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

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ClinicalTrials.gov Identifier: NCT04821063
Recruitment Status : Not yet recruiting
First Posted : March 29, 2021
Last Update Posted : March 29, 2021
Sponsor:
Information provided by (Responsible Party):
Italfarmaco

Brief Summary:
The study will evaluate the effect of a therapeutic dose and a supratherapeutic dose of ITF2357 on the QT/QTc interval.

Condition or disease Intervention/treatment Phase
Duchenne and Becker Muscular Dystrophy Polycytemia Vera Drug: ITF2357 10 mg/mL Drug: Placebo Drug: Moxifloxacin Hydrochloride Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: ITF2357 (therapeutic dose and supratherapeutic dose, and placebo) will be administered in a double-blinded fashion whereas no blinding will be needed with treatment moxifloxacin.
Primary Purpose: Treatment
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
Estimated Study Start Date : April 6, 2021
Estimated Primary Completion Date : May 11, 2021
Estimated Study Completion Date : May 11, 2021


Arm Intervention/treatment
Experimental: Therapeutic dose: ITF2357 100 mg
Participants will receive a single dose of ITF2357 100 mg administered as 10 milliliters (mL) of ITF2357 10 milligrams per milliliter (mg/mL) oral suspension and 20 mL of placebo matched to ITF2357 oral suspension under fasting conditions on Day 1 of respective period as per the assigned treatment sequence.
Drug: ITF2357 10 mg/mL
Dose: 100 mg (administered as 10 mL); Dosage form: suspension; Route of administration: oral
Other Name: Givinostat

Drug: Placebo
Dose: 20 mL; Dosage form: suspension; Route of administration: oral

Experimental: Supratherapeutic dose: ITF2357 300 mg
Participants will receive a single dose of ITF2357 300 mg administered as 30 mL of ITF2357 10 mg/mL oral suspension under fasting conditions on Day 1 of respective period as per the assigned treatment sequence.
Drug: ITF2357 10 mg/mL
Dose: 300 mg (administered as 30 mL); Dosage form: suspension; Route of administration: oral
Other Name: Givinostat

Placebo Comparator: Placebo
Participants will receive a single dose of placebo matched to ITF2357 administered as 30 mL oral suspension under fasting conditions on Day 1 of respective period as per the assigned treatment sequence.
Drug: Placebo
Dose: 30 mL; Dosage form: suspension; Route of administration: oral

Active Comparator: Moxifloxacin
Participants will receive a single dose of moxifloxacin 400 mg tablet under fasting conditions on Day 1 of respective period as per the assigned treatment sequence.
Drug: Moxifloxacin Hydrochloride
Dose: 400 mg; Dosage form: tablet; Route of administration: oral




Primary Outcome Measures :
  1. Cardiodynamic Electrocardiogram (ECG) Assessment: Placebo-corrected Change From Baseline in Fridericia's corrected QT interval (QTcF) of the ECG [ Time Frame: -45, -30, -15 minutes pre-dose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36 post-dose ]

