Trial Outcomes & Findings for A Phase 1, Drug-Drug Interaction Study of TBAJ-876 in Healthy Adults (NCT NCT05526911)

Last Updated: 2024-10-08

Results Overview

Geometric mean and range of midazolam's area under the (plasma concentration vs. time) curve when co-administered with TBAJ-876 versus when administered alone.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

28 participants

Primary outcome timeframe

Day 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours; Day 20: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours

Results posted on

2024-10-08

Participant Flow

A total of 75 subjects were screened for the trial of whom 47 failed screening, 28 were randomized, and 26 completed treatment.

No participants were assigned to Group 2

Participant milestones

Participant milestones
Measure	Group 1 The pharmacokinetics of midazolam, a CYP3A4 substrate, and digoxin, a P-gp substrate, will be studied before and after dosing with TBAJ-876. TBAJ-876: • Day 6 to Day 13: 200 mg TBAJ-876 oral suspension, fed * Day 14 to Day 19: 165 mg TBAJ-876 oral suspension, fed * Day 20 and Day 21: 200 mg TBAJ-876 oral suspension, fasting * Day 22 to Day 24: 150 mg TBAJ-876 oral suspension, fed Midazolam: Day 1 and Day 20: Midazolam oral syrup: 2 mg, fasted Digoxin: Day 2 and Day 21: Digoxin tablet: 0.25 mg, fasted
Overall Study STARTED	28
Overall Study COMPLETED	26
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Group 1 The pharmacokinetics of midazolam, a CYP3A4 substrate, and digoxin, a P-gp substrate, will be studied before and after dosing with TBAJ-876. TBAJ-876: • Day 6 to Day 13: 200 mg TBAJ-876 oral suspension, fed * Day 14 to Day 19: 165 mg TBAJ-876 oral suspension, fed * Day 20 and Day 21: 200 mg TBAJ-876 oral suspension, fasting * Day 22 to Day 24: 150 mg TBAJ-876 oral suspension, fed Midazolam: Day 1 and Day 20: Midazolam oral syrup: 2 mg, fasted Digoxin: Day 2 and Day 21: Digoxin tablet: 0.25 mg, fasted
Overall Study Adverse Event	2

Baseline Characteristics

A Phase 1, Drug-Drug Interaction Study of TBAJ-876 in Healthy Adults

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 1 n=28 Participants The pharmacokinetics of midazolam, a CYP3A4 substrate, and digoxin, a P-gp substrate, will be studied before and after dosing with TBAJ-876. TBAJ-876: • Day 6 to Day 13: 200 mg TBAJ-876 oral suspension, fed * Day 14 to Day 19: 165 mg TBAJ-876 oral suspension, fed * Day 20 and Day 21: 200 mg TBAJ-876 oral suspension, fasting * Day 22 to Day 24: 150 mg TBAJ-876 oral suspension, fed Midazolam: Day 1 and Day 20: Midazolam oral syrup: 2 mg, fasted Digoxin: Day 2 and Day 21: Digoxin tablet: 0.25 mg, fasted
Age, Continuous	37.1 years STANDARD_DEVIATION 9.8 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	20 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	28 Participants n=5 Participants
Height at Screening	167.3 centimeters STANDARD_DEVIATION 10.41 • n=5 Participants
Weight at Screening	78.2 Kilogram STANDARD_DEVIATION 19.86 • n=5 Participants
BMI at Screening	28 kilogram per meter squared STANDARD_DEVIATION 8.03 • n=5 Participants

PRIMARY outcome

Timeframe: Day 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours; Day 20: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours

Population: All participants enrolled in the study were included. Participants who were withdrawn prior to Day 20 are not included in the analysis with TBAJ-876. Participants were excluded from AUC 0-inf analysis if they did not have at least 3 observations presented along what appears to be a terminal elimination phase when individual subject plots of each analyte concentration vs time were inspected visually to identify log-linear terminal segments corresponding to an exponential elimination phase.

Geometric mean and range of midazolam's area under the (plasma concentration vs. time) curve when co-administered with TBAJ-876 versus when administered alone.

Outcome measures

Outcome measures
Measure	Group 1 n=28 Participants Midazolam
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters AUC Area under curve from time 0 hours to last quantifiable concentration (AUC 0-last), with TBAJ-876	22.64 ng.hr/mL Interval 7.98 to 43.78
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters AUC AUC 0-last, alone	25.22 ng.hr/mL Interval 8.3 to 93.2
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters AUC Area under the curve from time 0 hours to infinity (AUC 0-inf), with TBAJ-876	24.28 ng.hr/mL Interval 8.65 to 46.52
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters AUC AUC 0-inf, alone	25.68 ng.hr/mL Interval 8.79 to 98.22

PRIMARY outcome

Timeframe: Day 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours; Day 20: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours

Population: All participants enrolled in the study were included. Participants who were withdrawn prior to Day 20 are not included in the analysis with TBAJ-876.

Geometric mean and range of midazolam's maximum concentration when co-administered with TBAJ-876 versus when administered alone.

Outcome measures

Outcome measures
Measure	Group 1 n=28 Participants Midazolam
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters CMAX Maximum Concentration (Cmax), with TBAJ-876	7.26 ng/mL Interval 3.37 to 19.9
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters CMAX Cmax, alone	8.90 ng/mL Interval 3.08 to 27.5

PRIMARY outcome

Timeframe: Day 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours; Day 20: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours

Population: All participants who completed the study were included. Participants were excluded from AUC 0-inf analysis if they did not have at least 3 observations presented along what appears to be a terminal elimination phase when individual subject plots of each analyte concentration vs time were inspected visually to identify log-linear terminal segments corresponding to an exponential elimination phase.

