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Trial registered on ANZCTR


Registration number
ACTRN12621000718842
Ethics application status
Approved
Date submitted
2/03/2021
Date registered
9/06/2021
Date last updated
1/10/2023
Date data sharing statement initially provided
9/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Open-Label, Randomized, Single Dose Study of Flecainide Acetate Inhalation Solution (FlecIH-103) to Flecainide Acetate Intravenous Infusion (Tambocor®) to Compare Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers
Scientific title
A Phase 1, Open-Label, Randomized, Single Dose Study of Flecainide Acetate Inhalation Solution (FlecIH-103) to Flecainide Acetate Intravenous Infusion (Tambocor®) to Compare Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers
Secondary ID [1] 303567 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrillation 320936 0
Condition category
Condition code
Cardiovascular 318745 318745 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Inhaled flecainide acetate inhalation solution as compared to IV flecainide (currently approved as tambacor)
The dose will be 70 mg administered once over 2 inhalations
Serial PK samples and ECGs will be analyzed for PK/PD assessments
There will be an approximately 1 week washout period between treatments of inhaled flecainide and IV administration. The treatment sequence will be randomized.
Intervention code [1] 319858 0
Treatment: Drugs
Comparator / control treatment
IV flecainide; 70 mg once
Serial PK samples and ECGs will be analyzed for PK/PD assessments
Control group
Active

Outcomes
Primary outcome [1] 326692 0
This is a composite primary outcome and is to directly compare the pharmacokinetics (PK) and pharmacodynamics (PD) of the same dose (70 mg) of flecainide acetate administered via oral inhalation of flecainide acetate inhalation solution (FlecIH-103, 75 mg/mL) versus intravenous infusion of commercially available flecainide acetate solution (Tambocor® injection 10 mg/mL)
Pharmacokinetics assessed by analysis of plasma samples for Cmax, tmax, AUC, and t1/2; Pharmacodynamics assessed by measurement of QRS duration, heart rate and heart rate variability on ECG, FEV1 and FVC on lung spirometry, and blood pressure measured by sphygmomanometer
Timepoint [1] 326692 0
Serial timepoints for PK and PD assessments. PK samples and ECGs will be collected at baseline, 1, 3, 5, 10, 15, 30, 60 minutes, and 2, 4, 6, 12 and 24 hours.
Secondary outcome [1] 392377 0
To determine the systemic bioavailability of FlecIH-103 administered via oral inhalation as compared to IV flecainide. Serial PK and ECG timepoints will be collected to compare the bioavailability of FlecIH-103.
Timepoint [1] 392377 0
Serial timepoints for PK and PD assessments. PK samples and ECGs will be collected at baseline, 1, 3, 5, 10, 15, 30, 60 minutes, and 2, 4, 6, 12 and 24 hours.
Secondary outcome [2] 395445 0
To assess the safety of oral inhaled flecainide
Timepoint [2] 395445 0
Adverse events, vital signs, and heart rhythm will be monitored during the course of the study to evaluate overall safety. The following timepoints apply:
Vital Signs: screening, Day -1, Day 1, Day 2 in each period
Blood Pressure: Pre dose at -60, -45, -30, -25, -15 minutes, and T0. Post dose at 1, 3, 4, 10, 15, 30, 60 minutes, 2, 4, 12, 24 hours.
12-Lead Holter will monitor ECGs continuously through 24 hours
Adverse Events will be monitored continuously

Eligibility
Key inclusion criteria
Be males or females, 18 to 55 years of age (inclusive), with body mass index (BMI) between 20 and 32 kg/m2 (inclusive) and a body weight (BW) greater than or equal to 70 kg, no significant medical history, and in good general health as determined by the PI or delegate at the clinical facility.
• Be non-smokers or former smokers who have not consumed tobacco, e-cigarettes and/or marijuana products within 6 months of Day 1 AND have a less than or equal to 5 pack year previous history. Light smokers who have consumed less than or equal to 5 cigarettes per week within 6 months of Day 1 AND who do not have a 5 pack per year previous history are eligible, but must abstain from smoking for 30 days prior to Day 1. All participants must pass a cotinine urine test to be enrolled.
• Have no evidence of asthma, chronic obstructive pulmonary disease (COPD) or major pulmonary airway disease, including participants with established pulmonary disease in need of inhalation medication (participants with history of childhood asthma but no subsequent episodes are eligible).
• Have no history of heart disease, including but not limited to, coronary artery disease, myocardial infarction, heart failure of any cause, clinically significant cardiac arrhythmias and valvular heart disease.
• Have no previous invasive cardiac procedures (participants having undergone invasive cardiac procedures which definitively demonstrated no cardiac issues are eligible).
• Have no clinically significant family history of cardiac arrhythmias, acquired or congenital.
• Have not participated in any other investigational study within 30 days prior to dose administration or within 5 half-lives of the experimental drug (whichever is longer).
• Have to meet a number of specific cardiovascular (measured with a 12-lead ECG) and hemodynamic parameters, as follows:

Heart Rate (HR) greater than 47 bpm
PR Interval less than or equal to 190 ms
QRS interval less than or equal to 105 ms
QTcF (QT interval corrected using Fridericia’s formula) less than or equal to 450 ms for males and less than or equal to 460 ms for females
Systolic Blood Pressure (BP) of greater than or equal to 100 to less than or equal to 140 mmHg
Diastolic BP of greater than or equal to 60 to less than or equal to 100 mmHg

•Have no clinical significant abnormalities detected on a standard diagnostic echocardiogram
• Have to meet a number of specific pulmonary assessments related to pulmonary function testing:

FEV1 (forced expiratory volume in 1 second) – report the largest value greater or equal to 80% of normal values
FVC (forced vital capacity) – report the largest value greater than or equal to 80% of normal values
Normal chest X-ray indicating no clinically significant anomaly
Oxygen saturation greater than 95%
FEF (forced expiratory flow) 25-75% - report the value from the test with the highest sum of FEV1 + FVC greater than or equal to 70% of predicted.
The average expired flow over the middle half of the FVC maneuver. It is regarded as a more sensitive measure of small airways narrowing than FEV1.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Evidence of asthma, chronic obstructive pulmonary disease (COPD) or major pulmonary airway disease, including participants with established pulmonary disease in need of inhalation medication; (participants with history of childhood asthma but no subsequent episodes are eligible)
2. Evidence of early repolarization pattern in the ECG, defined as elevated J-Point or end-QRS slurring with or without concave ST-segment elevation [MacFarlane, 2015]. A J-Point elevation of greater than or equal to 0.1 mV and prominent end-QRS notch or slur in 2 contiguous ECG leads should be flagged for review by the study cardiologist and/or medical monitor. Minor findings are considered acceptable.
3. History of heart disease such as, coronary artery disease, MI, cardiac arrhythmias, valvular heart disease and heart failure.
4. Previous invasive cardiac procedures (participants having undergone invasive cardiac procedures which definitively demonstrated no cardiac issues are eligible);
5. Clinically significant family history of cardiac arrhythmias, acquired or congenital (e.g., Brugada and/or long-QT syndromes), unexplained sudden cardiac death, and/or unexplained syncope
6. Family history of congenital airway lung obstructive disease
7. Use of prescription medication or over-the-counter products (including other antiarrhythmic drugs, anticoagulants and BP lowering drugs, medications known to prolong the QTc interval, natural food supplements, vitamins, and garlic as a supplement) within 7 days prior to administration of study treatment, except for topical products without systemic absorption, paracetamol, and/or protocol-compliant contraceptives

8. Any contraindications to flecainide as per Tambocor package insert
9. Has experienced any symptomatic heart failure (per New York Heart Association [NYHA] guidelines), or history of impaired LVEF.
10. Has human immunodeficiency virus infection, as shown by the presence of anti-human immunodeficiency virus (HIV) antibody (sero-positive).
11. Is sero-positive for hepatitis B or hepatitis C virus, and/or a history of delta virus hepatitis.
12. Has uncontrolled hypertension: Blood pressure (BP) greater than 150/100 mmHg.
13. Has a history of torsades de pointes, atrial and/or ventricular rhythm disturbances (e.g., atrial or ventricular tachycardia or fibrillation), sinus bradycardia (less than or equal to 47 bpm), Cardiac Conduction Disease (AV Nodal Block or PR interval greater than 190 ms), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG.
14. Has had episodes of syncope, including during blood draw.
15. Currently abuses and/or has a history of alcohol and/or drug abuse less than 12 months from Screening.
16. Regularly uses excessive alcohol within six months prior to the Screening visit (i.e., more than fourteen units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40 % alcohol]).
17. Has a positive standard 10x panel drug test at Screening and/or has a history of drug abuse within 12 months from Screening.
18. Use of investigational agents or devices within 30 days or 5 half-lives (whichever is longer) prior to planned study dosing or current participation in an investigational study
19. Has a clinically significant history or presence of any gastrointestinal pathology (e.g., chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g., diarrhea, vomiting), liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
20. Has any clinically significant history or presence of neurological, endocrine, cardiovascular, pulmonary, haematological, immunologic, psychiatric, metabolic or other uncontrolled systemic disease.
21. Has donated blood (greater than or equal to 500 mL) within 7 days prior to study treatment administration. Donation or loss of whole blood (excluding the volume of blood that will be drawn during the screening procedures of this study) prior to administration of the study treatment as follows: 50 mL to 499 mL of whole blood within 30 days, or more than 499 mL of whole blood within 56 days prior to study treatment administration.
22. Presence of any concomitant medical or psychiatric condition or social situation that, in the opinion of the PI, would make it difficult to comply with protocol requirements or put the participant at additional safety risk
23. Is unable or unwilling to return for all scheduled study visits.

