Trial Outcomes & Findings for Perpetrator DDI Potential of Givinostat as Inhibitor and Inducer of CYP3A and P-gp Activity (NCT NCT05492318)
NCT ID: NCT05492318
Last Updated: 2025-01-06
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
26 participants
Primary outcome timeframe
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.
Results posted on
2025-01-06
Participant Flow
Subjects were screened between Days -21 to -3 (both inclusive) of study part 1 to confirm that they met the subject selection criteria. Prior to any screening assessment, the Investigator (or an appropriate delegate) obtained informed consent from each subject in accordance with the procedures. 26 subjects were enrolled to study part 1. Please note that the overall figure n=104 is wrong; the system in fact automatically and inappropriately sums up the number of each IMP group.
Participant milestones
| Measure |
All Study Participants (SAF and PK Population)
Twenty-six (26) subjects (7 women and 19 men) were admitted to study Part 1:
* single doses of midazolam 1 mg IV + dabigatran etexilate 75 mg were administered 1 hour after the planned morning time of givinostat administration on Days 1, 6 and 17.
* a single oral dose of midazolam 2.5 mg oral solution was administered 1 hour after the planned morning time of givinostat administration on Days 2, 7 and 18, Please note that From Day 4 to Day 18, givinostat 50 mg as oral suspension was administered twice a day, in the morning and in the evening, while on Day 19 only the morning dose was administered.
Midazolam and dabigatran etexilate were administered following an overnight fasting of at least 8 hours and subjects remained fasted until at least 3 hours post-dose and were administered with the subjects in a semi-recumbent position. Subjects remained semirecumbent until at least 3 hours post-dose. Oral midazolam and dabigatran etexilate were administered with 150 mL of water. No other fluids were allowed from 1 hour before midazolam and dabigatran dosing until 2 hours postdose.
Water was provided ad libitum at all other times.
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|---|---|
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Overall Study
STARTED
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26
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Overall Study
Day 1 - Midazolam (IV) 1 mg + Dabigatran 75 mg
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26
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Overall Study
Day 2 - Midazolam (Oral) 2.5 mg
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26
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Overall Study
Days 4-5 - Givinostat 50 mg b.i.d.
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26
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Overall Study
Day 6 - Midazolam (IV) 1 mg + Dabigatran 75 mg + Givinostat 50 mg b.i.d.
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26
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Overall Study
Day 7 - Midazolam (Oral) 2.5 mg + Givinostat 50 mg b.i.d.
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26
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Overall Study
Days 8-16 - Givinostat 50 mg b.i.d.
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26
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Overall Study
Day 17 - Midazolam (IV) 1 mg + Dabigatran 75 mg + Givinostat 50 mg b.i.d.
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26
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Overall Study
Day 18 - Midazolam (Oral) 2.5 mg + Givinostat 50 mg b.i.d.
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26
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Overall Study
Day 19 - Givinostat 50 mg
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26
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Overall Study
COMPLETED
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26
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Overall Study
NOT COMPLETED
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0
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Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Perpetrator DDI Potential of Givinostat as Inhibitor and Inducer of CYP3A and P-gp Activity
Baseline characteristics by cohort
| Measure |
Number of Subjects Enrolled
n=26 Participants
Twenty-six (26) subjects (7 women and 19 men) were admitted to study Part 1.
