug treatment was completed prior to event, or event 
occurred prior to start of study drug treatment, or subject died. 
17.2.2.5 
Other action taken for event 
If the AE resolution requires any other action, this is captured in the eCRF as follows: 
a) None 
- 
No other treatment was required. 
b) Remedial drug therapy required 
- 
Prescription and/or over-the-counter medication was required to treat the 
AE. 
c) Hospitalization or prolongation of hospitalization required 
- 
Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
d) Other 
17.2.2.6 
Adverse event outcome 
The outcome of each individual AE is documented as follows: 
a) Recovered/Resolved 
- 
The subject fully recovered from the AE with no residual effect observed. 
b) Recovered/Resolved with Sequelae 
- 
The residual effects of the AE are still present and observable. 
- 
Include sequelae/residual effects. 
c) Not Recovered/Not Resolved 
- 
The AE itself is still present and observable. 


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d) Recovering/resolving 
- 
The AE itself is still present and observable, but improving 
e) Fatal 
f) Unknown 
17.3 Appendix 3: Study organization 
17.3.1 Data and Safety Monitoring Board (DSMB) 
An independent DSMB protects the rights, safety and well-being of subjects participating in this 
study. The primary role of the DSMB is to examine the open-label safety data for Part A, Part B, 
Part C (suspected, related SAEs) on an ongoing manner and to alert the Executive Committee in 
case of any clinically concerning safety issues. The frequency and extent of the data reviews by 
the DSMB, details about the reviews, and criteria for evaluating need for study protocol 
modifications are described and specified in the DSMB Charter. 
 
The DSMB can recommend modification of the study protocol, or study, or treatment regimen 
to the Executive Committee based on pre-specified rules described in the DSMB charter. All 
activities of the DSMB are documented. This documentation includes data summaries and 
analyses provided to the DSMB, and all documentation remains confidential within the DSMB 
until the study is completed.  
17.3.2 Executive Committee 
The Executive Committee is responsible for the overall design, conduct, and supervision of the 
study.  The Executive Committee also reviews the progress of the study at regular intervals to 
ensure subject safety and study integrity. The Executive Committee is comprised of designated 
scientific advisors, CRO, and Sponsor. 
17.3.3 Administrative information 
17.3.3.1 
Sponsor 
InCarda Therapeutics, Inc.  
Luiz Belardinelli, MD 
Chief Medical Officer and US Medical Monitor 
39899 Balentine Drive, Suite 185 
Newark, CA 94560, USA 
Tel.: +1 (650) 704-2805 
 
 


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17.3.3.2 
CRO 
Cardialysis 
Westblaak 98, 3012 KM Rotterdam, The Netherlands 
Tel.: +31(0) 206 2828 
Fax: +31(0) 206 2844 
17.3.3.3 
Data Management 
Cardialysis 
Westblaak 98, 3012 KM Rotterdam, The Netherlands 
Tel.: +31(0) 206 2828 
Fax: +31(0) 206 2844 
17.3.3.4 
Safety Management 
PrimeVigilance 
1 Occam Court 
Surrey Research Park 
Guildford, Surrey 
GU2 7HJ 
United Kingdom 
Tel.: +44 1483 307920 
Tel.: (+) 781-703-5540 
 
 


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17.4 Appendix 4: Schedule of Assessments 
17.4.1 PRE-STUDY SCREENING  
Table 3 - Pre-Study Screening - Schedule of Assessments  
Period 
Pre-Study Screening 
Day 
Pre-Study Screening 1 
Clinic Visits 2 
Assessment 
Informed consent 
X 
 
Contact eCRF for SID 
X 
 
Demographic information 
X 
 
Medical history  
X 
 
AeroEclipse II BAN (training) 
X 
X 
1 For subjects who (a) are prescribed a pill-in-the-pocket regimen (flecainide or propafenone) for paroxysmal AF, (b) are 
within 3 months of undergoing ablation of paroxysmal AF, (c) have experienced an episode of new AF but are not currently 
experiencing an episode of recent-onset paroxysmal AF, or (d) are known to have paroxysmal AF (or previously diagnosed 
with paroxysmal AF) and have had one or more previous symptomatic episodes but are not currently experiencing an 
episode of recent-onset paroxysmal AF. 
2 If the subject returns to clinic for a visit with the Investigator (related or unrelated to the study), repeat training and 
practice with the inhaler should be performed if possible. 
 