Secondary Outcome Measures :
  1. Change From Baseline in QTcF Interval, PR Interval, and QRS Interval of the ECG [ Time Frame: -45, -30, -15 minutes pre-dose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36 post-dose ]
  2. Change From Baseline in Heart Rate (HR) [ Time Frame: -45, -30, -15 minutes pre-dose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36 post-dose ]
  3. Change From Baseline on Placebo-corrected PR and QRS [ Time Frame: -45, -30, -15 minutes pre-dose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36 post-dose ]
  4. Change from baseline on Placebo-corrected HR [ Time Frame: -45, -30, -15 minutes pre-dose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36 post-dose ]
  5. Number of Categorical Outliers for QTcF, PR, and QRS Intervals in the ECG and HR [ Time Frame: -45, -30, -15 minutes pre-dose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36 post-dose ]
  6. Number of Treatment-Emergent Changes of T-Wave Morphology and U wave Presence [ Time Frame: -45, -30, -15 minutes pre-dose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 24, 36 post-dose ]
  7. Plasma Pharmacokinetic (PK): Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) [ Time Frame: Pre-dose and 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 ]
    AUC0-t was calculated using the trapezoidal method for ITF2357 and metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  8. Plasma PK: Area Under the Concentration-Time Curve From Time Zero to 12 Hours (AUC0-12) [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8 and 12 hours post-dose ]
    AUC0-12 was calculated using the trapezoidal method for ITF2357 and metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  9. Plasma PK: Area Under the Concentration-Time Curve From Time Zero to Infinity (extrapolated) (AUC0-inf) [ Time Frame: Pre-dose and 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 ]
    AUC0-inf was calculated as AUC0-t + Clast/Kel, where Clast is the last measurable concentration for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  10. Plasma PK: Residual Area [ Time Frame: Pre-dose and 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 ]
    Residual area was calculated as 100*(1- AUC0-t / AUC0-inf) for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  11. Plasma PK: Maximum Observed Concentration (Cmax) [ Time Frame: Pre-dose and 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 ]
    Cmax was calculated for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  12. Plasma PK: Time of Observed Cmax (Tmax) [ Time Frame: Pre-dose and 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 ]
    Tmax was calculated for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  13. Plasma PK: Elimination Half-life (T½ el) [ Time Frame: Pre-dose and 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 ]
    T½ el was calculated as ln(2)/kel for ITF2357 and Metabolites : ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  14. Plasma PK: Elimination Rate Constant (Kel) [ Time Frame: Pre-dose and 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 ]
    Kel was calculated for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  15. Plasma PK: Apparent Total Body Clearance (CL/F) [ Time Frame: Pre-dose and 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 ]
    CL/F will be calculated as Dose/AUC0-inf for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  16. Plasma PK: Apparent Volume of Distribution (Vd/F) [ Time Frame: Pre-dose and 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 ]
    Vd/F will be calculated as Dose/Kel x AUC0-inf for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide, and Moxifloxacin

  17. Urine PK: Cumulative Urinary Excretion From Time Zero to Time t (Ae0-t) [ Time Frame: Pre-dose (within 2 hours before dosing), 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours post-dose ]
    Ae0-t will be 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.

  18. Urine PK: Maximum Rate of Urinary Excretion (Rmax) [ Time Frame: Pre-dose (within 2 hours before dosing), 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours post-dose ]
    Rmax will be 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.

  19. Urine PK: Time of Rmax (TRmax) [ Time Frame: Pre-dose (within 2 hours before dosing), 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours post-dose ]
    TRmax will be calculated as the midpoint of the collection interval during which Rmax occurred for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide.

  20. Urine PK: Renal Clearance (Clr) [ Time Frame: Pre-dose (within 2 hours before dosing), 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours post-dose ]
    Clr will be calculated as Ae0-t / AUC0-t (plasma) for ITF2357 and Metabolites: ITF2374, ITF2375, ITF2440, ITF2563, ITF2955 glucuronide.

  21. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), and Treatment-Related TEAEs [ Time Frame: Up to 8 weeks ]
  22. Number of Participants With Treatment-Emergent Adverse Events Based on Severity [ Time Frame: Up to 8 weeks ]
    All adverse events (AEs) will be analyzed using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Graded from 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 will indicate more severe condition.

  23. Number of Participants With Clinically Significant Changes in Vital Signs, Clinical Laboratory Parameters, and Electrocardiogram Findings [ Time Frame: Up to 5 weeks ]


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04821063


Contacts
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Contact: Paolo Bettica, MD, PhD +390264432511 p.bettica@italfarmaco.com

Sponsors and Collaborators
Italfarmaco
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Responsible Party: Italfarmaco
ClinicalTrials.gov Identifier: NCT04821063    
Other Study ID Numbers: ITF/2357/54
2020-003105-63 ( EudraCT Number )
First Posted: March 29, 2021    Key Record Dates
Last Update Posted: March 29, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Muscular Dystrophy, Duchenne
Muscular Dystrophies
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Givinostat hydrochloride
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Histone Deacetylase Inhibitors