Trial Outcomes & Findings for Placebo-Corrected Effects of Therapeutic Dose (100 mg) and Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval (NCT NCT04821063)

The study was conducted at a single center in Canada. A total of 34 healthy non-smoker were screened in the study, of which 31 participants were enrolled and received the study treatment. Screen failures were mainly due to not meeting inclusion criteria.

Participants were administered the following treatments: Treatment T (Therapeutic dose of ITF2357 100 mg), Treatment ST (Supratherapeutic dose of ITF2357 300 mg), Treatment P (Placebo), and Treatment M (Moxifloxacin) in 4-periods and 12-sequences in this study.

Placebo-Corrected Effects of Therapeutic Dose (100 mg) and Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval

The cardio-dynamic assessment was performed through 12-lead electrocardiogram (ECG) extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Placebo-corrected change from baseline in QTcF (ΔΔQTcF) was calculated based on model-predicted effect.

The cardio-dynamic assessment was performed through 12-lead ECGs extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. QT interval was corrected for heart rate using Fridericia's correction (QTcF).

The cardio-dynamic assessment was performed through 12-lead ECGs extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The PR interval is the time from the onset of the P-wave to the start of the next QRS complex, corresponding to the end of atrial depolarization and onset of ventricular depolarization.

The cardio-dynamic assessment was performed through 12-lead ECGs extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. QRS interval is the time from electrocardiogram Q wave to the end of the S wave, corresponding to ventricle depolarization.

The cardio-dynamic assessment was performed through 12-lead ECGs extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. Baseline is defined as the last results (scheduled or unscheduled) obtained prior to drug administration in each period.

Placebo-corrected change from Baseline in PR, (ΔΔPR) was calculated based on model-predicted effect. PR interval was the time between the beginning of the P wave and the start of the QRS interval, corresponding to the end of atrial depolarization and onset of ventricular depolarization.

Placebo-corrected change from baseline for QRS interval, (ΔΔQRS) was calculated based on model-predicted effect. QRS interval is the time from Q wave to the end of the S wave, corresponding to ventricle depolarization.

Placebo-corrected change from baseline in HR, (ΔΔHR) was calculated based on model-predicted effect.

QTcF: Treatment-emergent value of greater than (\>) 450 and less than or equal to (\<=) 480 ms when not present at Baseline (new onset). Treatment-emergent value of \> 480 and \<= 500 ms when not present at Baseline (new onset). Treatment-emergent value of \> 500 ms when not present at Baseline (new onset). Increase of QTcF (ΔQTcF) from Baseline of \> 30 and \<= 60 ms. Increase of QTcF from Baseline \> 60 ms HR: Decrease of HR from Baseline \> 25% resulting in HR less than (\<) 50 bpm. Increase of HR from Baseline \> 25% resulting in HR \> 100 bpm. PR: Increase of PR from Baseline \> 25% resulting in PR \> 210 ms. QRS: Increase of QRS from Baseline \> 25% resulting in QRS \> 120 ms.

T-wave abnormalities were categorized as follows: Normal T wave (+): Any positive T wave not meeting any criterion below. Flat T wave: T amplitude \< 1 mm (either positive or negative) including flat isoelectric line. Notched T wave (+): Presence of notch(es) of at least 0.05 mV amplitude on ascending or descending arm of the positive T wave. Biphasic: T wave that contains a second component with an opposite phase that is at least 0.1 mV deep (both positive/negative and negative/positive and polyphasic T waves included). Normal T wave (-): T amplitude that is negative, without biphasic T wave or notches. Notched T wave (-): Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending arm of the negative T wave. U waves: Presence of abnormal U waves.

The area under the concentration time curve (AUC) from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. AUC0-t was calculated using the mixed log-linear trapezoidal rule (linear up, log down). AUC0-t of ITF2357 and metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide were reported.

The area under the concentration time curve (AUC) from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. AUC0-t was calculated using the mixed log-linear trapezoidal rule (linear up, log down).

AUC0-12 was calculated using the trapezoidal method for ITF2357 and metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide. AUC0-12:: of ITF2357 and its metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide were reported.

AUC0-12 was calculated using the trapezoidal method for Moxifloxacin.

AUC0-inf was calculated as AUC0-t + Clast/Kel, where Clast is the last measurable concentration. Elimination rate constant (Kel),was defined as the negative of the estimated slope of the linear regression of the in-transformed concentration versus time profile in the terminal elimination phase. AUC0-inf of ITF2357 and metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide were reported.

AUC0-inf was calculated as AUC0-t + Clast/Kel, where Clast is the last measurable concentration for Moxifloxacin.

Residual area was calculated as 100\*(1- AUC0-t / AUC0-inf) for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide.

Residual area was calculated as 100\*(1- AUC0-t / AUC0-inf) for moxifloxacin.

Cmax was calculated for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide. Cmax was taken directly from the observed concentration-time curve.

Cmax was calculated for moxifloxacin. Cmax was taken directly from the observed concentration-time curve.

Tmax was calculated for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide. The time to reach the maximum observed plasma concentration obtained directly from plasma concentration time curve.

Tmax was calculated for Moxifloxacin. The time to reach the maximum observed plasma concentration obtained directly from plasma concentration time curve.

Kel was defined as the negative of the estimated slope of the linear regression of the ln-transformed concentration versus time profile in the terminal elimination phase. Kel was calculated for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, andITF2955 glucuronide.

Kel was defined as the negative of the estimated slope of the linear regression of the ln-transformed concentration versus time profile in the terminal elimination phase. Kel was calculated for Moxifloxacin.

T½ el was calculated as ln(2)/kel for ITF2357 and Metabolites : ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin.

T½ el was calculated as ln(2)/kel for moxifloxacin.

CL/F was calculated as Dose/AUC0-inf for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide.

CL/F was calculated as Dose/AUC0-inf for moxifloxacin.

Vd/F was calculated as Dose/Kel x AUC0-inf for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide.

Vd/F was calculated as Dose/Kel x AUC0-inf for moxifloxacin.

Ae0-t was calculated as the sum of the amounts excreted over each collection interval. The amount excreted in the urine for each time interval is calculated as the urine concentration multiplied by the urine volume for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide.

Rmax was calculated by dividing the amount of drug excreted in each collection interval by the time over which it was collected for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide.

TRmax was calculated as the midpoint of the collection interval during which Rmax occurred for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide.

Clr was calculated as Ae0-t / AUC0-t (plasma) for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide.

Adverse event (AE) was defined as any untoward medical occurrence in a subject or clinical investigation participant administered a pharmaceutical product and which did not necessarily have a causal relationship with the study drug. Serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; required initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE were defined as an AEs following the start of treatment or AEs increasing in severity during treatment. TEAEs include both serious and non-serious TEAEs.

Adverse event (AE) was defined as any untoward medical occurrence in a subject or clinical investigation participant administered a pharmaceutical product and which did not necessarily have a causal relationship with the study drug. Any AEs which occurred due to study drug treatment are reported as Treatment-related AEs. Number of treatment related TEAEs were reported.

All AEs were analyzed using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 and were graded as Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL), Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE, where higher grade indicated more severe condition. Number of TEAEs based on severity were reported.

Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. Clinical significance was decided by the investigator. Number of participants with clinically significant change from baseline in vital signs were reported.

Clinical laboratory parameters included biochemistry, hematology, and urinalysis. Clinical significance was decided by the investigator. Number of participants with clinically significant change from baseline in clinical laboratory parameters were reported.

ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Clinical significance was decided by the investigator. Number of participants with clinically significant change from baseline in ECG were reported.