Duchenne and Becker Muscular Dystrophy Clinical Trial
Official title:
A Randomized, Partially Double-Blind, Four-Period, Four-Treatment, Crossover Study Investigating the Placebo-Corrected Effects of a Therapeutic Dose (100 mg) and a Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval in Healthy Male and Female Subjects
| Verified date | April 2023 |
| Source | Italfarmaco |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
The study will evaluate the effect of a therapeutic dose and a supratherapeutic dose of ITF2357 on the QT/QTc interval.
| Status | Completed |
| Enrollment | 31 |
| Est. completion date | June 18, 2021 |
| Est. primary completion date | June 18, 2021 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | 18 Years to 55 Years |
| Eligibility | Inclusion Criteria: 1. Male or female, non-smoker (no use of tobacco or nicotine products within 3 months prior to screening), greater than or equal to (>=) 18 and less than or equal to (<=) 55 years of age, with body mass index (BMI) greater than (>) 18.5 and less than (<) 30.0 kilograms per meter square (kg/m^2) and body weight >=55 kilograms (kg) and <=100 kg for females and body weight >=60 kg and <=100 kg for males. 2. Healthy as defined by: 1. The absence of clinically significant illness and major surgery within 4 weeks prior to dosing. Participants vomiting within 24 hours pre-dose will be carefully evaluated for upcoming illness/disease. Inclusion pre-dosing of the patient in the study is at the discretion of the Investigator, depending on his/her clinical judgement. 2. The absence of clinically significant history of neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease. 3. Non-childbearing potential female defined as: 1. Post-menopausal female (absence of menses for 12 months prior to the first study drug administration, bilateral oophorectomy or hysterectomy with bilateral oophorectomy at least 6 months prior to the first study drug administration); or 2. Surgically sterile female (hysterectomy or tubal ligation at least 6 months prior to drug administration). 4. Females of childbearing potential who are sexually active with a male partner must be willing to use one of the following acceptable contraceptive methods throughout the study and for at least 90 days after the last study drug administration: 1. Simultaneous use of intra-uterine contraceptive device, without hormone release system placed at least 4 weeks prior to study drug administration, and condom for the male partner; 2. Simultaneous use of diaphragm or cervical cap with intravaginally applied spermicide and male condom for the male partner, started at least 21 days prior to study drug administration; 5. Male participants who are not vasectomized for at least 6 months, and who are sexually active with a female partner of childbearing potential (childbearing potential females are defined as women that are neither post-menopausal nor surgically sterile) must be willing to use one of the following acceptable contraceptive methods from the first study drug administration until at least 90 days after the last study drug administration: 1. Simultaneous use of a male condom and, for the female partner, hormonal contraceptives used since at least 4 weeks or intra-uterine contraceptive device placed since at least 4 weeks; 2. Simultaneous use of a male condom and, for the female partner, a diaphragm or cervical cap with intravaginally applied spermicide. 6. Male participants (including men who have had a vasectomy) with a pregnant partner must agree to use a condom from the first study drug administration until at least 90 days after the last study drug administration. 7. Male participants must be willing not to donate sperm until 90 days following the last study drug administration. 8. Female participants must be willing not to donate ovules until 90 days following the last study drug administration. 9. Participant's written informed consent obtained prior to any study-related procedure. 10. Willingness and capability to comply with the requirements of the study and ability to understand the study procedures and the risks involved. 11. Willing to take out dentures and mouth piercings for study procedures. Exclusion Criteria: 1. Any clinically significant abnormality at physical examination, clinically significant abnormal laboratory test results or positive test for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C found during medical screening. 2. Clinically significant vital sign abnormalities (systolic blood pressure lower than 90 or over 140 millimeter of mercury [mmHg], diastolic blood pressure lower than 60 or over 90 mmHg, or heart rate less than 40 or over 100 beats per minute [bpm]) at screening. For eligibility purposes, not the mean value, but the two single measurements will be considered. 3. Any of the following abnormalities on 12-lead ECG at screening. PR (PR interval) >210 millisecond (msec); QRS (QRS complex) >120 msec; QTcF >450 msec; any abnormality of cardiac rhythm other than sinus arrhythmia; abnormality of T-wave morphology that will impair the ability to measure the QT interval reliably. The averaged value of three ECGs 5 minutes apart from each other will be used; evaluations have to be used for the evaluation of the QTc interval requested by this exclusion criteria. 4. Participants with history of sustained and non-sustained cardiac arrhythmias (ECG demonstrated), participants with a family history of sudden cardiac death and participants with a history of additional risk factors for TdP, heart failure, hypokalemia, LQTS). 5. Any of the following abnormal laboratory test values at screening or at baseline (Day -1) of Period 1: 1. Platelet count <125*10^9 per liter (/L) 2. Absolute neutrophil count <1.2*10^9/L 6. Participants who have cardiovascular condition such as, but not limited to unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular failure, acute ischemic heart disease in the last year prior to study screening, which may impact the safety of the participant or the evaluation of the result of the study according to the Investigator's judgment; cardiovascular conditions should be discarded based on the results obtained on the ECG, medical examination and routine lab test. 7. Positive urine drug screen, alcohol breath test or urine cotinine test at screening or at baseline (Day -1). 