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|---|---|
|
Age, Categorical
<=18 years
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0 Participants
n=5 Participants
|
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Age, Categorical
Between 18 and 65 years
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26 Participants
n=5 Participants
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Age, Categorical
>=65 years
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0 Participants
n=5 Participants
|
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Age, Continuous
|
34 years
STANDARD_DEVIATION 8.2 • n=5 Participants
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Sex: Female, Male
Female
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7 Participants
n=5 Participants
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Sex: Female, Male
Male
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19 Participants
n=5 Participants
|
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Race (NIH/OMB)
American Indian or Alaska Native
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0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
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0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
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0 Participants
n=5 Participants
|
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Race (NIH/OMB)
Black or African American
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1 Participants
n=5 Participants
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Race (NIH/OMB)
White
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22 Participants
n=5 Participants
|
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Race (NIH/OMB)
More than one race
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3 Participants
n=5 Participants
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Race (NIH/OMB)
Unknown or Not Reported
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0 Participants
n=5 Participants
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Region of Enrollment
Portugal
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26 participants
n=5 Participants
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PRIMARY outcome
Timeframe: 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.Population: 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.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
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|---|---|---|---|---|---|---|
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Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
1-hydroxymidazolam
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1426.41 pg/mL
Interval 1269.56 to 1602.64
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5229.06 pg/mL
Interval 4445.58 to 6150.63
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1335.02 pg/mL
Interval 1115.15 to 1598.25
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4451.49 pg/mL
Interval 3756.9 to 5274.51
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6303.67 pg/mL
Interval 5046.18 to 7874.53
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1306.05 pg/mL
Interval 1146.91 to 1487.26
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Cmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
midazolam
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50482.44 pg/mL
Interval 42802.65 to 59540.16
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15744.30 pg/mL
Interval 13936.13 to 17787.09
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46510.23 pg/mL
Interval 38309.42 to 56466.57
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12695.07 pg/mL
Interval 11193.89 to 14397.57
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17678.67 pg/mL
Interval 15782.69 to 19802.43
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53345.17 pg/mL
Interval 46868.39 to 60716.97
|
PRIMARY outcome
Timeframe: In the turn of 72 hours after administration of dabigatran on day 1,6,17Population: 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.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
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Oral Midazolam Alone (Day 2)
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
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|---|---|---|---|---|---|---|
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Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
total dabigatran
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69.44 ng/mL
Interval 51.9 to 92.92
