Perpetrator DDI Potential of Givinostat as Inhibitor and Inducer of CYP3A and P-gp Activity

Open-label, Single-center Study in Healthy Subjects to Investigate the Effect of Oral Givinostat on Pharmacokinetics (PK) of Intravenous and Oral Midazolam and Oral Dabigatran Etexilate (PART 1)

Primary objective:

1. To assess the potential inhibitory and inducing effect of oral givinostat on the single dose pharmacokinetics (PK) of intravenous or oral midazolam.
2. To assess the potential inhibitory and inducing effect of oral givinostat on the single dose PK of oral dabigatran etexilate.

Secondary objective:

To assess the safety and tolerability of concomitant administration of givinostat plus midazolam and dabigatran etexilate.

Study Overview

• Status: Completed
• Conditions: Drug-Drug Interaction; Heathy Volunteer
• Intervention / Treatment: Drug: Givinostat 10 mg/mL; Drug: Midazolam 1mg/ml IV; Drug: Midazolam 2.5 mg oromucosal solution; Drug: Dabigatran etexilate 75 mg oral hard capsules

Detailed Description

This study was planned as a phase I, open-label, 3-part, fixed-sequence, nonrandomized study in healthy male and female subjects. The study evaluated the givinostat (ITF2357) potential drug-drug interaction (DDI) at level of CYP3A-mediated metabolism and P-glycoprotein (P-gp) transport with intravenous or oral midazolam and with oral dabigatran etexilate.

More precisely, the study aimed at assessing the potential (inhibitory or inducing) effect of givinostat on the PK of midazolam IV, on the PK of oral midazolam and on the PK of dabigatran etexilate.

The study lasted from Day 1 to Day 20. Subjects were confined from Day -1 to Day 20. On Days 6 and 17, single doses of 1 mg midazolam IV and 75 mg dabigatran etexilate, were administered 1 hour after the planned morning time of givinostat administration. On day 1, however, drugs were not administered 1h after gininostat.

On Days 7 and 18, a single oral dose of 2.5 mg midazolam oral solution was administered 1 hour after the planned morning time of givinostat administration.

On day 2, however, the drugs were not administered 1h after gininostat.

From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening.

On Day 19, only the morning dose was administered.

The following assessments were performed:

• Blood collection for pharmacokinetic analysis on Days 1 to 4, 6 to 9 and 17 to 20.
• Vital signs measurements (BP, PR and RR) on Days 1, 2, and 4 to 19.
• 12-lead ECG on Days 3 to 19.
• Blood collection for laboratory tests (hematology, biochemistry and coagulation on Days 4 and 9 and hematology on Days 6, 12, 15 and 18). Subjects were discharged from BlueClinical Phase I in the morning of Day 20 if allowed by the investigator based on their medical condition. The following procedures were performed:
• Physical examination.
• Collection of body weight.
• Vital signs measurements (BP, PR, RR and body temperature).
• 12-lead ECG.
• Safety laboratory assessments (hematology, biochemistry, coagulation and urinalysis).
• Serum pregnancy test for all female subjects. Subjects returned to the site 10 to 14 days after the end of study to undergo additional assessments as required per protocol.

The total duration of Part 1 for each subject was up to approximately 8 weeks from Screening to Follow-up visit, divided as follows:

• Screening: up to 21 days
• Treatment Period: Days 1 to 20
• Safety follow-up visit: 12±2 days

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Portugal
  • Porto, Portugal, 153 4250-449
    • Hospital da Prelada, 3rd Floor & East Wing 4th Floor Rua Sarmento de Beires

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria

A subject was considered eligible for the study if he/she fulfilled all the inclusion criteria:

1. Subject's written informed consent obtained prior to any study-related procedure.
2. Male or female subject, ≥18 and ≤55 years of age, at the time of signing the informed consent.
3. Body mass index (BMI) of 18.5 to 32.0 kg/m2 inclusive, and body weight ≥55 kg and ≤100 kg for females and body weight ≥60 kg and ≤110 kg for males.
4. Non-smoker or ex-smoker (i.e. someone who abstained from using tobaccoor nicotine-containing products for at least 3 months prior to Screening).
5. No clinically relevant diseases.
6. No major surgery within 4 weeks prior to dosing.
7. No clinically relevant abnormalities on physical examination.
8. No clinically relevant abnormalities on 12-lead ECG.
9. No clinically relevant abnormalities on clinical laboratory tests.
10. Negative test results for anti-Human Immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab), Hepatitis B surface antigen (HBsAg) and anti-Hepatitis C virus antibodies (anti-HCVAb).