24. Has any other condition that, in the opinion, of the PI would render the participant unsuitable for enrolment or could interfere with his/her participation in the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Safety:
In general, safety analyses will be performed, and the results will be summarized by treatment groups. Baseline safety assessments will be compared with measurements recorded post-baseline. Treatment-emergent AEs will be summarized using the latest version of MedDRA by System Organ Class (SOC) and preferred term, classified from verbatim terms. The incidence and frequency of AEs, ADEs, SAEs, SADEs, related AEs, related SAEs, related SADEs and SUSARS will be summarized by dose and treatment group according to SOC and Preferred Terms. AEs and ADEs will also be summarized in listings. The duration of AEs and ADEs will be determined and included in listings, along with the action taken and outcome. Laboratory results will be classified according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 and summarized by treatment group. Laboratory results not corresponding to a coded term will not be graded. The incidence of laboratory abnormalities will be summarized. Vital signs measurements will be summarized at each scheduled time point using descriptive statistics. Physical examination findings will be summarized by time point and presented in participant listings. Overall changes in cardiac (12-lead ECG and telemetry), hemodynamic (systemic BP) and pulmonary function (chest X-ray, lung spirometry, auscultation) parameters will be summarized. Additionally, changes from baseline and qualitative assessments will be captured.
Pharmacokinetics:
Plasma concentrations following a single administration of FlecIH-103 (70 mg) will be used to calculate the following PK parameters: Cmax, tmax, AUC0-24, AUCinf, 97kel, and t1/2. These PK parameters will also be calculated for IV flecainide acetate. Pharmacokinetic parameters will be determined using non-compartmental method(s). Descriptive statistics of PK parameters will include mean, standard deviation, and coefficient of variation.

Pharmacodynamics:
Electrocardiographic, hemodynamic and lung spirometry results at baseline, each post-dose assessment and the change from baseline will be analysed and summarized by treatment groups.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
22/11/2022
Actual
22/11/2022
Date of last participant enrolment
Anticipated
21/12/2022
Actual
5/01/2023
Date of last data collection
Anticipated
30/12/2022
Actual
14/01/2023
Sample size
Target
18
Accrual to date
Final
19
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23314 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 38687 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 307990 0
Commercial sector/Industry
Name [1] 307990 0
InCarda Therapeutics Australia Pty Ltd.
Country [1] 307990 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
InCarda Therapeutics Australia Pty Ltd.
Address
Level 13, 41 Exhibition Street
Melbourne
VIC 3000, Australia
Country
Australia
Secondary sponsor category [1] 308712 0
None
Name [1] 308712 0
None
Address [1] 308712 0
NA
Country [1] 308712 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307984 0
Bellberry HREC
Ethics committee address [1] 307984 0
Ethics committee country [1] 307984 0
Australia
Date submitted for ethics approval [1] 307984 0
24/08/2022
Approval date [1] 307984 0
07/10/2022
Ethics approval number [1] 307984 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 109134 0
Dr Sepehr Shakib
Address 109134 0
CMAX Clinical Research
Level 6, 21 North Terrace | Adelaide SA 5000 | AUSTRALIA
Country 109134 0
Australia
Phone 109134 0
+61 0411 100 278
Fax 109134 0
Email 109134 0
sepehr.shakib@cmax.com.au
Contact person for public queries
Name 109135 0
Kate Beard
Address 109135 0
CMAX Clinical Research
Level 6, 21 North Terrace
Adelaide SA 5000
AUSTRALIA
Country 109135 0
Australia
Phone 109135 0
+618 7088 7900
Fax 109135 0
Email 109135 0
Kate.Beard@cmax.com.au
Contact person for scientific queries
Name 109136 0
Shakib Sepehr
Address 109136 0
CMAX Clinical Research
Level 6, 21 North Terrace
Adelaide SA 5000
AUSTRALIA
Country 109136 0
Australia
Phone 109136 0
+618 7088 7900
Fax 109136 0
Email 109136 0
sepehr.shakib@cmax.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.