Geometric mean ratio of midazolam's area under the (plasma concentration vs. time) curve and Cmax when co-administered with TBAJ-876 versus when administered alone. Inference will be based on analysis of variance applied to log-transformed parameters.

Outcome measures

Outcome measures
Measure	Group 1 n=26 Participants Midazolam
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Geometric Mean Ratios AUC 0-last Ratio of geometric means of midazolam with TBAJ-876 to midazolam alone	0.94 ratio of geometric mean Interval 0.84 to 1.06
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Geometric Mean Ratios AUC 0-inf Ratio of geometric means of midazolam with TBAJ-876 to midazolam alone	1 ratio of geometric mean Interval 0.88 to 1.12
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Geometric Mean Ratios Cmax Ratio of geometric means of midazolam with TBAJ-876 to midazolam alone	.86 ratio of geometric mean Interval 0.76 to 0.98

PRIMARY outcome

Timeframe: Day 2: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours; Day 21: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours

Geometric mean of digoxin's area under the (plasma concentration vs. time) curve when co-administered with TBAJ-876 versus when administered alone, and similarly for the maximum concentration.

Outcome measures

Outcome measures
Measure	Group 1 n=26 Participants Midazolam
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters AUC AUC 0-inf, alone	23.44 ng.hr/mL Interval 19.86 to 27.67
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters AUC AUC 0-last, with TBAJ-876	11.57 ng.hr/mL Interval 0.03 to 33.24
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters AUC AUC 0-last, alone	7.64 ng.hr/mL Interval 0.55 to 31.12
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters AUC AUC 0-inf, with TBAJ-876	24.57 ng.hr/mL Interval 19.73 to 27.89

PRIMARY outcome

Timeframe: Day 2: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours; Day 21: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours

Population: All participants who completed the study were included.

Geometric mean of digoxin's Cmax when co-administered with TBAJ-876 versus when administered alone, and similarly for the maximum concentration.

Outcome measures

Outcome measures
Measure	Group 1 n=26 Participants Midazolam
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters CMAX Cmax, with TBAJ-876	1.19 ng/mL Interval 0.11 to 2.64
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters CMAX Cmax, alone	1.01 ng/mL Interval 0.39 to 2.18

PRIMARY outcome

Timeframe: Day 2: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours; Day 21: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours

Population: All participants who completed the study were included.

Geometric mean ratio of digoxin's area under the (plasma concentration vs. time) curve and Cmax when co-administered with TBAJ-876 versus when administered alone, and similarly for the maximum concentration. Inference will be based on analysis of variance applied to log-transformed parameters.

Outcome measures

Outcome measures
Measure	Group 1 n=26 Participants Midazolam
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Geometric Mean Ratio AUC 0-last Ratio of geometric means of digoxin with TBAJ-876 to digoxin alone	1.51 ratio of geometric mean Interval 1.13 to 2.03
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Geometric Mean Ratio Cmax Ratio of geometric means of digoxin with TBAJ-876 to digoxin alone	1.18 ratio of geometric mean Interval 0.91 to 1.53

SECONDARY outcome

Timeframe: from date of the start of treatment to the end of study at 25 days

Population: Enrolled participants will be monitored for any adverse events from the signing of the consent form until the end-of-study visit

Participants will be monitored for any adverse events from the signing of the consent form until the end-of-study visit. The Investigator or a Sub-Investigator will assess its relationship to the study drug. Note about ST segment elevation which was reported as a treatment-related adverse event. Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not a TEAE however the AE remained in the database instead of being removed.

Outcome measures

Outcome measures
Measure	Group 1 n=28 Participants Midazolam
Number of Participants With Treatment-Related Adverse Events (TEAE) in Group 1 Population	5 Participants

Adverse Events

Group 1

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Group 1 n=28 participants at risk The pharmacokinetics of midazolam, a CYP3A4 substrate, and digoxin, a P-gp substrate, will be studied before and after dosing with TBAJ-876. TBAJ-876: • Day 6 to Day 13: 200 mg TBAJ-876 oral suspension, fed * Day 14 to Day 19: 165 mg TBAJ-876 oral suspension, fed * Day 20 and Day 21: 200 mg TBAJ-876 oral suspension, fasting * Day 22 to Day 24: 150 mg TBAJ-876 oral suspension, fed Midazolam: Day 1 and Day 20: Midazolam oral syrup: 2 mg, fasted Digoxin: Day 2 and Day 21: Digoxin tablet: 0.25 mg, fasted
Cardiac disorders Atrioventricular block first degree	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Gastrointestinal disorders Diarrhea	3.6% 1/28 • Number of events 2 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Gastrointestinal disorders Oral discomfort	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
General disorders Chest discomfort	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
General disorders Pyrexia	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Infections and infestations Pneumonia	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Investigations Alanine aminotransferase increased	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Investigations Electrocardiogram PR interval elongation	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Investigations Electrocardiogram ST segment elevation	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Musculoskeletal and connective tissue disorders Flank pain	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Nervous system disorders Headache	7.1% 2/28 • Number of events 3 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Nervous system disorders Lethargy	3.6% 1/28 • Number of events 2 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Respiratory, thoracic and mediastinal disorders Cough	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Respiratory, thoracic and mediastinal disorders Dyspnea	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.
Vascular disorders Orthostatic hypotension	3.6% 1/28 • Number of events 1 • Beginning of treatment on Day 1 through follow up on Day 32. Note about ST segment elevation which was reported as an adverse event (AE). Upon review of the screening ECG, early repolarization was noted and therefore the ST segment elevation was considered pre-existing and not an AE however the AE remained in the database instead of being removed.

Additional Information

Antonio Lombardi

TB Alliance

Phone: 917.601.0024

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place