11. Female subjects are eligible if they are of non-childbearing potential or agree to use a non-hormonal highly effective contraceptive method from 28 days prior to Screening until at least 90 days after the last study drug administration. Nonchildbearing potential female is defined as:

    1. Menopausal, i.e. no menses for ≥ 12 months without an alternative medical cause other than menopause, and a high FSH level.
    2. Pre-menopausal female with documented hysterectomy, bilateral salpingectomy and/or bilateral oophorectomy.

    A non-hormonal effective contraceptive method is defined as:

    1. Intrauterine device.
    2. Bilateral tubal occlusion.
    3. Total abstinence of heterosexual intercourse, in accordance with the lifestyle of the subject.
    4. Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner.
12. Male subjects who are sexually active with a female partner of childbearing potential (pregnant or non-pregnant) must use contraception (condom) from investigational product administration up to at least 90 days following the last study drug administration.
13. Male subjects must ensure that his non-pregnant female partner of childbearing potential agrees to consistently and correctly use for the same period a highly effective method of contraception (see Section 8.5.3).
14. Male subjects must be willing not to donate sperm until 90 days following the last study drug administration.
15. Willingness and capability to comply with the requirements of the study and ability to understand the study procedures and the risks involved.

Exclusion Criteria

A subject was excluded from the study if he/she fulfilled any of the exclusion criteria:

At Screening

1. Previous use of givinostat.
2. History of anaphylaxis reaction or clinically significant drug hypersensitivity reaction (e.g., angioedema, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, drug-induced hypersensitivity syndrome, druginduced neutropenia).
3. Known history of hypersensitivity and/or allergic reactions to givinostat, histone deacetylases (HDAC) inhibitors or to any excipient in the formulation.
4. History of sorbitol intolerance, sorbitol malabsorption or fructose intolerance.
5. Any medical condition (e.g. gastrointestinal, renal or hepatic, including peptic ulcer, inflammatory bowel disease or pancreatitis) or surgical condition (e.g. cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion) or subject safety.
6. Systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 60 or over 90 mmHg, or pulse rate lower than 50 or over 100 bpm.
7. QTcF ˃450 msec.
8. Subjects with history of cardiac arrhythmias (documented), family history of sudden cardiac death or history of additional risk factors for torsades-depointes (e.g. heart failure, hypokalemia, long QT syndrome).
9. Having an estimated glomerular filtration (eGFR) < 90 mL/min, based on creatinine clearance calculation by the Cockcroft-Gault formula and normalized to an average surface area of 1.73 m2.

10. Any of the following abnormal laboratory test values:

    1. Platelet count below the lower limit of the normal range (LLN)
    2. Total white blood cells count below the LLN
    3. Hemoglobin below the LLN
    4. Triglycerides above the upper limit of normal range (ULN)
    5. Potassium or magnesium below the LLN
11. Positive urine alcohol, drugs-of-abuse or cotinine screen tests.
12. Positive serum pregnancy test.
13. If woman, she is breast-feeding.
14. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to the screening visit (i.e. more than 14 units of alcohol per week for males or more than 7 units for females).
15. History of 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. Participation in any clinical trial within the previous 2 months.
17. Participation in more than 2 clinical trials within the previous 12 months.
18. Blood donation or significant blood loss (≥ 450 mL) due to any reason or had plasmapheresis within the previous 2 months.
19. Veins unsuitable for intravenous puncture on either arm.
20. Difficulty in swallowing capsules, tablets or suspensions.

21. Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

    Exclusion Criteria:

    At Admission to Treatment Period

22. Any clinically relevant abnormalities on clinical laboratory tests.
23. Positive urine alcohol, drugs-of-abuse or cotinine screen tests.
24. Positive urine pregnancy test.
25. Positive or inconclusive SARS-CoV-2 test prior to admission.
26. Use of prescription or non-prescription medicinal products within the previous 28 days or within 5-half-lives of the medicinal product, whichever is longer.

27. Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

    For Part 1 subjects:

    At Screening

28. Known history of hypersensitivity and/or allergic reactions to midazolam, other benzodiazepines, dabigatran etexilate or to any excipient of the formulations.
29. Clinically relevant history of impaired respiratory function, obstructive sleep apnea, myasthenia gravis, respiratory arrest and/or cardiac arrest.
30. History of glaucoma.
31. Presence of respiratory failure.
32. Presence of active clinically significant bleeding.
33. Lesion or condition considered to pose a significant risk factor for major bleeding including, but not limited to: current or recent gastrointestinal ulceration, malignant neoplasms, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.

34. Presence of a medical condition requiring anticoagulant treatment.

    At Admission to Treatment Period

35. Treatment with anticoagulants within 28 days or 5 drug half-lives, whichever was longer, before admission.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam; On Days 1, 6 and 17, single doses of midazolam 1 mg IV and dabigatran etexilate 75 mg were administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. On Days 2, 7 and 18, a single oral dose of midazolam 2.5 mg oral solution was administered 1 hour after the planned (as per Day 4) morning time of givinostat administration. From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening. On Day 19, only the morning dose was administered.

Drug: Givinostat 10 mg/mL; 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Days 1, 2, 6, 7, 17 and 18), and twice a day (50 mg as oral suspension), in the morning and in the evening, from the Day 4 to Day 18. On Day 19, only the morning dose was administered.; Other Names: ITF2357; Drug: Midazolam 1mg/ml IV; Midazolam 1 mg/ml, solution for intravenous administration. Midazolam 1mg/ml IV, single dose, was administered on Days 1, 6 and 17, 1 hour after the planned morning time of givinostat administration. Midazolam IV were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.; Other Names: Aurobindo®; Drug: Midazolam 2.5 mg oromucosal solution; Dose: 2.5 mg oromucosal solution. Midazolam 2.5 mg single oral solution was administered on Days 2, 7 and 18, 1 hour after the planned morning time of givinostat administration. Oral midazolam (and dabigatran etexilate) was administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose. Oral midazolam (and dabigatran etexilate) was administered with 150 mL of water. Except for water given with the investigational products, no fluids were allowed from 1 hour before midazolam and dabigatran dosing until 2 hours postdose. Water was provided ad libitum at all other times. Midazolam (and dabigatran etexilate) were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.; Other Names: Buccolam®; Drug: Dabigatran etexilate 75 mg oral hard capsules; Dose: 75 mg; Dosage form: hard capsules On Days 1, 6 and 17, dabigatran etexilate 75 mg was administered (with midazolam 1mg IV) 1 hour after the planned morning time of givinostat administration. Dabigatran etexilate (and midazolam) was administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose Oral dabigatran etexilate (and oral midazolam) was administered with 150 mL of water. Except for water given with the investigational products, no fluids were allowed from 1 hour before dabigatran (and midazolam) dosing until 2 hours postdose. Water was provided ad libitum at all other times. Dabigatran etexilate (and Midazolam) was administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose.; Other Names: Pradaxa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug	Maximum observed plasma concentration (Cmax) of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Administration of Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.	In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug	Maximum observed plasma concentration (Cmax) of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected in K2-EDTA collection tubes at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.	In the turn of 72 hours after administration of dabigatran on day 1,6,17
Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug	tmax =Time of occurrence of Cmax. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.	In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug	The time of occurrence of maximum observed concentration (tmax) of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.	In the turn of 72 hours after administration of dabigatran on day 1,6,17
t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat	T1/2 is the Apparent terminal elimination half-life, calculated as ln(2)/λz. t1/2 of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Administration of Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.	In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug	Apparent terminal elimination half-life, calculated as ln(2)/λz. The t1/2 of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.	In the turn of 72 hours after administration of dabigatran on day 1,6,17
AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat	AUC0-t =area under the curve from time zero to last sampling time with quantifiable concentrations. AUC0-t of midazolam and 1-hydroxymidazolam following Administration of Midazolam IV Alone (Day 1) and Co-Administration of Midazolam IV and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect) and following Oral Midazolam Alone (Day 2) and Co-Administration of Oral Midazolam and Givinostat (Day 7 - Potential Inhibitory Effect, and Day 18 - Potential Inducing Effect). 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.	In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug	AUC0-t =area under the curve from time zero to last sampling time with quantifiable concentrations. AUC0-t of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.	In the turn of 72 hours after administration of dabigatran on day 1,6,17
AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat	AUC0-inf=Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.	In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug	AUC0-inf = Total AUC extrapolated to infinity, calculated as AUC0-t + Clast/λz, where Clast is the last measurable concentration and λz is the apparent terminal elimination rate constant. AUC0-inf of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.	In the turn of 72 hours after administration of dabigatran on day 1,6,17
%AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat	Area under the curve or AUC is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analyzed (normally plasma, blood or serum). Standard calculation of AUC involves using non-compartmental techniques to calculate the AUC from time 0 to the last measurable concentration. This is called AUC0-t and represents the observed exposure to a drug. The total AUC or AUC0-∞ is the area under the curve from time 0 extrapolated to infinite time. %AUCextrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ∙(AUC0-∞ - AUC0-t) / AUC0-∞.	In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
%AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug	Area under the curve (AUC) is a pharmacokinetic statistic used to describe the total exposure to a drug. More specifically, it is the time-averaged concentration of drug circulating in the body fluid analyzed. The total AUC (AUC0-∞) is the area under the curve from time 0 extrapolated to infinite time.; AUC0extrap = Percentage of AUC0-∞ due to extrapolation from the time of the last measurable concentration (tlast) to infinity, i.e., residual area, calculated as 100 ∙(AUC0-∞ - AUC0-t) / AUC0-∞.; AUC0extrap of total dabigatran and free dabigatran following Administration of Dabigatran Etexilate Alone (Day 1) and Co-Administration of Dabigatran Etexilate and Givinostat (Day 6 - Potential Inhibitory Effect, and Day 17 - Potential Inducing Effect). Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatra	In the turn of 72 hours after administration of dabigatran on day 1,6,17
λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat	Apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non-zero concentrations. 13 blood samples were collected at pre-dose and at 2 minutes, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12 and 24 hours after the administration of IV midazolam, on Days 1, 6 and 17, to determine midazolam and 1-hydroxymidazolam plasma concentrations. 11 blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after the administration of oral midazolam, on Days 2, 7 and 18, to determine midazolam and 1-hydroxymidazolam plasma concentrations.	In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.
λz of Dabigatran (Total and Free), Following Single Doses of Givinostat	Apparent first order elimination rate constant associated with the terminal (log-linear) portion of the concentration versus time curve. The parameter is estimated by linear least square regression analysis using the last three (or more) non-zero concentrations. Fifteen (15) blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after the administration of dabigatran etexilate, on Days 1, 6 and 17, for the determination of total and free dabigatran plasma concentrations.	In the turn of 24 hours after IV midazolam, single dose, administered at day 1,6,17 or after oral midazolam, single dose, administered at days 2, 7 and 18.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events by Severity (Mild, Moderate, Severe)	An AE was considered as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily imply a causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The period of observation for the collection of medical occurrences extended from the time when the subject gave Informed Consent until the follow-up visit.	Throughout the study and 10-14 days after the EoS (follow-up visit), i.e. up to date 30-34
Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe)	An AE was considered as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily imply a causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The period of observation for the collection of medical occurrences extended from the time when the subject gave Informed Consent until the follow-up visit.	During the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34

Collaborators and Investigators

• Sponsor: Italfarmaco
• Investigators: Principal Investigator: Marlene Fonseca, MD, Blueclinical, Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2022
• Primary Completion (Actual): May 8, 2022
• Study Completion (Actual): May 24, 2022

Study Registration Dates

• First Submitted: June 9, 2022
• First Submitted That Met QC Criteria: August 4, 2022
• First Posted (Actual): August 8, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 23, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; PK; Midazolam; Dabigatran; Givinostat
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Anesthetics; Central Nervous System Depressants; Neurotransmitter Agents; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; GABA Modulators; GABA Agents; Anticoagulants; Antithrombins; Serine Proteinase Inhibitors; Dabigatran; Midazolam
• Other Study ID Numbers: ITF/2357/55 - PART 1; 2021-005756-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No