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Trial registered on ANZCTR


Registration number
ACTRN12620000461998
Ethics application status
Approved
Date submitted
24/03/2020
Date registered
9/04/2020
Date last updated
19/11/2020
Date data sharing statement initially provided
9/04/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of FlecIH-104 in Healthy Volunteers
Scientific title
A Phase 1, Open-Label, Single Ascending Dose Study of FlecIH-104 (Flecainide Acetate Inhalation Solution) to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers
Secondary ID [1] 300847 0
FLE-014
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paroxysmal atrial fibrillation 316757 0
Condition category
Condition code
Cardiovascular 314982 314982 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A single dose of FlecIH-104 (flecainide acetate inhalation solution) administered via oral inhalation as described below:
- 35 mg FlecIH-104: 1 inhalation stage of 2 minutes
- 70 mg FlecIH-104: 2 inhalation stages of 2 minutes each, with a 1-minute break in between
- 90 mg FlecIH-104: 2 inhalation stages of 2.5 minutes each, with a 1-minute break in between
Each inhalation stage consists of the participant inhaling aerosolized FlecIH-104 through the mouth using a breath-actuated nebuliser for the specified time.
The study will first enrol 6 participants at the 35 mg dose, then 6 participants at the 70 mg dose, and finally 6 participants at the 90 mg dose. Each participant will only receive one dose (the dose to which they are assigned).
Monitoring of adherence to the inhalation procedure will be done by direct observation by study personnel.
Intervention code [1] 317175 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 323287 0
To evaluate the safety and tolerability of a single 35, 70, and 90 mg doses of FlecIH-104 in healthy volunteers. This will be assessed by looking at the incidence, severity, causality and seriousness of adverse events; changes in clinical laboratory evaluations; changes in vital signs parameters, physical examinations; and ECGs (electrocardiograms).
Clinical laboratory evaluations include biochemistry, haemotology, coagulation, and urinalysis. Physical examinations include complete and symptom-driven physical examinations, heart and lung auscultations, and lung spirometry.
Timepoint [1] 323287 0
Adverse events will be recorded from the start of inhalation study drug on Day 1 through the end of the study (Day 9). Clinical laboratory evaluations will be assessed on Day -1 and on Day 2. Vital sign parameters will be assessed on Day 1 prior to dosing and on Day 2. A complete physical examination will be completed during screening (and on Day 1 if the screening physical examination was done more than 2 weeks prior) and a symptom-driven physical examination will be done on Day 2. Heart and lung auscultations are assessed on Day -1, multiple time points on Day 1 (15, 30, 45, and 60 minutes post dose, and 2 and 4 hours post dose), and on Day 2. Lung spirometry is assessed on Day -1, 3-4 hours post dose on Day 1, and on Day 2. ECGs are recorded at multiple time points on Day 1 (45, 30, 25, and 15 minutes prior to dosing; just prior to dosing; just before the end of each inhalation stage; during the 1-minute break between inhalation stages [if applicable]; at the end of dosing; 1, 3, 5, 10, 15, 30, and 60 minutes post dose; and 2, 4, and 12 hours post dose) and on Day 2.
Secondary outcome [1] 381441 0
Pharmacokinetics (Cmax, Tmax, AUC0-24, AUCinf, 97kel, and T1/2) of the 35, 70, and 90 mg doses of FlecIH-104 in plasma following administration of FlecIH-104 in healthy volunteers
Timepoint [1] 381441 0
Blood samples for pharmacokinetic analysis will be obtained at the following time points: pre-dose, during dosing (two samples during the approximately 1-minute breaks in between each of the inhalation stages [75 and 90 mg doses only] and one sample at the end of dosing), and at 1, 3, 5, 10, 15, 30, and 60 minutes and 2, 4, 6, 12 and 24 hours after the completion of inhalation.
Secondary outcome [2] 381442 0
Pharmacodynamics of the 35, 70, and 90 mg doses of FlecIH-104 by measuring electrocardiogram (ECG) intervals (QRS interval, PR interval, QTc, and JTc) following administration of FlecIH-104 in healthy volunteers
Timepoint [2] 381442 0
ECGs for pharmacodynamic analysis will be obtained at the following time points: prior to dosing (60, 45, 30, 25, and 15 minutes pre-dose), during dosing (one recording during the approximately 1-minute break in between inhalation stages [70 and 90 mg only] and one recording at the end of dosing), and at 1, 3, 5, 10, 15, 30, and 60 minutes and 2, 4, 12 and 24 hours after the completion of inhalation.

