Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000181909
Ethics application status
Approved
Date submitted
3/02/2020
Date registered
18/02/2020
Date last updated
5/07/2021
Date data sharing statement initially provided
18/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A 2-part, randomized, double-blind, placebo-controlled study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of FTP 198 in healthy volunteers
Scientific title
A 2-part, randomized, double-blind, placebo-controlled study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of FTP 198 in healthy volunteers
Secondary ID [1] 300389 0
FTP198-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Idiopathic pulmonary fibrosis 316011 0
Condition category
Condition code
Respiratory 314285 314285 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A suspension of FTP-198 in a sugar-free, alcohol-free syrup vehicle (ORA-Sweet SF) will be administered to participants.
Part A: FTP-198 will be administered at the following nominal dose levels in each cohort:
• Cohort 1 - 50 mg
• Cohort 2 - 100 mg
• Cohort 3 - 200 mg
• Cohort 4 - 300 mg
• Cohort 5 - 450 mg
• Cohort 6 - 600 mg
Part B: It is anticipated that FTP-198 at 3 dose levels in the range of 50 to 600 mg will be evaluated in 3 cohorts (Cohorts 7 to 9). The dose levels to be administered will be decided following review of safety and PK data from Part A.

Part A: 1 dose.
Part B: There will be a total of 7 dosing days. Depending on PK data from Part A, each daily dose may be administered once daily or twice daily.

Adherence to the intervention will be monitored via direct supervision of the intake of suspension by the CMAX staff.
Intervention code [1] 316670 0
Treatment: Drugs
Comparator / control treatment
The syrup vehicle without FTP-198 will be administered as a placebo
Control group
Placebo

Outcomes
Primary outcome [1] 322673 0
The primary objective of the study is to assess the safety and tolerability of single and 7-day repeat oral doses of FTP-198 in healthy adult volunteers.
Timepoint [1] 322673 0
Part A:
Physical examination will be conducted at Screening, Day -1, Day 1 pre-dose, and 2, 6, 12, 24 and 48 hours post dose.
Vital signs: blood pressure, heart rate, respiratory rate and temperature will be measured at Screening, Day -1, Day 1 pre-dose, and 2, 6, 12, 24, 48 hours post dose and on Day 7.
Clinical laboratory tests: haematology, serum chemistry, coagulation and urinalysis will be measured at Screening, Day -1, 6 hours post dose and on Day 7.
ECGs: Continuous 5-lead ECG telemetry monitoring will be conducted from 12 hr pre dose to 24 h post-dose. A 12-lead ECG will be performed if abnormalities are observed during continuous telemetry monitoring. Twelve-lead ECGs will be recorded at 60, 45 and 30 minutes pre dose and at 0.5, 1, 2, 4, 6, 8, 12, 24 and 48 hours post dose.
Adverse event monitoring will occur throughout study conduct from Day -1 to Day 7.
Part B:
Physical examination will be conducted at Screening, Day -1, Day 1 pre-dose, and 2, 6, 12 hours post dose, Days 2, 3, 4, 5 and 6, and 30 min prior to dose plus 2 and 12 hours post dose on Day 7, and Day 8 and 9.
Vital signs: blood pressure, HR, RR and temperature will be measured at Screening, Day -1, pre-dose, and 2, 6, 12 hours post dose on Days 1, 2, 3, 4, 5 and 6, and 30 min prior to dose plus 2 and 12 hours post dose on Day 7, and Day 8, 9 and 14..
Clinical laboratory tests: haematology, serum chemistry, coagulation and urinalysis will be measured at Screening, Day -1, 6 hours post dose and on Days 2, 4, 8 and 14.
ECGs: Twelve-lead ECGs will be recorded at 60, 45 and 30 minutes pre dose and 6 hours post dose on Day 1 and at Days 2, 3, 4, 5, 6 pre and post doing, and 30 min prior to dosing and 1, 2, 4, 6, 8, 12, 24 and 48 hours post dose on Day 7.
Adverse event monitoring will occur throughout study conduct from Day -1 to Day 14.
Secondary outcome [1] 379261 0
To assess the pharmacokinetics (PK) of FTP-198 following administration of single and 7 day repeat oral doses in healthy adult volunteers.
The following PK parameters will be determined in Part A (SAD):
• Maximum observed drug concentration (Cmax);
• Time of the maximum drug concentration (tmax), obtained without interpolation. If the maximum value occurs at more than 1 timepoint, tmax is defined as the first timepoint with this value;
• Area under the drug concentration-time curve, calculated using linear trapezoidal summation, from time zero to time of the last measurable drug concentration (AUC0–last);
• Apparent elimination rate constant (Lambda-z), calculated by linear regression of the terminal linear portion of the log concentration versus time curve, where Lambda-z = - slope;
• Area under the drug concentration-time curve from time zero to infinity (AUC0–inf) calculated as AUC0-t + Ct/Lambda-z, where Lambda-z is the apparent terminal elimination rate constant;
• Area under the drug concentration-time curve from time zero to 24 hours following dose administration (AUC0-24);
• Area under the drug concentration-time curve from time zero to 48 hours following dose administration (AUC0-48);
• Apparent total clearance of the drug from plasma following oral administration (CL/F), calculated as dose/AUC0-inf;
• Apparent terminal elimination half-life (t1/2), calculated as ln(2)/Lambda-z;
• Apparent volume of distribution Vd/F; calculated as (CL)/Lambda-z.