 
 


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17.4.2 PART A: Schedule of Assessments 
Refer to a previous version of the protocol. 
 


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17.4.3 PART B and PART C Medically-Led Cardioversion Study: Schedule of Assessments 
Table 4 - PART B and PART C Medically-Led Cardioversion Study 120 mg FlecIH-103 (75 mg/mL) REPEAT DOSE REGIMEN - Schedule of Assessments  
Period 
Screening 
Treatment 
Extended observation 
Follow-up 
 
Day 1 
Day 2 
Day 5 ±1 
Phase 
Pre-screening 
AF-monitoring 
1st IH 
Break 
2nd IH 
Post dose 
At SR 
Visit 1 
Visit 2= EOS 
Time points (min) 1 
≥ —45 
—45 
—30 
—15 
0 – 3.5 
3.5 - 4.5 
4.5 - 8 
1 
3 
10 
30 
60 
90 2 
t 3 
 
 
Assessment 
Qualification criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact eCRF for SID 4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AF stability 
 
Continuous 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Handheld echocardiogram 6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Remote ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Telemetry 
 
Continuous 
 
 
AECG 
 
Continuous 
 
 
ECG extracted from AECG 7 
 
X 
X 
X 
X 8 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs 9 
 
X 
X 
X 
X 8 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PK blood sample 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Enrollment (Allocation) in eCRF 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AeroEclipse II BAN (training) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study drug 10 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Subject in seated position 11 
 
 
Continuous 
 
 
 
 
 
 
 
 
 
Hematology panel 12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive metabolic panel 12 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Coagulation panel 12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy test 12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment satisfaction questions 13 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
AF symptoms 
 
 
 
 
X 8 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Concomitant medications & therapies 
 
Continuous 
Adverse events 
 
Continuous 
1 Time zero is the start of the inhalation. Time points after dosing are based on the end time of the inhalation (e.g., 1 = 1 minute 
post completion of dosing). 
2 Assessments have a ±10-minute window (i.e., 80-100 minutes) 
3 The actual time of conversion to SR is recorded. 
4 Only if not already done during pre-study screening 
5 Including height, weight and derived-BMI at baseline and auscultation of the heart and the lungs. 
6 A diagnostic echocardiogram using a Sponsor-provided handheld portable ultrasound device (HHE) is performed during screening 
to evaluate for exclusionary structural heart or functional abnormality for US subjects who do not already have a standard 
diagnostic echocardiogram (including LVEF) within 6 months prior to screening, or for EU subjects who have specifically consented 
to the HHE Sub-Study. 
7 Triplicate ECGs are extracted from the AECG by the ECG Core Laboratory after data are transmitted by the site. ECGs are extracted 
within 5 minutes after the scheduled time point or up to the next scheduled time point, whichever comes first. 
8 Just before starting inhalation (IH) regimen. 
9 Heart rate, systolic and diastolic blood pressure, respiratory rate (breaths/min) and SpO2. Body 
temperature is recorded at screening only. When time-points coincide for blood draws and vital 
signs, procedures are performed in that order. 
10 Record the start and stop times for each inhalation stage. If a subject's AF converts to SR within 
the first inhalation stage, then the break and the second inhalation stage will not take place. 
11 The subject shall be seated upright after the –30-minute time point assessments are completed.  
12 Refer to Section 9.2 B. 
13 After 90 minutes post dose and prior to discharge, subjects whose AF is converted to SR by 
study drug will be asked questions related to their treatment satisfaction (refer to Section 7.4 B).  