Eligibility
Key inclusion criteria
1. Male or female, 18 to 55 years of age (inclusive), at the time of screening;
2. Agree to use protocol specified method(s) of contraception, if a male participant or a female participant of childbearing potential who engages in heterosexual intercourse;
3. Agree to refrain from egg or sperm donation for the duration of the study;
4. Able and willing to sign the informed consent as approved by the Human Research Ethics Committee (HREC);
5. Have a body mass index (BMI) between 18.5 and 32 kg/m2 and a BW greater than or equal to 55 kg;
6. No significant medical history, and in good general health;
7. Have no electrocardiographic abnormalities during a 12-lead ECG screening that, in the opinion of the PI (or delegate), may compromise the participant’s safety in the study;
8. Have no clinically significant abnormalities detected on a standard diagnostic echocardiogram;
9. Be non-smokers (including tobacco, e-cigarettes and marijuana) without a significant smoking history (former cigarette smokers with less than or equal to 5 pack years history are eligible) or be light smokers (less than or equal to 5 cigarettes per week) who abstain from smoking for 30 days prior to Day 1. Up to 2 light smokers per cohort will be allowed to enrol. All participants must pass a cotinine urine test to be enrolled;
10. Be willing and able to comply with all study assessments and adhere to the protocol schedule;
11. Have suitable venous access for blood sampling and/or injection of medication if needed;
12. Have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values less than 1.5 times the upper limit of normal (ULN) and Cockcroft-Gault estimated creatinine clearance greater than 70 mL/min at screening;
13. Have electrolytes within the normal range (specifically potassium greater than or equal to 3.8 MEq/L) at screening;
14. Have no abnormal finding of clinical significance at screening;
15. Has specific cardiovascular parameters measured using a 12 lead ECG and other hemodynamic criteria:
Heart Rate (HR): greater than or equal to 50 bpm
PR Interval: less than or equal to 190 ms
QRS interval: less than or equal to 105 ms
QTcF duration: less than or equal to 450 ms for males, less than or equal to 460 ms for females
Systolic BP: between 100 and 140 mmHg, inclusive
Diastolic BP: between 60 and 100 mmHg, inclusive
16. Has specific pulmonary parameters related to pulmonary function:
FEV1 (forced expiratory volume in 1 second): greater than or equal to 80% of normal values
FVC (forced vital capacity): greater than or equal to 80% of normal values
FEF (forced expiratory flow) 25-75%: greater than 75% of predicted.
Chest X-ray: Normal chest X-ray indicating no clinically significant anomaly
Oxygen saturation: greater than 95%
Minimum age
18 Years
Maximum age
55 Years
Gender
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;
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 blood pressure 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 oral contraceptives;
8. Any contraindications to flecainide as per Tambocorâ„¢ 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 50 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 equals 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 or admits to a history of drug abuse;
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, hematological, 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 enrollment or could interfere with his/her participation in the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Statistical Analysis will be performed using SAS v9.3 (SAS Institute, Cary, USA).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 16155 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 29689 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 305303 0
Commercial sector/Industry
Name [1] 305303 0
InCarda Therapeutics Australia, Pty, Ltd
Address [1] 305303 0
Level 13, 41 Exhibition Street
Melbourne
VIC 3000, Australia
Country [1] 305303 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] 305666 0
None
Name [1] 305666 0
Address [1] 305666 0
Country [1] 305666 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305642 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 305642 0
The Alfred Hospital,
55 Commercial Road,
Melbourne VIC 3004
Ethics committee country [1] 305642 0
Australia
Date submitted for ethics approval [1] 305642 0
01/04/2020
Approval date [1] 305642 0
13/05/2020
Ethics approval number [1] 305642 0

Summary
Brief summary
This research project is being conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single 35, 70, and 90 mg doses of FlecIH-104 when administered in healthy adult subjects via oral inhalation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101058 0
Dr Ben Snyder
Address 101058 0
Nucleus Network
Level 5, Burnet Tower, AMREP Precinct,
89 Commercial Road,
Melbourne VIC 3004
Country 101058 0
Australia
Phone 101058 0
+610390768960
Fax 101058 0
Email 101058 0
b.snyder@nucleusnetwork.com.au
Contact person for public queries
Name 101059 0
Mr Stuart Gribble
Address 101059 0
Nucleus Network,
Level 5, Burnet Tower, AMREP Precinct,
89 Commercial Road,
Melbourne VIC 3004
Country 101059 0
Australia
Phone 101059 0
+610385354808
Fax 101059 0
Email 101059 0
s.gribble@nucleusnetwork.com.au
Contact person for scientific queries
Name 101060 0
Dr Luiz Belardinelli
Address 101060 0
InCarda Therapeutics
39899 Balentine Drive, Suite 185
Newark, CA 94560
United States of America
Country 101060 0
United States of America
Phone 101060 0
+16507042805
Fax 101060 0
Email 101060 0
luiz@incardatherapeutics.com

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 other documents available
Summary results
No Results