The following PK parameters will be determined in Part B (MAD):
• Day 1: Cmax, tmax, area under the drug concentration-time curve from time zero to the end of the dosing interval at steady state (AUC0-tau), AUC0–inf, Lambda-z, t1/2, CL/F, Vd/F
• Day 4, 5, 6 and 7: Predose trough concentration
• Day 7: Cmax, tmax, AUC0-tau, AUC0–last, AUC0–inf, Lambda-z, t1/2, CL/F, Vd/F
• Accumulation factor - Cmax = Cmax on Day 7/Cmax on Day 1
• Accumulation factor - AUC0-tau = AUC0-tau on Day 7/AUC0-tau on Day 1
Timepoint [1] 379261 0
In Part A, blood samples for PK analysis will be drawn on Day 1 (within 10 minutes before dosing) and following study drug administration at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 and 48 hours.
In Part B, blood samples for PK analysis will be drawn on:
• Day 1, within 10 minutes before dosing and following study drug administration at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours;
• Within 30 minutes before dosing on Days 2, 3, 4, 5 and 6;
• Day 7, within 10 minutes before dosing and following study drug administration at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 and 48 hours.
Secondary outcome [2] 379262 0
To evaluate the effect of FTP-198 on the corrected QT (QTc) interval and other electrocardiogram (ECG) parameters. This includes:
• Change-from-baseline QTcF, HR, PR interval and QRS duration (delta QTcF, delta HR, delta PR and delta QRS)
• Placebo-corrected delta QTcF, delta HR, delta PR and delta QRS (delta delta QTcF, delta delta HR, delta delta PR and delta delta QRS)
• Categorical changes in HR, QTcF, PR interval and QRS duration
• Exposure response related changes in cardiodynamic parameters (QTcF, HR, PR interval and QRS duration)
Timepoint [2] 379262 0
In Part A, triplicate ECG recording will be performed at pre dose and post dose time points to assess potential drug concentration induced QT changes. These ECG recordings will be performed immediately before sampling for PK at corresponding time points.
These time points are on Day 1 at 60, 45, 30 and 10 minutes pre dose, and following study drug administration at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours. Telemtery will also be measured 30 and 10 minutes pre dose, at study drug administration and 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours following drug administration.

