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

Phase 1

Completed

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

Interventions: Drug: TBAJ-876
Drug: Midazolam
Drug: Digoxin

Registration Number: NCT05526911

Lead Sponsor: Global Alliance for TB Drug Development

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Group 1	TBAJ-876	The pharmacokinetics of midazolam, a CYP3A4 substrate, and digoxin, a P-gp substrate, will be studied before and after dosing with TBAJ-876.
Group 1	Midazolam	The pharmacokinetics of midazolam, a CYP3A4 substrate, and digoxin, a P-gp substrate, will be studied before and after dosing with TBAJ-876.
Group 1	Digoxin	The pharmacokinetics of midazolam, a CYP3A4 substrate, and digoxin, a P-gp substrate, will be studied before and after dosing with TBAJ-876.

Primary Outcome Measures

Name	Time	Method
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 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 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.
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.

Secondary Outcome Measures

Name	Time	Method
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.