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—
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45.35 ng/mL
Interval 34.87 to 58.99
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—
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—
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51.17 ng/mL
Interval 39.62 to 66.08
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Cmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
free dabigatran
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60.19 ng/mL
Interval 44.64 to 81.14
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—
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37.41 ng/mL
Interval 29.01 to 48.23
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—
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—
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44.03 ng/mL
Interval 34.49 to 56.21
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PRIMARY outcome
Timeframe: 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.Population: 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,
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
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Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
midazolam
|
0.03 hours
Interval 0.03 to 0.03
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0.50 hours
Interval 0.5 to 1.5
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0.03 hours
Interval 0.03 to 0.25
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0.55 hours
Interval 0.5 to 1.5
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0.50 hours
Interval 0.5 to 1.02
|
0.03 hours
Interval 0.03 to 0.03
|
|
Tmax for Midazolam, 1-hydroxymidazolam, Following Single Doses of the Parent Drug
1-hydroxymidazolam
|
0.50 hours
Interval 0.25 to 1.0
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0.50 hours
Interval 0.5 to 1.5
|
0.51 hours
Interval 0.25 to 2.0
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0.55 hours
Interval 0.5 to 1.5
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0.50 hours
Interval 0.5 to 1.02
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0.50 hours
Interval 0.25 to 2.0
|
PRIMARY outcome
Timeframe: In the turn of 72 hours after administration of dabigatran on day 1,6,17Population: 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.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
total dabigatran
|
2.00 hours
Interval 1.5 to 4.0
|
—
|
2.00 hours
Interval 1.0 to 4.0
|
—
|
—
|
2.00 hours
Interval 1.0 to 4.02
|
|
Tmax for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
free dabigatran
|
2.00 hours
Interval 1.0 to 4.0
|
—
|
2.00 hours
Interval 1.5 to 6.0
|
—
|
—
|
2.00 hours
Interval 1.5 to 4.02
|
PRIMARY outcome
Timeframe: 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.Population: Pharmacokinetic Analysis includes all subjects enrolled in Part 1 who provided evaluable pk data for at least one IMP. These were: n=26 for (1-Hydroxy)midazolam IV alone, n=25 for (1-Hydroxy)midazolam + givinostat at day 6, n=23 for (1-Hydroxy)midazolam + givinostat at day 17, n=25 for oral (1-Hydroxy)midazolam alone at day 2, n=25 for oral (1-Hydroxy)midazolam + givinostat at day 18 , n=26 for oral midazolam + givinostat at day 7, n=24 for oral 1-Hydroxymidazolam + givinostat at day 7.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
midazolam
|
5.27 hours
Interval 4.6 to 6.04
|
5.84 hours
Interval 5.08 to 6.7
|
6.62 hours
Interval 5.83 to 7.51
|
5.48 hours
Interval 4.75 to 6.32
|
6.73 hours
Interval 5.89 to 7.7
|
5.22 hours
Interval 4.61 to 5.9
|
|
t1/2 of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
1-hydroxymidazolam
|
4.02 hours
Interval 3.41 to 4.74
|
6.09 hours
Interval 4.76 to 7.8
|
5.74 hours
Interval 4.7 to 7.03
|
4.62 hours
Interval 3.63 to 5.89
|
6.43 hours
Interval 5.16 to 8.01
|
5.00 hours
Interval 4.2 to 5.95
|
PRIMARY outcome
Timeframe: In the turn of 72 hours after administration of dabigatran on day 1,6,17Population: 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.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
total dabigatran
|
7.96 hours
Interval 7.52 to 8.42
|
—
|
8.74 hours
Interval 8.17 to 9.36
|
—
|
—
|
8.01 hours
Interval 7.21 to 8.9
|
|
t1/2 for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
free dabigatran
|
7.28 hours
Interval 6.73 to 7.89
|
—
|
8.05 hours
Interval 7.3 to 8.88
|
—
|
—
|
7.03 hours
Interval 6.35 to 7.77
|
PRIMARY outcome
Timeframe: 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.Population: 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,
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Midazolam
|
44094.42 pg.h/mL