In Part B, triplicate ECG recording will be performed at pre dose and post dose time points to assess potential drug concentration induced QT changes. These ECG recordings will be performed immediately before sampling for PK at corresponding time points.
These time points are on Day 1 at 60, 45 and 30 minutes pre dose and following study drug administration at 6 hours. On Days 2, 3, 4, 5 and 6 ECG recordings will be performed pre dose and within 60 minutes post dose. On Day 7, ECG recordings will be performed 30 minutes pre dose and following drug administration at 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours.
Secondary outcome [3] 379263 0
To investigate pharmacodynamic (PD) marker changes associated with administration of FTP 198 in healthy adult volunteers via the percentage reduction from baseline in LPA18:2 plasma concentration.
Timepoint [3] 379263 0
In Part A, blood samples for PD analysis will be drawn on Day 1 (within 10 minutes before dosing) and following study drug administration at 2 and 24 hours.
In Part B, blood samples for PD analysis will be drawn on:
• Day 1, within 10 minutes before dosing and following study drug administration at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours;
• Within 30 minutes before dosing on Days 2 and 3;
• Day 7, within 10 minutes before dosing and following study drug administration at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 and 48 hours.

Eligibility
Key inclusion criteria
Healthy volunteers will be included in Part A or Part B of the study if they satisfy all the following criteria:
1. Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects;
2. Adult males and females, 18 to 55 years of age (inclusive) at screening;
3. Body mass index greater than or equal to 18.0 and less than or equal to 30.0 kg/m2, with a body weight greater than or equal to 50 kg at screening;
4. Be nonsmokers (including tobacco, e-cigarettes and marijuana) for at least 1 month prior to first study drug administration;
5. Medically healthy without clinically significant abnormalities at screening and pre dose on Day 1, including:
a. Physical examination without any clinically relevant findings;
b. Systolic blood pressure in the range of 90 to 160 mmHg and diastolic blood pressure in the range of 50 to 95 mmHg after 5 minutes in supine position;
c. Heart rate in the range of 50 to 100 bpm after 5 minutes rest in supine position;
d. Body temperature, between 35.0°C and 37.5°C;
e. No clinically significant findings in serum chemistry, hematology, coagulation and urinalysis tests as judged by the investigator;
6. Conventional 12-lead ECG recording in triplicate (the mean of triplicate measurements will be used to determine eligibility at screening and predose on Day 1) consistent with normal cardiac conduction and function, including:
• Normal sinus rhythm with HR between 50 and 100 bpm, inclusive;
• QT interval corrected using the Fridericia method (QTcF) between 350 to 450 msec for male subjects and 350 to 470 msec for female subjects, inclusive;
• QRS duration of less than 120 msec;
• PR interval of less than or equal to 210 msec;
• Electrocardiogram morphology consistent with healthy cardiac ventricular conduction and normal rhythm, and with measurement of the QT interval;
• No family history of short or long QT syndrome;
• No history of risk factors for torsade de pointes or the diagnosis;
7. Female participants must:
a. Be of nonchildbearing potential ie, surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
b. If of childbearing potential, must have a negative pregnancy test at screening (blood test) and before the first study drug administration (Day -1 urine test). They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method from signing the consent form until at least 30 days after the last dose of study drug.
8. Male participants, if not surgically sterilized, must be willing not to donate sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, must be willing to use a condom in addition to having the female partner use a highly effective contraceptive method from signing the consent form until at least 90 days after the last dose of study drug;
9. Have suitable venous access for blood sampling;
10. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy volunteers will be excluded from Part A or Part B of the study if there is evidence of any of the following at screening, Day -1 or pre dose on Day 1:
1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or surgery within the past 3 months determined by the PI to be clinically relevant;
2. Current infection that requires antibiotic, antifungal, antiparasitic or antiviral medications;
3. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma);
4. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia;
5. Use of or plans to use systemic immunosuppressive (eg, corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (eg, interferon) during the study or within 4 months prior to the first study drug administration;
6. Liver function test results (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gammaglutamyl transferase [GGT]) and total bilirubin must not be elevated more than 1.2-fold above the upper limit of normal (ULN);
7. Positive test results for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies (Abs);
8. History of active, latent or inadequately treated tuberculosis infection;
9. Presence or having sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs;
10. Estimated creatinine clearance (CrCl) < 40 mL/min using the Cockcroft-Gault formula or serum creatinine more than 1.5-fold above the ULN;
11. History of substance abuse or alcohol abuse within 12 months prior to first study drug administration;
12. Positive drug or alcohol test results;
13. Use of any prescription or over-the-counter medication (including herbal products, diet aids, and hormone supplements) within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration, except occasional use of paracetamol;
14. Demonstrated clinically significant (required intervention, eg, emergency room visit, epinephrine administration) allergic reactions (eg, food, drug, or atopic reactions, asthmatic episodes) which, in the opinion of the investigator, would interfere with the volunteer’s ability to participate in the trial;
15. Known hypersensitivity to any of the study drug ingredients;
16. Use of any live vaccinations within 30 days prior to the first study drug administration except for the influenza vaccine;
17. For women of childbearing potential, a positive serum pregnancy test at screening or a positive urine pregnancy test with confirmatory serum pregnancy test on Day -1;
18. Donation of blood or plasma within 30 days prior to first study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood transfusion within 1 year of first study drug administration;
19. Participation in another investigational clinical trial within 60 days prior to the first study drug administration;
20. Any other condition or prior therapy that in the opinion of the PI would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements;
21. Is an employee of an investigator or sponsor or an immediate relative of an investigator.