8. History of anaphylaxis reaction or clinically significant drug hypersensitivity reaction (e.g., angioedema, Stevens-Johnson syndrome, Acute Generalized Exanthematous Pustulosis, Drug-induced hypersensitivity syndrome, Drug-induced neutropenia). 9. History of allergic reactions to ITF2357, histone deacetylases (HDAC) inhibitors, or other related drugs, moxifloxacin, other quinolones, or to any excipient in the formulation. 10. Positive pregnancy test at screening or at baseline (Day -1). 11. Participants with a sorbitol intolerance or sorbitol malabsorption or have fructose intolerance. 12. Current or recent (within 3 months of study drug administration) clinically significant gastrointestinal disease that can interfere with drug absorption. 13. Gastrointestinal surgery that interferes with physiological absorption and motility (i.e., gastric bypass, duodenectomy) or gastric bands. 14. History of significant alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to the screening visit (more than 14 units of alcohol per week [1 unit = 150 milliliter [mL] of wine, 360 mL of beer, or 45 mL of 40 percent [%] alcohol]). 15. History of significant drug abuse within 1 year prior to screening or use of soft drugs (such as marijuana) within 3 months prior to the screening visit or hard drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to screening. 16. Use of ITF2357 for a medical condition or in the context of another clinical trial within a period of 30 days prior to the first dosing. 17. Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to the first dosing, administration of a biological product in the context of a clinical research study within 90 days prior to the first dosing, or concomitant participation in an investigational study involving no drug or device administration. 18. Use of medications for the timeframes specified below, with the exception of medications exempted by the Investigator on a case-by-case basis because they are judged unlikely to affect the pharmacokinetic profile of the study drug or participant safety (e.g., topical drug products without significant systemic absorption): 1. Prescription medications within 14 days prior to the first dosing; 2. OTC products (with the exception of the occasional use of acetaminophen [up to 2 grams [g] daily]) and natural health products (including herbal remedies, homeopathic and traditional medicines, probiotics, food supplements such as vitamins, minerals, amino acids, essential fatty acids, and protein supplements used in sports) within 7 days prior to the first dosing; 3. Depot injection or implant of any drug within 3 months prior to the first dosing; 4. Any drugs known to induce or inhibit hepatic drug metabolism (including St. John's wort) within 30 days prior to the first dosing. 19. Donation of plasma within 7 days prior to dosing. Donation or loss of blood (excluding volume drawn at screening) of 50 mL to 499 mL of blood within 30 days, or more than 499 mL within 56 days prior to the first dosing. 20. Breast-feeding participant. 21. Inability to be venipunctured and/or tolerate catheter venous access; 22. Inability or difficulty to swallow tablets or suspension. 23. Any reason which, in the opinion of the Investigator, would prevent the participant from participating in the study. 24. History or presence of other diseases, metabolic dysfunctions, physical examination findings, or any clinically relevant abnormal laboratory value at screening suggesting an unknown disease and requiring further clinical investigation or which may impact the safety of the participant or the evaluation of the result of the study according to the Investigator's judgment. |
| Country | Name | City | State |
|---|---|---|---|
| Canada | Québec | Québec |
| Lead Sponsor | Collaborator |
|---|---|
| Italfarmaco |
Canada,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 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 (??QTcF) was calculated based on model-predicted effect. | At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Change From Baseline in QTcF Interval | 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). | At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Change From Baseline in PR Interval | 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. | At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Change From Baseline in QRS Interval | 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. | At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Change From Baseline in Heart Rate (HR) Interval | 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. | At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Placebo-corrected Change From Baseline in PR Interval | Placebo-corrected change from Baseline in PR, (??PR) 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. | At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Placebo-corrected Change From Baseline in QRS Interval | Placebo-corrected change from baseline for QRS interval, (??QRS) 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. | At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Placebo-corrected Change From Baseline in HR Interval | Placebo-corrected change from baseline in HR, (??HR) was calculated based on model-predicted effect. | At 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Number of Participants With Changes in Categorical Outliers for QTcF, PR, and QRS Intervals in the ECG and HR | 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 (?QTcF) 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. |
Baseline, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, and 36 hours post-dose | |
| Secondary | Number of Participants With Treatment-Emergent Changes of T-Wave Morphology and U Wave Presence | 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. |
Up to 44 days | |
