Pulmonary Disease, Tuberculosis, Pulmonary, Tuberculosis, Multi Drug Resistant Tuberculosis, Drug Sensitive Tuberculosis, Drug-resistant Tuberculosis, Mycobacterium Tuberculosis Infection
Conditions
Keywords
TBAJ-876, Diarylquinoline, DARQ
Brief summary
A Phase 1, Drug-Drug Interaction Study to Evaluate the Safety, Tolerability, and the Induction Potential of TBAJ-876 on CYP3A4 and P-glycoprotein and the Inhibition Potential of TBAJ-876 on P-glycoprotein in Healthy Adult Subjects
Detailed description
This study was a two-part, open-label drug-drug interaction study conducted in one study center in the United States. Two groups were planned, Group 1 and Group 2. Group 2 to be conducted based on the Group 1 results. Group 1 to assess the induction potential of TBAJ-876 on the sensitive CYP3A4 substrate midazolam (M) and inhibition and induction potential of TBAJ-876 on the sensitive P-glycoprotein substrate Digoxin (D). Group 2 was only to be conducted if the results of Group 1 show that TBAJ-876 is a moderate inducer of either CYP3A4 (geometric mean ratio \[GMR\] of midazolam area under the curve \[AUC\] \<0.50 when co-administered with TBAJ-876) or P-glycoprotein (GMR of digoxin AUC \<0.50 when co-administered with TBAJ-876) or a moderate inhibitor of P-glycoprotein (GMR of digoxin AUC ≥2.0 when co-administered with TBAJ-876). These results were used to decide that a second phase of the study was not needed. If Group 1 concluded that TBAJ-876 is a moderate inducer or inhibitor, Group 2 had intended to quantify the magnitude of inhibition or induction of TBAJ-876 of the antiretroviral regimen TLD, a fixed dose combination of tenofovir disoproxil fumarate (TFD), lamivudine (3TC) and dolutegravir (DTG), a regimen likely to be used in future clinical studies of TBAJ-876 by subjects living with HIV Safety was assessed throughout the study for all subjects. Safety assessments included physical examinations, vital signs, serial ECGs, adverse events (AEs), clinical and laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis).
Interventions
DRUGTBAJ-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
DRUGMidazolam
Day 1 and Day 20: Midazolam oral syrup: 2 mg, fasted
DRUGDigoxin
Day 2 and Day 21: Digoxin tablet: 0.25 mg, fasted
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Is a healthy adult male or female, 18 to 55 years of age (inclusive) at the time of screening. * Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no less than 50.0 kg at the time of screening and check-in. * Is medically healthy with no clinically significant screening results (e.g., laboratory profiles normal or up to Grade 1 per Division of Microbiology and Infectious Diseases (DMID) Toxicity Tables), as deemed by the Investigator. * Has not used tobacco- or nicotine-containing products (including smoking cessation products), for a minimum of 6 months before dosing. * Is willing and able to consume the entire high-calorie, high-fat breakfast meal in the timeframe required. Key
Exclusion criteria
* History or presence of significant cardiovascular abnormalities, heart murmur, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease as determined by the Investigator to be clinically relevant. * Any musculoskeletal abnormality (severe tenderness with marked impairment of activity) or musculoskeletal toxicity (frank necrosis). * Positive results at screening for Human Immunodeficiency Virus (HIV), Hepatitis B Surface Antigen (HBsAg), or Hepatitis C antibodies (HCV). * Positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) results within 6 days prior to Day 1. * Current or history of prolonged QT syndrome. * Family history of Long-QT Syndrome or sudden death without a preceding diagnosis of a condition that could be causative of sudden death (such as known coronary artery disease, congestive heart failure or terminal cancer). * Use of any drugs or substances known to be inducers of CYP enzymes and/or P-gp, including St. John's Wort, within 30 days prior to the first dose of study drug. * Is lactose intolerant. * History or presence of allergic, or adverse response to midazolam, digoxin, dolutegravir, tenofovir, lamivudine or any related drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Geometric Mean Ratios | 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 | 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. |
| TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters AUC | 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 | 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. |
| TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters CMAX | 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 | Geometric mean and range of midazolam's maximum concentration when co-administered with TBAJ-876 versus when administered alone. |
| TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Geometric Mean Ratio | 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 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. |
| TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters AUC | 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. |
| TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters CMAX | 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 Cmax when co-administered with TBAJ-876 versus when administered alone, and similarly for the maximum concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Related Adverse Events (TEAE) in Group 1 Population | from date of the start of treatment to the end of study at 25 days | 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. |
Countries
United States
Participant flow
Recruitment details
A total of 75 subjects were screened for the trial of whom 47 failed screening, 28 were randomized, and 26 completed treatment.
Pre-assignment details
No participants were assigned to Group 2
Participants by arm
| Arm | Count |
|---|---|
| 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 | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Group 1 |
|---|---|
| Age, Continuous | 37.1 years STANDARD_DEVIATION 9.8 |
| BMI at Screening | 28 kilogram per meter squared STANDARD_DEVIATION 8.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height at Screening | 167.3 centimeters STANDARD_DEVIATION 10.41 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 28 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 14 Participants |
| Weight at Screening | 78.2 Kilogram STANDARD_DEVIATION 19.86 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 28 |
| other Total, other adverse events | 9 / 28 |
| serious Total, serious adverse events | 0 / 28 |
Outcome results
Primary
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Geometric Mean Ratios
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1 | 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 |
| Group 1 | 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 |
| Group 1 | 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 |
Primary
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters AUC
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1 | 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 |
| Group 1 | 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 |
| Group 1 | 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 |
| Group 1 | 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 |
Primary
TBAJ-876 Effect on the Pharmacokinetics of the CYP-3A4 Substrate Midazolam in Healthy Adult Subjects: Pharmacokinetic Parameters CMAX
Geometric mean and range of midazolam's maximum concentration when co-administered with TBAJ-876 versus when administered alone.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1 | 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 |
| Group 1 | 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 |
Primary
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Geometric Mean Ratio
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1 | 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 |
| Group 1 | 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 |
Primary
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters AUC
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.
Time frame: 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. 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1 | 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 |
| Group 1 | TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters AUC | AUC 0-last, alone | 7.64 ng.hr/mL |
| Group 1 | 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 |
| Group 1 | TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters AUC | AUC 0-inf, alone | 23.44 ng.hr/mL |
Primary
TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters CMAX
Geometric mean of digoxin's Cmax when co-administered with TBAJ-876 versus when administered alone, and similarly for the maximum concentration.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1 | TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters CMAX | Cmax, alone | 1.01 ng/mL |
| Group 1 | TBAJ-876 Effect on the Pharmacokinetics of the P-gp Substrate Digoxin: Pharmacokinetic Parameters CMAX | Cmax, with TBAJ-876 | 1.19 ng/mL |
Secondary
Number of Participants With Treatment-Related Adverse Events (TEAE) in Group 1 Population
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.
Time frame: 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 | Number of Participants With Treatment-Related Adverse Events (TEAE) in Group 1 Population | 5 Participants |