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)
Enrolment confirmed on Day 1 following pre-dose eligibility checks. Randomisation and allocation of treatment done by sequentially allocating the next randomisation number starting with R01001 through to R01008 to the subjects as the eligibility is confirmed.

The randomisation schedules will be prepared by unblinded statisticians at Avance Clinical and will be maintained under controlled access. A copy of the randomisation schedule will be provided to unblinded site pharmacy staff for the purposes of dispensing the study drugs. Site pharmacy staff will store the randomisation schedule in a secure, restricted access area of the pharmacy. As the study is double-blinded, sealed participant-specific code break envelopes will also be produced by the unblinded statisticians and will be retained at the clinical facility in a secure, accessible location.
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
The people analysing the results/data
Intervention assignment
Other
Other design features
Multiple cohort trial, 9 cohorts in total.

Part A: 48 healthy volunteers will be enrolled in a total of 6 cohorts. Each cohort will enroll 8 participants with 6 participants randomized to receive FTP-198 and 2 participants randomized to receive placebo.

Part B: 30 healthy volunteers will be enrolled in a total of 3 cohorts. Each cohort will enroll 10 participants with 8 participants randomized to receive FTP-198 and 2 participants randomized to receive placebo.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Statistical analysis sets:
1. Full analysis set (FAS) will include all randomized participants who have received at least one dose of study drug (FTP-198 or placebo) and have at least one post-dose assessment.
2. The Safety Analysis Set will include all participants who receive at least 1 dose of study drug (FTP-198 or placebo) and have at least 1 post dose safety assessment.
3. The PK Analysis Set will include all participants in the Safety Analysis Set who have sufficient plasma concentration data to derive at least 1 PK parameter.
4. QT/QTc Analysis Set will include all participants in the Safety Analysis Set with measurements at baseline as well as on-treatment with at least 1 post dose time point with a valid delta QTcF value. The QT/QTc Analysis Set will be used for the by-time point and categorical analyses.
5. PK/QTc Analysis Set will include all participants who are in both the QT/QTc and PK Analysis Sets with at least 1 pair of post dose PK and QTc data from the same time point. The PK/QTc Analysis Set will be used for the exposure-response analysis.

Sample size consideration:
This study is the first in human study with FTP-198 and as such no formal sample size calculation was performed.

Demographic data:
Demographic data (gender, age, race, ethnicity and BMI) will be summarized for all participants who receive at least 1 dose of study drug using descriptive statistics (mean, standard deviation, median, minimum, and maximum) and tabulated by dose group.

