Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001156471
Ethics application status
Approved
Date submitted
4/08/2016
Date registered
25/08/2016
Date last updated
14/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Double-Blind, Randomized, Placebo-controlled, Single Ascending Dose Study of Flecainide Acetate Inhalation Solution to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers
Scientific title
A Phase 1, Double-Blind, Randomized, Placebo-controlled, Single Ascending Dose Study of Flecainide Acetate Inhalation Solution to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers
Secondary ID [1] 289852 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recent Onset Paroxsymal Atrial Fibrillation 299792 0
Condition category
Condition code
Cardiovascular 299721 299721 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The investigational agents are:
1. Sterile flecainide acetate inhalation solution 35 mg/mL
2. Sterile placebo inhalation solution
3. Intravenous flecainide acetate (Tambocor (Trademark) Injection 10 mg/mL).

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

Part C is an open label crossover comparing the PK/PD of inhaled flecainide administered using two different sources of compressed air through a nebulizer. In Part C participants will receive 2 inhaled doses of flecainide acetate, one using the AeroEclipse XL nebulizer connected to a compressed medical air source from a cylinder and the other using the AeroEclipse XL nebulizer connected to a battery operated portable compressed medical air source (Ombra portable). In Period 1, up to 3 participants will receive a single dose of flecainide acetate solution by inhalation using the AeroEclipse XL nebulizer connected to a compressed medical air source from a cylinder whereas up to 3 participants will receive a single dose of flecainide acetate solution by inhalation using the AeroEclipse XL nebulizer connected to a battery operated portable compressed medical air source (Ombra portable). In Period 2, the participants who were administered flecainide using the AeroEclipse XL nebulizer connected to a compressed medical air source from a cylinder in Period 1 will now receive a single dose of flecainide acetate solution by inhalation using the AeroEclipse XL nebulizer connected to a battery operated portable compressed medical air source (Ombra portable), while participants who were administered flecainide using the AeroEclipse XL nebulizer connected to a battery operated portable compressed medical air source (Ombra portable) in Period 1 will now receive a single dose of flecainide acetate solution by inhalation using the AeroEclipse XL nebulizer connected to a compressed medical air source from a cylinder.
Intervention code [1] 295537 0
Treatment: Drugs
Comparator / control treatment
Part A participants will receive a single Ascending Dose (inhalation only) in the following amounts:
Cohort 1: 20mg Flecainide Acetate or Placebo (Acetate Buffer Sterile Solution PH 5.2)
Cohort 2: 40mg Flecainide Acetate or Placebo (Acetate Buffer Sterile Solution PH 5.2)
Cohort 3: 60mg Flecainide Acetate or Placebo (Acetate Buffer Sterile Solution PH 5.2)


Part B, the open label crossover part of the study consists of one Cohort that is scheduled for two Periods, Period 1 and Period 2. In Period 1 the administration of open label flecainide will be via inhalation for all participants, whereas in Period 2 for the same participants the administration of open label flecainide will be intravenous for all participants. The two Periods will be separated by a 10 day washout period.

In Part C, six participants will be enrolled, in a cross-over arrangement where two different sources of compressed medical air will be compared using the AeroEclipse XL device to deliver an inhaled flecainide acetate dose of up to 60 mg.
Control group
Placebo

Outcomes
Primary outcome [1] 299179 0
To evaluate the safety and tolerability of single ascending doses (SADs) of flecainide acetate inhalation solution in normal healthy volunteers.

