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Trial registered on ANZCTR


Registration number
ACTRN12624000223538
Ethics application status
Approved
Date submitted
6/12/2023
Date registered
7/03/2024
Date last updated
3/11/2024
Date data sharing statement initially provided
7/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Study of FlecIH-103 (Flecainide Acetate Inhalation Solution) Administered Using an Investigational, Single Use, Vibrating Mesh Nebulizer Delivery System to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers
Scientific title
A Phase 1 Study of FlecIH-103 (Flecainide Acetate Inhalation Solution) Administered Using an Investigational, Single Use, Vibrating Mesh Nebulizer Delivery System to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers
Secondary ID [1] 311124 0
FLE-016
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrilation 332283 0
Condition category
Condition code
Cardiovascular 328997 328997 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Administration of FlecIH-103 (flecainide acetate inhalation solution) using an investigational vibrating mesh nebulizer delivery system

The doses emitted, meaning what is delivered by the nebulizer are as follows:
Dose 1: 58 mg
Dose 2: 70 mg
Dose 3: 83 mg

Each dose is administered once only on Day 1.

The subjects are closely monitored for proper inhalation technique to ensure the full dose is administered. The serial PK samples will be used to determine the maximum concentration of FlecIH-103 in the systemic circulation.

For Cohort 1, there are 3 dose groups and the participants will not be involved in more than 1 dose group. For Cohort 2, participants from Cohort 1 are able to participate if they signed the PICF and are still eligible for the study.

TStudy Design/Methods:
This is a single-center study. Participants must sign a Human Research Ethics Committee (HREC) approved informed consent form and meet all of the protocol eligibility criteria during screening. Participants will be monitored for cardiac and hemodynamic parameters using a standard 12-lead ECG, a continuous Holter and telemetry for 4-hour monitoring, blood pressure monitoring, pulmonary function testing, including tidal volume, auscultation, chest X ray and oxygen saturation (SpO2).
Additional evaluations will include medical/surgical history, physical examinations, vital sign measurements (blood pressure, temperature, heart rate, respiratory rate), height/weight, urinalysis, and blood sample collection (hematology, coagulation, biochemistry, hepatitis, HIV, drug screening). Blood samples will also be collected from each participant for PK analysis.
The study comprises three cohorts with variations of dose and dosing regimen of FlecIH-103 inhalation solution delivered via oral inhalation using an investigational, single use, hand-held VMN delivery system to healthy adult male and female volunteers as follows:
Cohort 1: 38 evaluable participants will be included and up to three doses of FlecIH-103 inhalation solution will be tested.
• Dose 1: 1.4 mL (75 mg/mL) = 105 mg dispensed; 58 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)
• Dose 2: 1.7 mL (75 mg/mL) = 127.5 mg dispensed; 70 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)
• Dose 3: 2.0 mL (75 mg/mL) = 150 mg dispensed; 83 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)
Each of the doses used will first be tested in 3 sentinel participants. Additional participants will be administered study drug only after an evaluation of the safety, PK and PD from the sentinel participants has been completed.
The first 3 sentinel participants will receive Dose 1 (i.e., 1.4 mL of a 75 mg/mL solution) yielding a dose of 105 mg of flecainide dispensed into the nebulizer. In in vitro studies, the dose of flecainide emitted from the mouthpiece of the nebulizer is estimated to be 58 mg. Participants will inhale the dose until all dispensed solution has been aerosolized and inhaled. In instances where only a partial dose is administered, dose escalation can still occur based on the SRC data review. Prior to proceeding with dosing of the remaining participants, an evaluation of the safety, PK and PD from the Dose 1 sentinel participants will be completed.
Potential outcomes are to continue with Dose 1, increase to either Dose 2 or Dose 3, or proceed with Cohort 2.
If the decision is made to proceed to Dose 2, then 3 sentinel participants will receive 1.7 mL of a 75 mg/mL solution, yielding a dose of 127.5 mg of flecainide dispensed into the nebulizer. In in vitro studies, the dose of flecainide emitted from the mouthpiece of the nebulizer is estimated to be 70 mg. Participants will inhale the dose until all dispensed solution has been aerosolized and inhaled. In instances where only a partial dose is administered, dose escalation can still occur based on the SRC data review. Prior to proceeding with dosing of the remaining participants, an evaluation of the safety, PK and PD from the Dose 2 sentinel participants will be completed.
Potential outcomes are to continue with Dose 2, increase to Dose 3, decrease to Dose 1 or proceed with Cohort 2.
If the decision is made to proceed to Dose 3, then 3 sentinel participants will receive 2.0 mL of a 75 mg/mL solution, yielding a dose of 150 mg of flecainide dispensed into the nebulizer. In in vitro studies, the dose of flecainide emitted from the mouthpiece of the nebulizer is estimated to be 83 mg. Participants will inhale the dose until all dispensed solution has been aerosolized and inhaled. In instances where only a partial dose is administered, dose escalation can still occur based on the SRC data review. Prior to proceeding with dosing of the remaining participants, an evaluation of the safety, PK, and PD from the Dose 3 sentinel participants will be completed.
Potential outcomes are to continue with Dose 3, decrease to Dose 2 or proceed with Cohort 2.