Safety/Tolerability Data:
All participants who receive at least 1 dose of the study drug (FTP-198 or placebo) and have at least 1 post dose safety assessment will be included in the safety and tolerability analysis (ie, the Safety Analysis Set). Baseline for analysis of physical examination, vital signs, body weight, 12-lead ECG, and clinical laboratory data will be defined as the last evaluation done before the first administration of study drug for each participant. For ECG data, if there is more than 1 replicate at the baseline timepoint the mean of those replicates will be used as the baseline value.
Safety evaluations will be based on the incidence, severity and relationship of AEs and changes from baseline in physical examination findings, vital signs, body weight, 12 lead ECGs, and clinical laboratory results.
Abnormalities in clinical laboratory parameters, vital signs, and ECGs will be based on predefined normal ranges and will be tabulated by dose group showing participant counts and percentages.

Adverse Event Data:
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the current version of the Medical Dictionary for Regulatory Activities by system organ class (SOC) and preferred term, classified from verbatim terms. The number of TEAEs and serious TEAEs as well as the number and percentage of participants with TEAEs and serious TEAEs, will be summarized by SOC and preferred term and tabulated for each dose group. Summaries by severity and relationship will also be presented. The percentage of participants who discontinued treatment due to a TEAE will be summarized and tabulated for each dose group. The duration of AEs will be determined and included in the listings.
Clinical Laboratory Data:
Clinical laboratory data will be summarized by the laboratory parameter. Normal reference ranges and abnormal results will be used in the summary of laboratory data. Observed values and changes from baseline for continuous clinical laboratory parameters will be summarized at each scheduled timepoint using descriptive statistics (n, mean, SD, median, minimum, and maximum) and tabulated for each dose group. Categorical clinical laboratory data will be summarized at each scheduled timepoint using participant counts and percentages and tabulated by dose group. A listing of participants with any laboratory results outside the reference ranges will be provided.
Vital Signs and Body Weight Data:
Observed values and changes from baseline for vital signs and body weight (Part B only)will be summarized at each scheduled time point using descriptive statistics (n, mean, SD, median, minimum, and maximum) and tabulated for each dose group.
Physical Examination Data:
Physical examination outcomes will only be listed.
Safety Electrocardiogram Data:
The following ECG parameters will be analyzed: PQ or PR interval, QT interval, QRS duration, QTcF and HR. For all ECG parameters, baseline will be identified as the mean of the 3 replicates obtained predose on Day 1.
Observed values and changes from baseline will be summarized at each scheduled timepoint using descriptive statistics (n, mean, SD, median, minimum, and maximum) and tabulated for each dose group.
Cardiodynamic Data:
Cardiodynamic ECG assessments will be performed for Part A or Part B of the study, or both parts combined. The decision on which parts to analyze will be made based on observed PK.
Cardiodynamic Data Analysis:
The following ECG parameters will be analyzed: QT interval, QTcF, RR interval, PR interval and QRS duration. For all ECG parameters, baseline will be identified as the mean of the measured parameters from the 3 predose timepoints (60, 45 and 30 min predose) on Day 1.
Triplicate ECGs will be captured at nominal timepoints corresponding to the projected tmax of FTP-198 (based on preclinical PK data). These timepoints may be revised based on emerging PK data during study conduct. All recorded beats that are deemed acceptable in each replicate will be included in the analysis. The Fridericia's correction of the QT interval is defined as: QTcF = QT/RR1/3. The QT interval and RR interval value for each acceptable beat will be used for HR correction.
The median value for QT interval, QTcF and RR interval from each extracted replicate will be calculated, and then the mean of all available medians (minimum 3 medians) from a nominal timepoint will be used as the participant’s reportable value at that timepoint.
For each parameter, absolute values, changes from baseline and placebo-corrected changes from baseline will be summarized at each scheduled timepoint using descriptive statistics (n, mean, SD, median, minimum, and maximum) and tabulated for each dose group.