| Secondary | Plasma Pharmacokinetic (PK): Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of ITF2357 and Its Metabolites | 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. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Moxifloxacin | 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). | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Area Under the Concentration-Time Curve From Time Zero to 12 Hours (AUC0-12) of ITF2357 and Its Metabolites | 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. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, and 12 hours post-dose | |
| Secondary | Plasma PK: Area Under the Concentration-Time Curve From Time Zero to 12 Hours (AUC0-12) of Moxifloxacin | AUC0-12 was calculated using the trapezoidal method for Moxifloxacin. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8 and 12 hours post-dose | |
| Secondary | Plasma PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of ITF2357 and Its Metabolites | 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. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Moxifloxacin | AUC0-inf was calculated as AUC0-t + Clast/Kel, where Clast is the last measurable concentration for Moxifloxacin. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Percentage of Residual Area for ITF2357 and Its Metabolites | Residual area was calculated as 100*(1- AUC0-t / AUC0-inf) for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Percentage of Residual Area for Moxifloxacin | Residual area was calculated as 100*(1- AUC0-t / AUC0-inf) for moxifloxacin. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Maximum Observed Plasma Concentration (Cmax) of ITF2357 and Its Metabolites | Cmax was calculated for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide. Cmax was taken directly from the observed concentration-time curve. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Maximum Observed Plasma Concentration (Cmax) of Moxifloxacin | Cmax was calculated for moxifloxacin. Cmax was taken directly from the observed concentration-time curve. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Time of Observed Cmax (Tmax) of ITF2357 and Its Metabolites | 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. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Time of Observed Cmax (Tmax) of Moxifloxacin | Tmax was calculated for Moxifloxacin. The time to reach the maximum observed plasma concentration obtained directly from plasma concentration time curve. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Elimination Rate Constant (Kel) of ITF2357 and Its Metabolites | 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. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Elimination Rate Constant (Kel) of Moxifloxacin | 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. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Elimination Half-life (T½ el) of ITF2357 and Its Metabolites | T½ el was calculated as ln(2)/kel for ITF2357 and Metabolites : ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Elimination Half-life (T½ el) of Moxifloxacin | T½ el was calculated as ln(2)/kel for moxifloxacin. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Apparent Total Body Clearance (CL/F) of ITF2357 and Its Metabolites | CL/F was calculated as Dose/AUC0-inf for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Apparent Total Body Clearance (CL/F) of Moxifloxacin | CL/F was calculated as Dose/AUC0-inf for moxifloxacin. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Apparent Volume of Distribution (Vd/F) of ITF2357 and Its Metabolites | Vd/F was calculated as Dose/Kel x AUC0-inf for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, and ITF2955 glucuronide. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Plasma PK: Apparent Volume of Distribution (Vd/F) of Moxifloxacin | Vd/F was calculated as Dose/Kel x AUC0-inf for moxifloxacin. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60, and 72 hours post-dose | |
| Secondary | Urine PK: Cumulative Urinary Excretion From Time Zero to Time t (Ae0-t) for ITF2357 and Its Metabolites | 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. | Pre-dose (within 2 hours before dosing), 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours post-dose | |
| Secondary | Urine PK: Maximum Rate of Urinary Excretion (Rmax) for ITF2357 and Its Metabolites | 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. | Pre-dose (within 2 hours before dosing), 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours post-dose | |
| Secondary | Urine PK: Time of Rmax (TRmax) for ITF2357 and Its Metabolites | TRmax was calculated as the midpoint of the collection interval during which Rmax occurred for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide. | Pre-dose (within 2 hours before dosing), 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours post-dose | |
| Secondary | Urine PK: Renal Clearance (Clr) for ITF2357 and Its Metabolites | Clr was calculated as Ae0-t / AUC0-t (plasma) for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide. | Pre-dose (within 2 hours before dosing), 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours post-dose | |
| Secondary | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and 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. 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. | Baseline up to 44 days | |
| Secondary | Number of Treatment-Related 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. | Baseline up to 44 days | |
| Secondary | Number of TEAEs Based on Severity | 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. | Baseline up to 44 days | |
| Secondary | Number of Participants With Clinically Significant Changes in Vital Signs | 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. | Baseline up to 44 days | |
| Secondary | Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters | 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. | Baseline up to 44 days | |
| Secondary | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings | 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. | Baseline up to 44 days |