Cohort 2
After Cohort 1, regardless of doses administered, all data will be reviewed by the SMG and a decision to move forward to Cohort 2 will be based on the analyses of these data. The dose and inhalation duration for Cohort 2 will be based on the safety and PK results from Cohort 1. The dose chosen will be the one that is targeted to yield plasma levels of flecainide of 400 – 900 ng/mL (which is within therapeutic range [200 – 1000 ng/mL]), when administered in a series of two successive inhalation periods separated by a break of up to 1 minute. The total dose selected for administration in Cohort 2 could be up to twice the highest emitted dose studied in Cohort 1. Only a fraction of the emitted dose will be absorbed by the lungs and enter the systemic circulation; the data from Cohort 1 will provide information on the actual fraction.
The dose chosen for Cohort 2 will first be tested in 3 sentinel participants with evaluable PK data. Prior to proceeding with dosing of the remaining participants, an evaluation of the safety, PK and PD from the sentinel participants will be completed. Potential outcomes are to continue with the current dose in Cohort 2 or increase or decrease to a higher (i.e., Dose 2 or Dose 3) or lower dose, respectively, to target a plasma flecainide level of 200 to 1000 ng/mL. The lower doses that may be used are:
• Dose 4: 1.0 mL (75 mg/mL) = 75 mg dispensed; 41 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)
• Dose 5: 1.1 mL (75 mg/mL) = 82.5 mg dispensed; 45 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)
• Dose 6: 1.2 mL (75 mg/mL) = 90 mg dispensed; 49 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)
• Dose 7: 1.3 mL (75 mg/mL) = 97.5 mg dispensed; 54 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)

Cohort 3:
This cohort will evaluate the safety, PK and PD of a booster dosing regimen (i.e., an initial dose followed by a booster dose 25 (+5) minutes later).
The initial dose will be 1.4 mL (75 mg/mL) = 105 mg dispensed; 58 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing) and it is estimated that the inhalation duration for the initial dose will be 4 – 6 min.
Twenty-five (25) minutes (+5 minutes) after completion of the initial dose, subjects will inhale one of the following two booster doses:
• Dose 8 (N = 8): 0.7 mL (75 mg/mL) = 52.5 mg dispensed; 29 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)
• Dose 9 (N = 8): 1.4 mL (75 mg/mL) = 105 mg dispensed; 58 mg emitted from the nebulizer mouthpiece (estimated based on in-vitro testing)
Each of the two booster doses will first be tested in 3 sentinel participants with evaluable PK data and an assessment of the safety, PK and PD from the sentinel participants will be completed prior to dosing additional subjects.
Intervention code [1] 327571 0
Treatment: Drugs
Intervention code [2] 328020 0
Treatment: Devices
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336789 0
To evaluate the safety (pulmonary, cardiovascular [CV], and overall safety) and tolerability of FlecIH-103 (75 mg/mL flecainide acetate inhalation solution) delivered via oral inhalation using an investigational, single use, vibrating mesh nebulizer (VMN) delivery system.
All safety and tolerability will be assessed as a composite primary outcome.
Timepoint [1] 336789 0
Adverse events and tolerability issues are collected from the time of consent through the end of study.
Secondary outcome [1] 429672 0
To assess the pharmacokinetics (PK) of FlecIH-103 delivered via oral inhalation using an investigational, single use, vibrating mesh nebulizer (VMN) delivery system to determine its inhaled bioavailability.