The analysis for QTcF will be based on a linear mixed-effects model with delta QTcF as the dependent variable, time (categorical), treatment (each dose level of FTP-198 and pooled placebo), and time-by-treatment interaction as fixed effects, and baseline QTcF as a covariate. Participant will be included as a random effect for the intercept. Participants dosed with placebo will be analyzed as a pooled group. An unstructured covariance matrix will be specified for the repeated measures at postdose timepoints for participants within treatment period. If the model with unstructured covariance matrix fails to converge, other covariance matrix such as autoregressive and compound symmetry or separate analysis of variance models for each timepoint will be considered. From this analysis, the LS mean, and 2-sided 90% CI will be calculated for the contrast “FTP-198 vs placebo” for each dose and each postdose timepoint, separately.
For HR, PR interval, and QRS duration, the analysis will be based on the change-from-baseline postdosing. The same model will be used as described for QTcF. The least squares means, standard error (SE) and 90% confidence interval (CI) from the statistical modelling for both change-from-baseline and placebo-corrected change-from-baseline values will be presented in the tables and graphically displayed.
The results for categorical outliers will be summarized in frequency tables with counts and percentages for both participants and time points. For categorical outliers, the number (percentage) of participants as well as time points with increases in absolute QTcF values > 450, 480, and 500 msec and changes from pre dose baseline of > 30 or > 60 msec; increase in PR interval from pre dose baseline > 25% or to a PR interval > 200 msec; increase in QRS duration from pre dose baseline > 25% or to a QRS duration > 120 msec; decrease in HR from pre dose baseline > 25% or to a HR < 50 bpm; and increase in HR from pre dose baseline > 25% or to a HR > 100 bpm will be determined.
Exposure-Response Analysis:
The relationship between FTP-198 plasma concentration and delta QTcF will be quantified using a linear mixed-effects model with delta QTcF as the dependent variable, plasma concentration of FTP 198 as a continuous covariate (ie. 0 for placebo), centered baseline QTcF as an additional covariate, treatment (active or placebo) and timepoint as categorical factors, and a random intercept and slope per participant. The degrees of freedom for the model estimates will be determined by the Kenward-Roger method. From the model, the slope (ie, the regression parameter for the concentration) and the treatment effect-specific intercept (defined as the difference between active and placebo) will be estimated together with 2-sided 90% CI. The estimates for the time effect will be reported with degrees of freedom and SE.
The geometric mean of the individual Cmax values for FTP-198 plasma concentrations for participants in each of the study dose groups will be determined. In the event the same dose of FTP-198 is repeated in a different cohort, Cmax values obtained from the 2 (or more) cohorts at the same dose will be pooled as one of the FTP-198 dose group. The predicted effect and its 2-sided 90% CI for delta delta QTcF (ie, slope estimate *concentration + treatment effect) at this geometric mean Cmax will be obtained.
The plot of the observed median-quantile FTP-198 concentrations and associated mean delta delta QTcF (90% CI) adjusted for diurnal effects together with the regression line presenting the predicted delta delta QTcF (90% CI) will be used to evaluate the adequacy of the model fit to the assumption of linearity and the impact on quantifying the exposure response. Additional plots may be used to validate the model assumptions.
Exploratory analyses (via graphical displays and/or model fitting) will also include accounting for a delayed effect (hysteresis) and the justification for the choice of PD model.
If a QTc effect (delta delta QTcF) exceeding 10 msec cannot be excluded in the by-timepoint analysis of the 2 highest dose groups, hysteresis, ie, difference in peak QT response and Cmax, will be explored through visual inspection of overlaid FTP-198 plasma concentration and delta delta QTc time curves and through so called hysteresis loops for each dose of FTP-198.
To assess the appropriateness of a linear model, normal QQ-plots for the residuals and plots of weighted residuals vs concentration and vs fitted values will be produced. The scatter plot of residuals vs concentration by Loess (ie, locally weighted scatterplot smoothing) fitting will also be produced with an optimal smoothing parameter selected by the Akaike information criterion with a correction. If there is an indication that a linear model is inappropriate, additional models may be fitted (e.g. an E-max model). The exposure-response analysis will then be repeated for the model found to best accommodate the nonlinearity detected.