Interval 39998.55 to 48609.7
|
50134.44 pg.h/mL
Interval 42444.64 to 59217.42
|
53692.16 pg.h/mL
Interval 48609.52 to 59306.23
|
36483.20 pg.h/mL
Interval 31064.96 to 42846.48
|
57559.53 pg.h/mL
Interval 49279.79 to 67230.4
|
47333.50 pg.h/mL
Interval 43297.8 to 51745.35
|
|
AUC0-t of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
1-hydroxymidazolam
|
5050.60 pg.h/mL
Interval 4441.81 to 5742.83
|
14264.35 pg.h/mL
Interval 12357.51 to 16465.42
|
6210.86 pg.h/mL
Interval 5374.62 to 7177.22
|
10871.00 pg.h/mL
Interval 9475.99 to 12471.38
|
17208.29 pg.h/mL
Interval 14624.58 to 20248.46
|
5362.65 pg.h/mL
Interval 4757.51 to 6044.76
|
PRIMARY outcome
Timeframe: In the turn of 72 hours after administration of dabigatran on day 1,6,17Population: 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.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
total dabigatran
|
552.25 ng.h/mL
Interval 424.19 to 718.98
|
—
|
386.23 ng.h/mL
Interval 306.46 to 486.78
|
—
|
—
|
386.05 ng.h/mL
Interval 299.12 to 498.25
|
|
AUC0-t for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
free dabigatran
|
460.16 ng.h/mL
Interval 341.52 to 620.01
|
—
|
332.71 ng.h/mL
Interval 268.91 to 411.66
|
—
|
—
|
341.01 ng.h/mL
Interval 268.24 to 433.52
|
PRIMARY outcome
Timeframe: 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.Population: Pharmacokinetic Analysis includes all subjects enrolled in Part 1 who provided evaluable pk data for at least one IMP. These were: n=26 for (1-Hydroxy)midazolam IV alone, n=26 for Mid IV + givinostat (G) at days 6 and 17, for oral hydroxymid alone at day 2, oral Mid + G at day 7. n=25 for 1-Hydroxymid + G at day 6, oral mid alone at day 2, oral (1-Hydroxy)mid + G at day 18. n=24 for oral 1-Hydroxymid + G at day 7 n=23 for oral 1-hydroxymid + G at day 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. 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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Midazolam
|
46054.19 pg.h/mL
Interval 41834.5 to 50699.5
|
53379.48 pg.h/mL
Interval 45107.58 to 63168.29
|
57112.86 pg.h/mL
Interval 51342.91 to 63531.25
|
39037.54 pg.h/mL
Interval 33096.57 to 46044.94
|
62904.03 pg.h/mL
Interval 52906.81 to 74790.32
|
49532.66 pg.h/mL
Interval 45406.0 to 54034.35
|
|
AUC0-inf of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
1-Hydroxymidazolam
|
5720.13 pg.h/mL
Interval 4981.56 to 6568.21
|
15895.61 pg.h/mL
Interval 13769.86 to 18349.51
|
7821.70 pg.h/mL
Interval 6736.26 to 9082.04
|
11914.16 pg.h/mL
Interval 10292.86 to 13790.84
|
19199.79 pg.h/mL
Interval 16300.75 to 22614.41
|
6404.39 pg.h/mL
Interval 5615.24 to 7304.43
|
PRIMARY outcome
Timeframe: In the turn of 72 hours after administration of dabigatran on day 1,6,17Population: 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.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
total dabigatran
|
563.09 ng.h/mL
Interval 436.43 to 726.51
|
—
|
396.25 ng.h/mL
Interval 315.23 to 498.1
|
—
|
—
|
393.93 ng.h/mL
Interval 306.01 to 507.11
|
|
AUC0-inf for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
free dabigatran
|
467.79 ng.h/mL
Interval 349.48 to 626.16
|
—
|
347.73 ng.h/mL
Interval 280.67 to 430.81
|
—
|
—
|
347.56 ng.h/mL
Interval 273.95 to 440.95
|
PRIMARY outcome
Timeframe: 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.Population: 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,
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-∞.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
%AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Midazolam
|
3.87 Percentage of AUC0-inf
Interval 3.23 to 4.63
|
5.33 Percentage of AUC0-inf
Interval 4.31 to 6.59
|
5.12 Percentage of AUC0-inf
Interval 4.07 to 6.43
|
5.02 Percentage of AUC0-inf
Interval 4.28 to 5.9
|
5.79 Percentage of AUC0-inf
Interval 4.46 to 7.52
|
3.96 Percentage of AUC0-inf
Interval 3.27 to 4.81
|
|
%AUCextrap of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
1-Hydroxymidazolam
|
9.72 Percentage of AUC0-inf
Interval 7.55 to 12.52
|
8.42 Percentage of AUC0-inf
Interval 6.62 to 10.7
|
15.97 Percentage of AUC0-inf
Interval 12.14 to 21.02
|
6.95 Percentage of AUC0-inf
Interval 5.18 to 9.33
|
8.80 Percentage of AUC0-inf
Interval 7.42 to 10.44
|
13.20 Percentage of AUC0-inf
Interval 10.09 to 17.27
|
PRIMARY outcome
Timeframe: In the turn of 72 hours after administration of dabigatran on day 1,6,17Population: 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.
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
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
%AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
total dabigatran
|