Timepoint [1] 429672 0
Various timepoints at pre-dose, during the inhalation and post dose
Blood samples for PK analyses will be collected at the following timepoints: ust prior to initiating dosing at T0, during the inhalation, immediately after inhalation (dosing), 1, 3, 5, 10, 15, 30, 60, 90 minutes post dose and at 2 hours, 4 hours, 6 hours, 12 hours and 24 hours post dose.
Secondary outcome [2] 431861 0
To assess the pharmacodynamics (PD) effects of FlecIH-103 delivered via oral inhalation using an investigational, single use, vibrating mesh nebulizer (VMN) delivery system to determine its inhaled bioavailability.
Timepoint [2] 431861 0
The following ECG timepoints will be evaluated: -60 min, -45 min, -30 min, -25 min, -15, min, just prior to dosing at T0, during inhalation (dosing), just post dose, as well as at 1 min, 3 min, 5, min, 10 min, 15 min, 30 min, 60 min, 90 min and at 2 hours, and 4 hours post dose.

Eligibility
Key inclusion criteria
1. Be male or female, 18 to 70 years of age (inclusive), at the time of screening;
2. Agree to use protocol specified method(s) of contraception. Acceptable Methods of Contraception During Study Participation, if a male participant or a female participant of childbearing potential who engages in heterosexual intercourse.
For the purposes of this study, a female born subject 18 years or older is considered of childbearing potential until becoming post-menopausal, unless permanently sterile or with medically documented ovarian failure. Women are considered to be in a postmenopausal state when they have cessation of previously occurring menses for at least 12 months without an alternative cause. Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female subject of any age;
3. Agree to refrain from egg or sperm donation for the duration of the study;
4. Be able and willing to sign the informed consent for (ICF) as approved by the Human Research Ethics Committee (HREC). Written consent must be provided before initiating any screening evaluations. Participants must have read and understood the ICF, must fully understand the requirements of the study, and must be willing to comply with all study visits and assessments;
5. Have a body mass index (BMI) greater than or equal to 18.0 and less than or equal to 35.0 kg/m2 and a body weight greater than or equal to 60 kg and less than or equal to 120 kg;
6. Have no significant medical history, condition, and be in good general health as determined by the Principal Investigator (PI) or delegate at the clinical facility;
7. Have no electrocardiographic abnormalities during a 12-lead ECG conducted at screening and/or pre-dose assessment (measured after the participant is semi-recumbent for at least 5 minutes) that, in the opinion of the PI (or delegate), may compromise the participant’s safety in the study. Final study eligibility for the ECG criteria is to be approved by the PI and/or the SC;
8. Have no clinically significant abnormalities (i.e., structural heart disease) or left ventricular (LV) dysfunction detected on standard diagnostic or hand-held echocardiogram in the opinion of the Investigator;
9.. Be willing and able to comply with all study assessments and adhere to the protocol schedule;
10. Have suitable venous access for blood sampling and/or injection of medication if needed;
11. 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. Meets the following specific cardiovascular (measured with a 12-lead ECG) and hemodynamic parameters:

-Heart Rate (HR) greater than or equal to 47 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 470 ms for females
-Systolic BP greater than or equal to 100 to less than or equal to 140 mmHg
-Diastolic BP greater than or equal to 60 to less than or equal to 100 mmHg