Pharmacokinetic Data
All participants in the Safety Analysis Set who have sufficient plasma concentration data to derive at least 1 PK parameter will be included in the PK analysis (ie, the PK Analysis Set).
Reasons for exclusion of a participant or a sample from the analysis include, but are not limited to, the following:
• Vomiting within 6 hours after study drug administration (or within (2 x median tmax) if median tmax > 3 hours);
• Too few data (greater than 10% missing values for a participant);
• Noncompliance with study procedures affecting PK (eg, concomitant medication).
All participants and samples excluded from the analysis will be clearly documented in the clinical study report.
Plasma concentrations of FTP-198 at specified time points pre– and post dose will be used to calculate PK parameters using validated PK software. In all calculations, zero will be substituted for concentrations below the quantification limit of the assay. Participants dosed with placebo will be analyzed as a pooled group.
Individual and mean FTP-198 plasma concentrations at each time point will be tabulated for each dose group and presented graphically with concentration displayed on a linear and logarithmic scale. Pharmacokinetic parameters will be determined using noncompartmental methods and summarized by dose group using descriptive statistics (n, mean, SD, coefficient of variation, minimum, maximum and median). In addition, geometric mean will be calculated for all PK parameters. Analyses using linear models will be performed to assess dose proportionality (both single dose and multiple dose), time dependence (multiple dose), accumulation (multiple dose), and attainment of steady state (multiple dose). Dose-normalised PK parameters may also be used to assess dose proportionality.
Pharmacodynamic Data:
All participants in the Safety Analysis Set who have evaluable LPA18:2 concentration data will be included in the PD analysis.
Individual percentage reductions in plasma LPA18:2 concentrations relative to baseline will be determined at each timepoint and summarized by dose group using descriptive statistics (n, mean, SD, minimum, maximum and median). In addition, geometric mean and SD may be calculated. Participants dosed with placebo will be analyzed as a pooled group. Percentage reduction data will be presented graphically. The maximum percentage reduction from baseline observed (Emax) following dosing on Day 1 (Part A and Part B) and Day 7 (Part B only) will be determined for each dose group and tabulated.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
25/02/2020
Actual
25/02/2020
Date of last participant enrolment
Anticipated
30/09/2020
Actual
22/10/2020
Date of last data collection
Anticipated
9/10/2020
Actual
5/11/2020
Sample size
Target
78
Accrual to date
Final
75
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 15710 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 29132 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 304811 0
Commercial sector/Industry
Name [1] 304811 0
Haisco Pharmaceutical (Australia) Pty Ltd
Country [1] 304811 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Avance Clinical
Address
Level 1, 2 Ann Nelson Drive, Thebarton, SA, 5031
Country
Australia
Secondary sponsor category [1] 305134 0
None
Name [1] 305134 0
Address [1] 305134 0
Country [1] 305134 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305225 0
Bellberry HREC
Ethics committee address [1] 305225 0
Ethics committee country [1] 305225 0
Australia
Date submitted for ethics approval [1] 305225 0
18/12/2019
Approval date [1] 305225 0
28/01/2020
Ethics approval number [1] 305225 0
2019-12-1152

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

Contacts
Principal investigator
Name 99674 0
Prof Sepher Shakib
Address 99674 0
CMAX
Level 5, 18a North Terrace
Adelaide, SA, 5000
Country 99674 0
Australia
Phone 99674 0
+61 411 100 278
Fax 99674 0
Email 99674 0
[email protected]
Contact person for public queries
Name 99675 0
Katherine Mudge
Address 99675 0
CMAX
Level 5, 18a North Terrace
Adelaide, SA, 5000
Country 99675 0
Australia
Phone 99675 0
+61 8 7088 7900
Fax 99675 0
+61 8 7088 7999
Email 99675 0
[email protected]
Contact person for scientific queries
Name 99676 0
Li Chen
Address 99676 0
Haisco Pharmaceutical, 136 Baili Road Chengdu Cross-Straits IT Industry
Development Zone, Wenjiang District, Chengdu,
Sichuan province 611130, P.R. China
Country 99676 0
China
Phone 99676 0
+86 10 13699296464
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Email 99676 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

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

Documents added automatically
No additional documents have been identified.