Method of assessment: Pulmonary, Cardiac and Hemodynamic Safety Measurements

Participants will be monitored for cardiac and hemodynamic parameters using 12-Lead ECG, continuous telemetry and blood pressure monitoring, pulmonary function testing, auscultation, chest X-ray and oxygen saturation. Additional evaluations will include medical history, physical examinations, vital sign measurements (heart rate, blood pressure, temperature and respiratory rate), adverse events, pregnancy test (females), concomitant medication and blood sample collection for hematology, coagulation and chemistry, as well as urine collected for urinalysis. Blood samples will also be collected from each participant for pharmacokinetic (plasma) analysis. Participants will be screened for HIV antibodies, Hepatitis B surface antigen and Hepatitis C antibody. Height and weight will be measured at screening in order to calculate BMI.
Timepoint [1] 299179 0
Part A: Safety and Tolerability timeframe: The assessments will be carried out daily from Day -1 (pre-dose) to Day 2 (post dose); and again at Day 9 (post dose) of the study.
Part B: Safety and Tolerability timeframe: The assessments will be carried out daily from Day -1 (pre-dose) to Day 2 for Period 1 and again following the 10 day washout from Day -1 (pre-dose ) to Day 2 (post dose) in Period 2 for a total of 15 days. .
Secondary outcome [1] 326433 0
To assess the pharmacokinetics (PK) of SADs of inhaled flecainide acetate.

Method of assessment: Blood samples
Plasma concentrations following a single administration of flecainide acetate inhalation solution at different dose levels will be used to calculate the following pharmacokinetic parameters: Cmax, tmax, AUC0-24, AUCinf, and t1/2. These pharmacokinetic parameters will also be calculated for intravenously administered flecainide acetate (Part B, period 2). Pharmacokinetic parameters will be determined using non-compartmental method(s). Descriptive statistics of pharmacokinetic parameters will include mean, standard deviation, and coefficient of variation.


Timepoint [1] 326433 0
Sample collection times from ALL Cohorts will be as follows:
1. Baseline (before drug administration) –T0
2. After administration of study drug is complete –Tx (1, 3, 5, 10, 15, 30, 60 minutes and 2, 4, 6, 12, and 24 hours).
Secondary outcome [2] 326434 0
To assess the pharmacodynamics (PD) of SADs of inhaled flecainide acetate by measuring ECG intervals.

Method of assessment: Pharmacodynamic measurements on the 12-Lead ECG will be made during the study:
i. QRS interval
ii. PR interval
iii. QTc (and JTc
Timepoint [2] 326434 0
ECG collection times from both Part A and Part B and ALL Cohorts will be as follows.
Continuous ECG monitoring and collection using a holter monitor for 1 hour prior to dosing and 24 hours post dose.

Single readings will be printed for the 1, 3, 5, 10, and 15 minute post dose time points. Triplicate readings, at least 2 minutes apart, will be printed for all other time points; including:
30, 60, 120, 240, 360, 480, and pre-dose 15, 30, and 45 minutes or as required by the PI.
Secondary outcome [3] 326435 0
To directly compare the PK/PD relationship of inhaled flecainide acetate to intravenous administered flecainide acetate.

Method of assessment: Blood samples and ECG assessments
Timepoint [3] 326435 0
PK sample collection times from both Part A and Part B and ALL Cohorts will be as follows:
1. Baseline (before drug administration) –T0
2. After administration of study drug is complete –Tx (1, 3, 5, 10, 15, 30, 60 minutes and 2, 4, 6, 12, and 24 hours).