16. Meets the following specific pulmonary assessments related to pulmonary function testing;

-FEV1 (forced expiratory volume in 1 second) – report the largest value. The enrollment criteria is FEV1 greater than or equal to 80% of normal values.
-FVC (forced vital capacity) – report the largest value. The enrollment criteria is FVC greater than or equal to 80% of normal values.
-FEF (forced expiratory flow) 25-75% - report the value from the test with the highest sum of FEV1 + FVC b. The enrollment criteria is > 70% of predicted.
-Chest X-ray: Normal chest X-ray indicating no clinically significant anomaly.
-Oxygen saturation: > 95%
Minimum age
18 Years
Maximum age
70 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. This exclusion criterion also applies to individuals with established pulmonary disease in need of inhalation medication. However, individuals with history of childhood asthma but no subsequent episodes are eligible to participate in this study;
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. Has a history of heart disease, including but not limited to, atherosclerotic cardiovascular disease (ASCVD), myocardial infarction (MI), heart failure of any cause, clinically significant cardiac arrhythmias and valvular heart disease;
4. Has existing cardiac issues secondary to a prior invasive cardiac procedure;
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 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 (HIV) infection, as shown by the presence of anti HIV antibody (i.e., sero-positive);
11. Is sero-positive for hepatitis B or hepatitis C virus, and/or has a history of delta virus hepatitis;
12. Any of the following related to COVID-19:
a. Known ongoing COVID-19 infection;
b. Significant pulmonary sequelae that limit the participant’s ability to inhale medication or secondary cardiomyopathy from a previous COVID-19 infection, in the opinion of the Investigator.
13. Has uncontrolled hypertension: BP greater than 150/100 mmHg;
14. 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 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;
15. Has had episodes of syncope, including during blood draw;
16. Currently abuses and/or has a history of alcohol and/or drug abuse less than 12 months from screening;
17. Regularly uses excessive alcohol within six months prior to the screening visit (i.e., more than fourteen units of alcohol per week [1 Unit of 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]);
18. Has a positive standard 10x panel drug test at screening and/or has a history of drug abuse within 12 months from screening;
19. Are currently participating in and have not participated in any other investigational study(ies) within 28 days or 5 half-lives of the experimental drug (whichever is longer) prior to planned study dosing;
20. 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;
21. Has any clinically significant history or presence of neurological, endocrine, cardiovascular, pulmonary, hematological, immunologic, psychiatric, metabolic or other uncontrolled systemic disease;
22. Has donated blood (greater than or equal to 500 mL) within 7 days or 50 mL to 499 mL of whole blood within 30 days prior to study treatment administration;
23. Presence of any concomitant medical or psychiatric condition or social situation that, in the opinion of the PI, would make it difficult for the participant to comply with protocol requirements or put the participant at additional safety risk;
24. Is unable or unwilling to return for all scheduled study visits;
25. 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
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
25/10/2024
Actual
15/03/2024
Date of last participant enrolment
Anticipated
19/12/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
48
Accrual to date
48
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 315382 0
Commercial sector/Industry
Name [1] 315382 0
InCarda Therapeutics Australia, Pty, Ltd
Country [1] 315382 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] 317443 0
Commercial sector/Industry
Name [1] 317443 0
InCarda Therapeutics, Inc
Address [1] 317443 0
39899 Balentine Drive, Suite 105 Newark, CA 94560 United States of America
Country [1] 317443 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314299 0
The Alfred
Ethics committee address [1] 314299 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 314299 0
Australia
Date submitted for ethics approval [1] 314299 0
18/12/2023
Approval date [1] 314299 0
15/02/2024
Ethics approval number [1] 314299 0

Summary
Brief summary
The primary objective is to evaluate the safety (pulmonary, cardiovascular [CV], and overall safety) and tolerability of FlecIH-103 (75 mg/mL flecainide acetate inhalation solution) delivered via oral inhalation using an investigational, single use, vibrating mesh nebulizer (VMN) delivery system. Up to three doses of FlecIH-103 inhalation solution will be tested.
• Dose 1: 1.4 mL (75 mg/mL) = 105 mg dispensed; 58 mg emitted from the nebulizer mouthpiece
• Dose 2: 1.7 mL (75 mg/mL) = 127.5 mg dispensed; 70 mg emitted from the nebulizer mouthpiece
• Dose 3: 2.0 mL (75 mg/mL) = 150 mg dispensed; 83 mg emitted from the nebulizer mouthpiece

After Cohort 1 is completed, all data will be reviewed by the SMG and a decision to move forward to Cohort 2 will be based on the analyses of these data. The dose and inhalation duration will be based on the safety and PK results from Cohort 1.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131110 0
Dr Sam Francis
Address 131110 0
Necleus Network Level 5, Burnet Tower 89 Commercial Road Melbourne, Victoria, 3004 Australia
Country 131110 0
Australia
Phone 131110 0
+61 03 8593 9800
Fax 131110 0
Email 131110 0
[email protected]
Contact person for public queries
Name 131111 0
Meisa Propst
Address 131111 0
InCarda Therapeutics Pty, Ltd., 39899 Balentine Dr. Suite 105 Newark, CA 94560 USA
Country 131111 0
United States of America
Phone 131111 0
+1 510 422 5522
Fax 131111 0
Email 131111 0
[email protected]
Contact person for scientific queries
Name 131112 0
Meisa Propst
Address 131112 0
InCarda Therapeutics Pty, Ltd, 39899 Balentine Dr. Suite 105 Newark, CA 94560 USA
Country 131112 0
United States of America
Phone 131112 0
+1 510 422 5522
Fax 131112 0
Email 131112 0
[email protected]

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

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