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Study no. FLE-002 
Date 
16Feb2021 
Version 
8.0 EU-1 
Page: 114 of 117 
 
 
17.4.4 PART C Patient-Led Under Medical Supervision Cardioversion Study: Schedule of Assessments 
Table 5 – PART C Patient-Led Under Medical Supervision Cardioversion Study 120 mg FlecIH-103 (75 mg/mL) REPEAT DOSE REGIMEN - Schedule of 
Assessments  
Period 
Consenting 
Training 
Treatment (one recurrent episodes) 1 
Follow-up 
Visit 
Before or 
on Day 1 
Training 
Visit 
Phone 
Calls 
Clinic Visits 
Day 1 
Day 2 
Day 5 
Phase 
 
 
 
 
Before Dosing 
During Dosing 
After Dosing 
 
 
 
Visit Window / Time point (min) 2 
 
 
Monthly 
Q3 months 
~ 30 
– ≤ 10 
 
1 
3 
10 
30 
60 
90 
At SR 3 
+1 day 
±1 day 
Assessment 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Train subject on self-
administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject performs self-
administration evaluation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site certifies subject in self-
administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/CM check 
 
X 
X 
X 
Continuous 
X 
X 
Subject watches training video 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject completes refresher 
training (in clinic or by video call) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Changes to medical history 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum creatinine 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum potassium 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum/urine pregnancy test 4 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 5 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PK blood sample 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Symptom-driven physical 
examination 6, 7 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Telemetry 
 
 
 
 
Continuous 
 
 
AECG (Holter)10 
 
 
 
 
Continuous 
 
 
Vital signs 8 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
AF-related symptoms 7 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
Self-administration of drug 9 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
AE = adverse event; CM = concomitant medication; AECG = ambulatory electrocardiogram; PK = 
pharmacokinetic 
1 Subjects may return for to self-administer study drug for any recurrent episode of symptomatic paroxysmal 
AF within 8 months after signing informed consent.  
2 Time zero (T0) is the start of the inhalation. Time points after dosing are based on the end time of the 
inhalation (e.g., 1 = 1-minute post dose).  
3 Actual time of conversion to SR is recorded. 
4 For female subjects of child-bearing potential only  
5 To confirm AF diagnosis  
6 Per investigator discretion  
7 Any time prior to dosing 
8 Heart rate, systolic and diastolic blood pressure, respiratory rate (breaths/min), SpO2, and body 
temperature. Body temperature is recorded at 30 min pre-dose only. Weight must be recorded any time 
prior to dosing to confirm creatinine clearance eligibility. When time-points coincide for blood draws and 
vital signs assessment, procedures are performed in said order. 
9 Record each inhalation's start and stop times, as applicable.  
10 ECGs may be extracted per the timepoints specified in the Part B/Part C Medically-Led Cardioversion 
Study Schedule of Assessments 
11 Assessments have a ±10 minute window (i.e. 80-100 minutes) 


INSTANT Study 
Clinical Study Protocol 
Study no. FLE-002 
Date 
16Feb2021 
Version 
8.0 EU-1 
Page: 115 of 117 
 
 
17.5 Appendix 6: Handheld Echo (HHE) Sub-Study  
17.5.1 HHE Sub-Study design 
Subjects who consent to participate in Part B or in the Part C Medically-Led Cardioversion Study 
may also consent to participate in this optional HHE Sub-Study. If they consent, they will 
undergo a diagnostic echocardiogram (Figure 7) using the Sponsor-provided portable 
ultrasound device. The assessments and measurements to be made from the echocardiogram 
are described in Section 17.5.4. Only subjects with assessments that are normal, minimal, or 
absent, will be eligible for the study. If the subject's HHE indicates the subject has a clinically 
significant enlarged LV and/or reduced EF, or clinically significant structural heart disease (e.g., 
LV hypertrophy, valvular disease), they will be considered ineligible for enrollment and 
recorded as a screen failure. The Sub-Study design is shown in Figure 7. 
 
