Drug-Drug InteractionPhase 1NCT05492318

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

A Phase 1 study testing Givinostat 10 mg/mL, Midazolam 1mg/ml IV and Midazolam 2.5 mg oromucosal solution in people with Drug-Drug Interaction and Heathy Volunteer, run by Italfarmaco at 1 site in Portugal.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

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. Read more about this study

Who is it for?: Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for: Drug-Drug Interaction, Heathy Volunteer
What is being tested?: Givinostat 10 mg/mL, Midazolam 1mg/ml IV and Midazolam 2.5 mg oromucosal solution
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 26 participants
Where: 1 sitePortugal
Study dates: 21 Mar 2022to 24 May 2022
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 55 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

A subject was considered eligible for the study if he/she fulfilled all the inclusion criteria:
Subject's written informed consent obtained prior to any study-related procedure.
Male or female subject, ≥18 and ≤55 years of age, at the time of signing the informed consent.
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.
Non-smoker or ex-smoker (i.e. someone who abstained from using tobaccoor nicotine-containing products for at least 3 months prior to Screening).
No clinically relevant diseases.

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No major surgery within 4 weeks prior to dosing.
No clinically relevant abnormalities on physical examination.
No clinically relevant abnormalities on 12-lead ECG.
No clinically relevant abnormalities on clinical laboratory tests.
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).
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:
Menopausal, i.e. no menses for ≥ 12 months without an alternative medical cause other than menopause, and a high FSH level.
Pre-menopausal female with documented hysterectomy, bilateral salpingectomy and/or bilateral oophorectomy.
A non-hormonal effective contraceptive method is defined as:
Intrauterine device.
Bilateral tubal occlusion.
Total abstinence of heterosexual intercourse, in accordance with the lifestyle of the subject.
Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner.
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.
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).
Male subjects must be willing not to donate sperm until 90 days following the last study drug administration.
Willingness and capability to comply with the requirements of the study and ability to understand the study procedures and the risks involved.

Who cannot join

A subject was excluded from the study if he/she fulfilled any of the exclusion criteria:
At Screening
Previous use of givinostat.
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).
Known history of hypersensitivity and/or allergic reactions to givinostat, histone deacetylases (HDAC) inhibitors or to any excipient in the formulation.
History of sorbitol intolerance, sorbitol malabsorption or fructose intolerance.

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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.
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.
QTcF ˃450 msec.
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).
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.
Any of the following abnormal laboratory test values:
Platelet count below the lower limit of the normal range (LLN)
Total white blood cells count below the LLN
Hemoglobin below the LLN
Triglycerides above the upper limit of normal range (ULN)
Potassium or magnesium below the LLN
Positive urine alcohol, drugs-of-abuse or cotinine screen tests.
Positive serum pregnancy test.
If woman, she is breast-feeding.
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).
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.
Participation in any clinical trial within the previous 2 months.
Participation in more than 2 clinical trials within the previous 12 months.
Blood donation or significant blood loss (≥ 450 mL) due to any reason or had plasmapheresis within the previous 2 months.
Veins unsuitable for intravenous puncture on either arm.
Difficulty in swallowing capsules, tablets or suspensions.
Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.
At Admission to Treatment Period
Any clinically relevant abnormalities on clinical laboratory tests.
Positive urine alcohol, drugs-of-abuse or cotinine screen tests.
Positive urine pregnancy test.
Positive or inconclusive SARS-CoV-2 test prior to admission.
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.
Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.
For Part 1 subjects:
At Screening
Known history of hypersensitivity and/or allergic reactions to midazolam, other benzodiazepines, dabigatran etexilate or to any excipient of the formulations.
Clinically relevant history of impaired respiratory function, obstructive sleep apnea, myasthenia gravis, respiratory arrest and/or cardiac arrest.
History of glaucoma.
Presence of respiratory failure.
Presence of active clinically significant bleeding.
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.
Presence of a medical condition requiring anticoagulant treatment.
At Admission to Treatment Period
Treatment with anticoagulants within 28 days or 5 drug half-lives, whichever was longer, before admission.

Trial locations and contacts

1 site in 1 country.

Portugal1 site

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

Other trials in Portugal

About this study

Official title: 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:

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

Read the 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

Conditions: Drug-Drug Interaction, Heathy Volunteer
Being tested: Givinostat 10 mg/mL, Midazolam 1mg/ml IV, Midazolam 2.5 mg oromucosal solution, Dabigatran etexilate 75 mg oral hard capsules
Keywords: PK, Pharmacokinetics, Givinostat, Midazolam, Dabigatran

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Givinostat 10 mg/mLDrug
Also called ITF2357
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.
Midazolam 1mg/ml IVDrug
Also called Aurobindo®
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.
Midazolam 2.5 mg oromucosal solutionDrug
Also called Buccolam®
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.
Dabigatran etexilate 75 mg oral hard capsulesDrug
Also called Pradaxa
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.

