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

Study Overview
=================
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 is a two-part, open-label drug-drug interaction study conducted in one study center in the United States. Two groups are planned, Group 1 and Group 2. Group 2 will be conducted based on the Group 1 results. Group 1 will 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 will only be conducted if the results of Group 1 show that TBAJ-876 is a moderate inducer of either CYP3A4 (midazolam AUC <0.50 when co-administered with TBAJ-876) or P-glycoprotein (digoxin AUC <0.50 when co-administered with TBAJ-876) or a moderate inhibitor of P-glycoprotein (digoxin AUC ≥2.0 when co-administered with TBAJ-876. This group will quantify the magnitude of inhibition or induction of TBAJ-876 on 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 will be assessed throughout the study for all subjects. Safety assessments will include physical examinations, vital signs, serial ECGs, adverse events (AEs), clinical and laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis).

Official Title
-----------------
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

Conditions
-----------------
Pulmonary Disease, Tuberculosis, Pulmonary, Tuberculosis, Multi Drug Resistant Tuberculosis, Drug Sensitive Tuberculosis, Drug-resistant Tuberculosis, Mycobacterium Tuberculosis Infection

Intervention / Treatment
-----------------
* Drug: TBAJ-876
* Drug: TBAJ-876
* Drug: Midazolam
* Drug: Digoxin
* Drug: TLD


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>The pharmacokinetics of midazolam, a CYP3A4 substrate, and digoxin, a P-gp substrate, will be studied before and after dosing with TBAJ-876. | Drug: TBAJ-876<br>* 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<br>Drug: Midazolam<br>* Day 1 and Day 20: Midazolam oral syrup: 2 mg, fasted<br>Drug: Digoxin<br>* Day 2 and Day 21: Digoxin tablet: 0.25 mg, fasted<br>|
| Active Comparator: Group 2<br>The pharmacokinetics of antiretroviral regimen TLD will be studied before and after dosing with TBAJ-876. | Drug: TBAJ-876<br>* 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: 200 mg TBAJ-876 oral suspension, fasting Day 21 to Day 24: 150 mg TBAJ-876 oral suspension, fed<br>Drug: TLD<br>* Day 1 and Day 20: fixed dose combination of dolutegravir 50 mg + tenofovir disoproxil fumarate 300 mg + lamivudine 300 mg, fasted<br>* Other names: tenofovir disoproxil fumarate (TDF), lamivudine (3TC), dolutegravir (DTG);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TBAJ-876 effect on the pharmacokinetics of the CYP-3A4 substrate midazolam and the inhibition potential of TBAJ-876 on P-gp in healthy adult subjects | Geometric mean ratio of midazolam'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. Inference will be based on analysis of variance applied to log-transformed parameters. | 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 | 
| TBAJ-876 effect on the pharmacokinetics of the P-gp substrate digoxin | Geometric mean ratio 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. Inference will be based on analysis of variance applied to log-transformed parameters. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment-Related Adverse Events in Group 1 Population | Subjects 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. | from date of the start of treatment to the end of study at 25 days | 
| Number of Participants with Treatment-Related Adverse Events in Group 2 Population | Subjects 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. | from date of the start of treatment to the end of the study at 25 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TBAJ-876, Diarylquinoline, DARQ