Figure 7. HHE Sub-Study Design 
  
 
17.5.2 HHE Sub-Study population and eligibility criteria 
Approximately 20 subjects (only at select EU sites) are expected to participate in this HHE Sub-
Study. These 20 subjects will be a subset of those who consent to participate in Part B and the 
Medically-Led Cardioversion Study in Part C. 
yes
Subject 
consents to 
Sub-Study
Subject 
undergoes a 
diagnostic 
echocardiogram 
using a portable 
ultrasound 
device
Subject not 
eligible; 
screen failure
Normal LVEF 
(≥ 45%)
no
Subject 
continues 
screening for 
Part B or the 
Medically-Led 
Cardioversion 
Study in Part C
Part B or Medically-Led Cardioversion Study in Part C Screening Period
No clinically 
significant 
valvular 
disease
No clinically 
significant 
structural 
heart 
disease


INSTANT Study 
Clinical Study Protocol 
Study no. FLE-002 
Date 
16Feb2021 
Version 
8.0 EU-1 
Page: 116 of 117 
 
 
17.5.3 HHE Sub-Study procedures 
The recording of the echocardiogram must be obtained during the screening period for Part B, 
as described in Figure 7 above.  
17.5.3.1 
HHE Sub-Study Consenting 
Subjects who have consented to Part B or the Medically-Led Cardioversion Study in Part C may 
consent to this Sub-Study during the screening period. Only after signing consent for the Sub-
Study may the subject undergo any Sub-Study-related procedures. 
17.5.3.2 
HHE Sub-Study Evaluation 
After providing informed consent for this Sub-Study, subjects will undergo a diagnostic 
echocardiogram using a Sponsor-provided handheld portable ultrasound device (HHE). The site 
staff will evaluate the subject's echocardiogram for any structural heart and functional 
abnormality. Subjects with exclusionary valvular or structural heart disease (as per exclusion 
criteria, refer to Section 4.2 B) or clinically significant enlarged LV or decreased EF observed on 
the echocardiogram will be considered ineligible for enrollment and recorded as screen failures. 
17.5.4 HHE Sub-Study assessments 
17.5.4.1 
HHE Sub-Study Portable cardiac ultrasound 
Subjects undergo a diagnostic echocardiogram using a Sponsor-provided handheld portable 
ultrasound device (HHE) on Day 1 during the screening period. The subject may not be enrolled 
until evaluation of the echocardiogram is completed. 
 
The following data will be recorded from the HHE: 
• Date and time HHE administered 
• Who performed the HHE (e.g., professional title or study role) 
• Date and time HHE report/results became available 
• Who analyzed the HHE (e.g., professional title or study role) 
• The following assessments will be recorded: 
o LV size 
o LVEF  
o LV hypertrophy 
o Valvular disease 
o Other clinically significant findings 
 
HHE data will be submitted to an independent reviewer, at a later time, to compare with the 
assessments made by the site staff during the screening period. This independent review will 
not be used for the assessment of subject eligibility during screening. 


INSTANT Study 
Clinical Study Protocol 
Study no. FLE-002 
Date 
16Feb2021 
Version 
8.0 EU-1 
Page: 117 of 117 
 
 
17.5.5 HHE Sub-Study Other assessments 
17.5.5.1 
HHE Sub-Study Feasibility assessments 
The following parameters will be evaluated for feasibility in an exploratory manner: 
• Successful capture of the following data: 
o Left ventricular size 
o Left ventricular ejection fraction (LVEF) 
o Left ventricular hypertrophy 
o Valvular disease 
• 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 
17.5.6 HHE Sub-Study Schedule of Assessments 
Table 6 - HHE Sub-Study - Schedule of Assessments  
Visit 
Day 1 
Phase 
Screening 
Assessment 
Informed consent 
X 
Diagnostic 
echocardiogram (HHE) 1 
X 
1  A diagnostic echocardiogram using a Sponsor-provided handheld portable ultrasound device 
(HHE) will be performed during screening and prior to enrollment to evaluate for exclusionary 
structural heart or functional abnormality.