1.37 Percentage of AUC0-inf
Interval 1.04 to 1.8
|
—
|
2.23 Percentage of AUC0-inf
Interval 1.84 to 2.7
|
—
|
—
|
1.79 Percentage of AUC0-inf
Interval 1.5 to 2.15
|
|
%AUC0extrap (%) for Dabigatran (Total and Free), Following Single Doses of the Parent Drug
free dabigatran
|
1.27 Percentage of AUC0-inf
Interval 1.0 to 1.62
|
—
|
2.02 Percentage of AUC0-inf
Interval 1.58 to 2.58
|
—
|
—
|
1.69 Percentage of AUC0-inf
Interval 1.39 to 2.05
|
PRIMARY outcome
Timeframe: 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.Population: Pharmacokinetic Analysis includes all subjects enrolled in Part 1 who provided evaluable pk data for at least one IMP. These were: n=26 for (1-Hydroxy)midazolam IV alone, n=26 for Mid IV + givinostat (G) at days 6 and 17, for oral hydroxymid alone at day 2, oral Mid + G at day 7. n=25 for 1-Hydroxymid + G at day 6, oral mid alone at day 2, oral (1-Hydroxy)mid + G at day 18. n=24 for oral 1-Hydroxymid + G at day 7 n=23 for IV 1-hydroxymid + G at day 17
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
Midazolam
|
0.131 1/h
Interval 0.115 to 0.151
|
0.119 1/h
Interval 0.103 to 0.136
|
0.105 1/h
Interval 0.092 to 0.119
|
0.127 1/h
Interval 0.11 to 0.146
|
0.103 1/h
Interval 0.09 to 0.118
|
0.133 1/h
Interval 0.118 to 0.15
|
|
λz of Midazolam, 1-hydroxymidazolam, Following Single Doses of Givinostat
1-Hydroxymidazolam
|
0.172 1/h
Interval 0.146 to 0.203
|
0.114 1/h
Interval 0.089 to 0.146
|
0.121 1/h
Interval 0.099 to 0.148
|
0.150 1/h
Interval 0.118 to 0.191
|
0.108 1/h
Interval 0.087 to 0.134
|
0.139 1/h
Interval 0.116 to 0.165
|
PRIMARY outcome
Timeframe: 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.Population: 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,
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
λz of Dabigatran (Total and Free), Following Single Doses of Givinostat
Total Dabigatran
|
0.087 1/h
Interval 0.082 to 0.092
|
—
|
0.079 1/h
Interval 0.074 to 0.085
|
—
|
—
|
0.087 1/h
Interval 0.078 to 0.096
|
|
λz of Dabigatran (Total and Free), Following Single Doses of Givinostat
Free dabigatran
|
0.095 1/h
Interval 0.088 to 0.103
|
—
|
0.086 1/h
Interval 0.078 to 0.095
|
—
|
—
|
0.099 1/h
Interval 0.089 to 0.109
|
SECONDARY outcome
Timeframe: Throughout the study and 10-14 days after the EoS (follow-up visit), i.e. up to date 30-34Population: All subjects who receive at least one dose of an IMP in Part 1 of the study constitute the Part 1 Safety Analysis Population.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
Number of Adverse Events by Severity (Mild, Moderate, Severe)
AE mild severity
|
28 number of TEAE
|
—
|
74 number of TEAE
|
127 number of TEAE
|
—
|
25 number of TEAE
|
|
Number of Adverse Events by Severity (Mild, Moderate, Severe)
AE moderate severity
|
0 number of TEAE
|
—
|
2 number of TEAE
|
2 number of TEAE
|
—
|
0 number of TEAE
|
|
Number of Adverse Events by Severity (Mild, Moderate, Severe)
AE severe
|
0 number of TEAE
|
—
|
0 number of TEAE
|
0 number of TEAE
|
—
|
0 number of TEAE
|
SECONDARY outcome
Timeframe: During the study and 10-14 days after the EoS (follow-up visit), i.e. up to day 30-34Population: All subjects who receive at least one dose of an IMP in Part 1 of the study constitute the Part 1 Safety Analysis Population.
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.
Outcome measures
| Measure |
Dabigatran Etexilate Alone (Day 1)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 7)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 7, 1 hour after the planned morning time of givinostat administration. The potential Inhibitory Effect of midazolam was assessed (day 7)
|
Midazolam IV Co-administered With Givinostat (Day 17)
n=26 Participants
Midazolam IV 1 mg/ml, single dose, was co-administered with givinostat (at Day 17) to study this latter potential inducing effect on midazolam.
Givinostat 10 mg/mL oral suspension was administered once, in the morning, in Day 17.
Givinostat 10 mg/mL: 10 mg/mL oral suspension. Givinostat 10 mg/ml oral suspension was administered once, in the morning, in Day 17).
|
Oral Midazolam Alone (Day 2)
n=26 Participants
A single oral dose of midazolam 2.5 mg oral solution was administered alone.
|
Oral Midazolam Co-Administered With Givinostat (Day 18)
A single oral dose of midazolam 2.5 mg oral solution was administered on day 18, 1 hour after the planned morning time of givinostat administration. The potential inducing effect of midazolam was assessed.
|
Dabigatran Etexilate Co-Administered With Givinostat (Day 6)
n=26 Participants
Dabigatran etexilate 75 mg, 1 hard capsule, was administered 1 hour after the planned morning time of givinostat.
