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

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

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

Study Overview

• Status: Completed
• Conditions: Tuberculosis; Tuberculosis, Pulmonary; Pulmonary Disease; Multi Drug Resistant Tuberculosis; Drug Sensitive Tuberculosis; Drug-resistant Tuberculosis; Mycobacterium Tuberculosis Infection
• Intervention / Treatment: Drug: TBAJ-876; Drug: Midazolam; Drug: Digoxin

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).

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Fair Lawn, New Jersey, United States, 07410
      • TKL Research, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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; Drug: Midazolam; Day 1 and Day 20: Midazolam oral syrup: 2 mg, fasted; Drug: Digoxin; Day 2 and Day 21: Digoxin tablet: 0.25 mg, fasted

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

Collaborators and Investigators

• Sponsor: Global Alliance for TB Drug Development
• Investigators: Study Chair: Antonio Lombardi, MD, Global Alliance for TB Drug Development

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2022
• Primary Completion (Actual): September 26, 2022
• Study Completion (Actual): September 26, 2022

Study Registration Dates

• First Submitted: August 31, 2022
• First Submitted That Met QC Criteria: August 31, 2022
• First Posted (Actual): September 2, 2022

Study Record Updates

• Last Update Posted (Actual): October 8, 2024
• Last Update Submitted That Met QC Criteria: July 8, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: TBAJ-876; Diarylquinoline; DARQ
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Tuberculosis; Latent Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Protective Agents; Cardiotonic Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Digoxin; Midazolam
• Other Study ID Numbers: TBAJ-876-CL002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No