Study groups in NCT05492318
Study group	Role	What they receive
Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam	Experimental	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. Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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-∞.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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 outcomes (2)

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.
Measured: 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.
Measured: During the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

21 Mar 202224 May 2022

First posted8 Aug 2022
Study start21 Mar 2022
Primary completion8 May 2022
Study completion24 May 2022

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Drug-Drug InteractionStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

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Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Model description: An Open-label, Single-center trial in Healthy Subjects
Masking: None (open label)
Enrolment: 26 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT05492318
Sponsor's protocol ID: ITF/2357/55 - PART 1
Other IDs: 2021-005756-11
Status last verified: Dec 2024
First submitted: 9 Jun 2022
Last updated: 6 Jan 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

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Study at a glance

From the registry record, last updated by the sponsor on 6 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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)
ClinicalTrials.gov ID: NCT05492318
Acronym / sponsor ID: ITF/2357/55 - PART 1
Conditions: Drug-Drug Interaction, Heathy Volunteer
Keywords: PK, Pharmacokinetics, Givinostat, Midazolam, Dabigatran
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 26 participants (actual)
Lead sponsor: ItalfarmacoIndustry (pharma, biotech, devices)
Study start: 21 Mar 2022 (actual)
Primary completion: 8 May 2022 (actual)
Study completion: 24 May 2022 (actual)
First posted: 8 Aug 2022 (actual)
Results: Posted 6 Jan 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Primary objective:

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

Detailed description

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.

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 design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1
Model description: An Open-label, Single-center trial in Healthy Subjects

Arm	Type	Receives
Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam	Experimental	Drug: Givinostat 10 mg/mL, Drug: Midazolam 1mg/ml IV, Drug: Midazolam 2.5 mg oromucosal solution, Drug: Dabigatran etexilate 75 mg oral hard capsulesOn 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.

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (23 listed)

A subject was considered eligible for the study if he/she fulfilled all the inclusion criteria:
Subject's written informed consent obtained prior to any study-related procedure.
Male or female subject, ≥18 and ≤55 years of age, at the time of signing the informed consent.
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.
Non-smoker or ex-smoker (i.e. someone who abstained from using tobaccoor nicotine-containing products for at least 3 months prior to Screening).

Key exclusion criteria (46 listed)

At Screening
Previous use of givinostat.
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).
Known history of hypersensitivity and/or allergic reactions to givinostat, histone deacetylases (HDAC) inhibitors or to any excipient in the formulation.
History of sorbitol intolerance, sorbitol malabsorption or fructose intolerance.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Givinostat 10 mg/mLAlso: ITF235710 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.	Drug	Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam
Midazolam 1mg/ml IVAlso: Aurobindo®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.	Drug	Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam
Midazolam 2.5 mg oromucosal solutionAlso: Buccolam®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.	Drug	Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam
Dabigatran etexilate 75 mg oral hard capsulesAlso: PradaxaDose: 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.	Drug	Givinostat alone or combo with Midazolam IV and with oral Dabigatran, or combo with oral Midazolam

Primary outcome

Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
Time frame: 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.
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.
Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
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.
Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
Time frame: 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 =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.
Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
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.
t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Time frame: 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 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.
t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
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.
AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Time frame: 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 =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.
AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
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.
AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Time frame: 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=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.
AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
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.
%AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Time frame: 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.
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-∞.
%AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17
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
λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Time frame: 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.
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.
λz of Dabigatran (Total and Free), Following Single Doses of Givinostat
Time frame: 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.
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.

2 secondary outcomes

Number of Adverse Events by Severity (Mild, Moderate, Severe)
Time frame: 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)
Time frame: During the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34

Results and safety

Results posted to the registry on 6 Jan 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
All Study Participants (SAF and PK Population)	26	26

Primary outcome: Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug

Time frame: 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.. Geometric mean (95% Confidence Interval). Unit: pg/mL

Measure	Midazolam IV Alone (Day 1) n = 26	Midazolam IV Co-administered With Givinostat (Day 6) n = 26	Midazolam IV Co-administered With Givinostat (Day 17) n = 26	Oral Midazolam Alone (Day 2) n = 26	Oral Midazolam Co-Administered With Givinostat (Day 7) n = 26	Oral Midazolam Co-Administered With Givinostat (Day 18) n = 26
midazolam	50482.44 (42802.65 to 59540.16)	53345.17 (46868.39 to 60716.97)	46510.23 (38309.42 to 56466.57)	12695.07 (11193.89 to 14397.57)	15744.30 (13936.13 to 17787.09)	17678.67 (15782.69 to 19802.43)
1-hydroxymidazolam	1426.41 (1269.56 to 1602.64)	1306.05 (1146.91 to 1487.26)	1335.02 (1115.15 to 1598.25)	4451.49 (3756.90 to 5274.51)	5229.06 (4445.58 to 6150.63)	6303.67 (5046.18 to 7874.53)