ECG collection times from both Part A and Part B and ALL Cohorts will be as follows.
Continuous ECG monitoring and collection using a holter monitor for 1 hour prior to dosing and 24 hours post dose.
Single readings will be printed for the 1, 3, 5, 10, and 15 minute post dose time points. Triplicate readings, at least 2 minutes apart, will be printed for all other time points; including:
30, 60, 120, 240, 360, 480, and pre-dose 15, 30, and 45 minutes or as required by the PI.
Secondary outcome [4] 337860 0
To directly compare the PK of inhaled flecainide acetate administered using the AeroEclipse XL with two different sources of compressed medical air. Method of assessment: Blood samples
AUC0–24: The area under the plasma concentration versus time curve from the zero to 24 hours.
AUCinf: The area under the plasma concentration versus time curve from zero to infinity.
Cmax: The maximum plasma concentration will be obtained directly from the plasma concentration time profile.
tmax: The time to maximum plasma concentration will be obtained by inspection.
kel: The terminal elimination rate constant will be obtained from the slope of the line, fitted by linear least squares regression, through the terminal points of the log (e) concentration-time profiles
t½: The half-life will be calculated by the equation t½ = ln(2)/kel.
Timepoint [4] 337860 0
PK sample collection times from Part C will be as follows: 1. Baseline (before drug administration) –T0 2. During administration (2.5 min and end of inhalation) 3. After administration of study drug is complete –Tx (1, 3, 5, 10, 15, 30, 60 minutes and 2, 4, 6, 12, and 24 hours).
Secondary outcome [5] 337861 0
To directly compare the PD of inhaled flecainide acetate administered using the AeroEclipse XL with two different sources of compressed medical air. Method of assessment: ECG assessments looking at the QRS or PR value at each time point.
Timepoint [5] 337861 0
ECG collection times from both Part C will be as follows. Continuous ECG monitoring and collection using a holter monitor for 1 hour prior to dosing and 24 hours post dose. Single readings will be printed for just prior to dosing T0 and 1, 3, 5, 10, and 15 minute post dose time points. Triplicate readings, at least 2 minutes apart, will be printed for all other time points; including: 30, 60, 120, 240, 360, 480, and pre-dose 15, 30, and 45 minutes or as required by the PI.
Method of assessment: ECG assessments looking at the QRS or PR value at each time point.

Eligibility
Key inclusion criteria
To be eligible for randomization, the participants must meet the following criteria:
1. Be male (ages 18 to 35 years inclusive) or female (ages 18 to 50 years inclusive) at the time of screening;
2. Be female and of non-childbearing potential (e.g. post menopausal as demonstrated by FSH or surgical sterilization . i.e., tubal ligation or hysterectomy); males should wear condoms with female partners also using an acceptable form of contraception ;
3. Normal healthy volunteers with the ability to understand and give written informed consent for participation in this trial, including all evaluations and procedures as specified by this protocol;
4. Have a BMI between 20 and 28 kg/m2, and a BW of 60-90 kg (for the dose range 20-70 mg) and 65-85 kg (for participants receiving 110 mg), inclusive;
5. No significant medical history, and in good general health;
6. Have no electrocardiographic abnormalities during a 12-Lead ECG 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;
7. Have no clinically significant abnormalities detected on a standard diagnostic echocardiogram;
8. Non-smokers (including tobacco, e-cigarettes and marijuana) – tested for the absence of cotinine in urine; Non-smokers with significant history of smoking, >5 pack years, are not eligible;
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;
11. Have ALT and AST within the normal range and Cockcroft-Gault estimated creatinine clearance >70 ml/min;
12. Have no abnormal finding of clinical relevance at the screening evaluation.

Participants with baseline pulmonary parameters that are borderline as the values listed in this table may be excluded at the discretion of the PI and/or SC.
Parameter Baseline enrollment criteria
*FEV1 (Forced Expiratory Volume in 1 second) FEV1 greater than or equal to 80% of normal values
*FVC (Forced Vital Capacity) FVC greater than or equal to 80% of normal values
FEF25-75% - report the value from the test with the highest sum of FEV1 + FVC greater than 75% 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.
Chest X-ray Normal chest X-ray indicating no anomaly
Oxygen saturation monitor (performed before dosing and monitored every 15 mins up to 2hours than regularly until discharge) greater than 95%
*Report the largest value
http://www.nationalasthma.org.au/uploads/content/211-spirometer_handbook_naca.pdf