|
|---|---|---|---|---|---|---|
|
Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe)
AE mild severity
|
26 Participants
|
—
|
26 Participants
|
26 Participants
|
—
|
26 Participants
|
|
Incidence of Patients With at Least One Adverse Events by Severity (Mild, Moderate, Severe)
AE moderate severity
|
2 Participants
|
—
|
2 Participants
|
2 Participants
|
—
|
2 Participants
|
Adverse Events
Midazolam
Serious events: 0 serious events
Other events: 26 other events
Deaths: 0 deaths
Dabigatran
Serious events: 0 serious events
Other events: 26 other events
Deaths: 0 deaths
Givinostat
Serious events: 0 serious events
Other events: 26 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Midazolam
n=26 participants at risk
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 2.5 mg single oromucosal solution was administered on Days 2, 7 and 18, 1 hour after the planned morning time of givinostat administration.
|
Dabigatran
n=26 participants at risk
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.
|
Givinostat
n=26 participants at risk
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.
|
|---|---|---|---|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
73.1%
19/26 • Number of events 20 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
73.1%
19/26 • Number of events 20 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
73.1%
19/26 • Number of events 20 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Eye disorders
Dry eye
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Eye disorders
Eye pruritus
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Eye disorders
Ocular hyperaemia
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Abdominal discomfort
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Abdominal distension
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Abdominal pain
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Diarrhoea
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Dyspepsia
|
26.9%
7/26 • Number of events 8 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
26.9%
7/26 • Number of events 8 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
26.9%
7/26 • Number of events 8 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Epigastric discomfort
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Faeces soft
|
19.2%
5/26 • Number of events 7 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
19.2%
5/26 • Number of events 7 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
15.4%
4/26 • Number of events 6 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Nausea
|
19.2%
5/26 • Number of events 5 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
19.2%
5/26 • Number of events 5 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
19.2%
5/26 • Number of events 5 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Gastrointestinal disorders
Oesophageal discomfort
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
General disorders
Vessel puncture site haemorrhage
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Infections and infestations
Nasopharyngitis
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Investigations
Blood creatine phosphokinase increased
|
11.5%
3/26 • Number of events 3 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
11.5%
3/26 • Number of events 3 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
11.5%
3/26 • Number of events 3 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Investigations
Blood creatinine increased
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Investigations
Blood thyroid stimulating hormone increased
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Investigations
Transaminases increased
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Metabolism and nutrition disorders
Polydipsia
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Nervous system disorders
Dizziness
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
0.00%
0/26 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Nervous system disorders
Dysgeusia
|
11.5%
3/26 • Number of events 3 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
11.5%
3/26 • Number of events 3 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
11.5%
3/26 • Number of events 3 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Nervous system disorders
Headache
|
3.8%
1/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Nervous system disorders
Migraine
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
0.00%
0/26 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Nervous system disorders
Presyncope
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Nervous system disorders
Somnolence
|
65.4%
17/26 • Number of events 35 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
65.4%
17/26 • Number of events 35 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
65.4%
17/26 • Number of events 25 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Psychiatric disorders
Anxiety
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Reproductive system and breast disorders
Dysmenorrhoea
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Respiratory, thoracic and mediastinal disorders
Bradypnoea
|
3.8%
1/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Respiratory, thoracic and mediastinal disorders
Dysphonia
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Respiratory, thoracic and mediastinal disorders
Epistaxis
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal discomfort
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Respiratory, thoracic and mediastinal disorders
Rhinitis allergic
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Skin and subcutaneous tissue disorders
Alopecia
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
7.7%
2/26 • Number of events 2 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Skin and subcutaneous tissue disorders
Dry skin
|
38.5%
10/26 • Number of events 10 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
38.5%
10/26 • Number of events 10 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
34.6%
9/26 • Number of events 9 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
|
Skin and subcutaneous tissue disorders
Erythema
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
3.8%
1/26 • Number of events 1 • 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.
End-of-study was defined as the last study procedure on Day 11 or at early discontinuation of subjects administered at least one dose of investigational product. Early termination procedures were performed as soon as possible after subject withdrawal, within 10-14 days after last participation of the subject in the study, whenever possible
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place