Midazolam IV Alone (Day 1) vs Midazolam IV Co-administered With Givinostat (Day 6): ratio of the geometric least square mean: 105.67 (90% CI 91.72 to 121.74)
Midazolam IV Alone (Day 1) vs Midazolam IV Co-administered With Givinostat (Day 6): ratio of the geometric least square mean: 91.56 (90% CI 86.16 to 97.31)
Midazolam IV Alone (Day 1) vs Midazolam IV Co-administered With Givinostat (Day 17): ratio of the Geometric LSmeans: 92.13 (90% CI 75.97 to 111.73)

Population analysed: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP, without deviations affecting pharmacokinetic interpretation.

Primary outcome: Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug

Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17. Geometric mean (95% Confidence Interval). Unit: ng/mL

Measure	Dabigatran Etexilate Alone (Day 1) n = 26	Dabigatran Etexilate Co-Administered With Givinostat (Day 6) n = 26	Dabigatran Etexilate Co-Administered With Givinostat (Day 17) n = 26
total dabigatran	69.44 (51.90 to 92.92)	51.17 (39.62 to 66.08)	45.35 (34.87 to 58.99)
free dabigatran	60.19 (44.64 to 81.14)	44.03 (34.49 to 56.21)	37.41 (29.01 to 48.23)

Dabigatran Etexilate Alone (Day 1) vs Dabigatran Etexilate Co-Administered With Givinostat (Day 6): ratio of the Geometric LSmeans: 73.68 (90% CI 60.77 to 89.33)
Dabigatran Etexilate Alone (Day 1) vs Dabigatran Etexilate Co-Administered With Givinostat (Day 6): ratio of the Geometric LSmeans: 70.38 (90% CI 57.94 to 85.50)
Dabigatran Etexilate Alone (Day 1) vs Dabigatran Etexilate Co-Administered With Givinostat (Day 17): ratio of the Geometric LSmeans: 65.31 (90% CI 53.33 to 79.98)

Primary outcome: Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug

Time frame: 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.. Median (Full Range). Unit: hours

Measure	Midazolam IV Alone (Day 1) n = 26	Midazolam IV Co-administered With Givinostat (Day 6) n = 26	Midazolam IV Co-administered With Givinostat (Day 17) n = 26	Oral Midazolam Alone (Day 2) n = 26	Oral Midazolam Co-Administered With Givinostat (Day 7) n = 26	Oral Midazolam Co-Administered With Givinostat (Day 18) n = 26
midazolam	0.03 (0.03 to 0.03)	0.03 (0.03 to 0.03)	0.03 (0.03 to 0.25)	0.55 (0.50 to 1.50)	0.50 (0.50 to 1.50)	0.50 (0.50 to 1.02)
1-hydroxymidazolam	0.50 (0.25 to 1.00)	0.50 (0.25 to 2.00)	0.51 (0.25 to 2.00)	0.55 (0.50 to 1.50)	0.50 (0.50 to 1.50)	0.50 (0.50 to 1.02)

Population analysed: PK population: Part 1 Pharmacokinetic Analysis Population includes all subjects enrolled in Part 1 of the study, who provided evaluable pharmacokinetic data for at least one IMP,

Primary outcome: Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug

Time frame: In the turn of 72 hours after administration of dabigatran on day 1,6,17. Median (Full Range). Unit: hours

Measure	Dabigatran Etexilate Alone (Day 1) n = 26	Dabigatran Etexilate Co-Administered With Givinostat (Day 6) n = 26	Dabigatran Etexilate Co-Administered With Givinostat (Day 17) n = 26
total dabigatran	2.00 (1.50 to 4.00)	2.00 (1.00 to 4.02)	2.00 (1.00 to 4.00)
free dabigatran	2.00 (1.00 to 4.00)	2.00 (1.50 to 4.02)	2.00 (1.50 to 6.00)

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: Throughout the study and 10-14 days after the End of Study (safety follow-up visit), i.e. up to day 30-34, all TEAEs, considered related or not related to IMPs, were collected.. Other adverse events reported at 4% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Midazolam	0 of 26 (0%)	26 of 26 (100%)	0 of 26
Dabigatran	0 of 26 (0%)	26 of 26 (100%)	0 of 26
Givinostat	0 of 26 (0%)	26 of 26 (100%)	0 of 26

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 6 Jan 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Marlene Fonseca, MD principal investigator

Blueclinical, Ltd.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 46 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Portugal. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug (time frame: 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.). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05492318.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jan 2025.