Inclusion and repeatability criteria for pulmonary function testing:
*Participants with less than 80% of predicted values will be excluded using Knudson 1976 similar to NIOSH - http://www.cdc.gov/niosh/topics/lung spirometry/refcalculator.html
*Obtain 3 acceptable tests, i.e. each test should meet the stated acceptability criteria. http://www.nationalasthma.org.au/uploads/content/211-spirometer_handbook_naca.pdf
*The two largest values for FVC should agree to within 0.15L
*The two largest values for FEV1 should agree to within 0.15L
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants with ECG parameters that are borderline of the values listed in this table may be excluded at the discretion of the PI and/or the SC.
Parameter Baseline enrollment criteria
Heart Rate (HR) greater than or equal to 55 bpm (to 50bpm)
QRS interval less than 100 ms (to 105 ms)
Systolic BP greater than or equal to 100 to less than or equal to 160 mmHg

nclusion and repeatability criteria for pulmonary function testing:
*Participants with less than 80% of predicted values will be excluded using Knudson 1976 similar to NIOSH - http://www.cdc.gov/niosh/topics/lung spirometry/refcalculator.html
*Obtain 3 acceptable tests, i.e. each test should meet the stated acceptability criteria. http://www.nationalasthma.org.au/uploads/content/211-spirometer_handbook_naca.pdf
*The two largest values for FVC should agree to within 0.15L (this criteria has been removed)
*The two largest values for FEV1 should agree to within 0.15L (this criteria has been removed)

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)
Allocation Concealment via sealed envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Other
Other design features
Part A: Randomised single ascending doses (SADs) of flecainide acetate inhalation solution or placebo

Part B: non-randomized crossover to intravenous administered flecainide acetate solution for injection

Part C: non-randomized cross-over arrangement where two different sources of compressed medical air will be compared using the AeroEclipse XL device to deliver an inhaled flecainide acetate dose of up to 60 mg.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
In general, safety analyses will be performed and the results summarized by-cohort and treatment group.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
26/08/2016
Actual
26/08/2016
Date of last participant enrolment
Anticipated
Actual
1/04/2017
Date of last data collection
Anticipated
Actual
9/08/2017
Sample size
Target
44
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
SA
Recruitment postcode(s) [1] 13949 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 294230 0
Commercial sector/Industry
Name [1] 294230 0
InCarda Therapeutics Inc.
Country [1] 294230 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
InCarda Therapeutics Australia
Address
Level 13, 41 Exhibition Street
Melbourne VIC, 3000
Country
Australia
Secondary sponsor category [1] 293059 0
Commercial sector/Industry
Name [1] 293059 0
InCarda Therapeutics Inc.
Address [1] 293059 0
39899 Balentine Dr, Suite 185
Newark, CA 94560, USA
Country [1] 293059 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295651 0
Bellberry Ethics Committee
Ethics committee address [1] 295651 0
Ethics committee country [1] 295651 0
Australia
Date submitted for ethics approval [1] 295651 0
15/06/2016
Approval date [1] 295651 0
01/08/2016
Ethics approval number [1] 295651 0
2016-05-450

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

Contacts
Principal investigator
Name 68018 0
Prof Sepehr Shakib
Address 68018 0
CMAX
Level 5, 18a North Terrace,
Adelaide,
South Australia 5000
Country 68018 0
Australia
Phone 68018 0
+61 8 8222 3923
Fax 68018 0
Email 68018 0
[email protected]
Contact person for public queries
Name 68019 0
Gabriel Kremmidiotis
Address 68019 0
CPR Pharma Services
28 Dalgleish Street
Thebarton SA 5031
Country 68019 0
Australia
Phone 68019 0
+61 8 8159 6296
Fax 68019 0
Email 68019 0
[email protected]
Contact person for scientific queries
Name 68020 0
Gabriel Kremmidiotis
Address 68020 0
CPR Pharma Services
28 Dalgleish Street
Thebarton SA 5031
Country 68020 0
Australia
Phone 68020 0
+61 8 8159 6296
Fax 68020 0
Email 68020 0
[email protected]

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No Supporting Document Provided



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