Healthy Adult Participants
Conditions
Keywords
Mycobacterium tuberculosis, TBD11, Rifampicin, Itraconazole, Multiple Dose, Drug-Drug Interactions, Fixed Daily Dosing, Safety, Tolerability, Pharmacokinetics, DDI
Brief summary
This is a Phase 1, randomized, double-blind, placebo-controlled, multiple dose trial of TBD11 in healthy adults. It includes a dedicated open-label cohort in which TBD11 will be administered as a single dose with either a strong cytochrome P450 3A (CYP3A) inhibitor (itraconazole) or a strong CYP3A inducer (rifampicin) in 2 trial periods to evaluate DDI. The trial will consist of 3 cohorts; Cohort 1 will occur prior to Cohort 2 and Cohort 3. Cohort 2 and Cohort 3 will start after completion of Cohort 1 and will run in parallel. Cohort 1 will be double-blind and participants will receive 300 mg TBD11 or placebo once daily for 14 days. Cohort 2 will be the open-label DDI cohort. Cohort 3 will be double-blind and participants will receive TBD11 or placebo once daily for 84 days.
Interventions
DRUGTBD11 (300 mg)
TBD11: TBD11 administered orally at 300 mg
DRUGPlacebo
Matching placebo administered orally according to the cohort-specific dosing schedule.
Itraconazole 200 mg orally once daily, with a 400 mg loading dose on the first day of administration.
DRUGRifampicin 600mg
Rifampicin 600 mg orally once daily.
DRUGTBD11 (50 mg)
TBD11: TBD11 administered orally at 50 mg
DRUGTBD11 (up to 300 mg)
TBD11: TBD11 administered orally at up to 300 mg
Sponsors
Gates Medical Research Institute
IQVIA RDS Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* 18 to 55 years of age, inclusive. * Healthy, as determined by the Investigator through medical history and clinical examination before enrolment. * Able to understand and comply with trial and site procedures, understand study risks, and provide written informed consent before any trial-specific procedure. * Able to complete all Screening evaluations and remain in the clinical research facility for required inpatient periods. * BMI between 18 and 32 kg/m², inclusive, and body weight of at least 50 kg at Screening. * Resting vital signs within protocol-defined ranges at Screening and Day -1. * 12-lead ECG consistent with normal cardiac conduction and function at Screening. * Non-smoker within the previous 90 days, with negative urine cotinine at Screening and no use of tobacco- or nicotine-containing products. * Screening clinical chemistry, coagulation, complete blood count, and urinalysis within laboratory reference ranges, unless assessed as not clinically significant by the Investigator/designee. * Negative HBsAg and HCV antibody at Screening. * Negative IGRA test for TB infection. * Negative HIV antibody test at Screening. * Negative urine drug screen and urine alcohol screen at Screening and Day -1. * For participants assigned female sex at birth: negative urine and serum pregnancy tests at Screening and non-childbearing potential as defined in the protocol. * For participants assigned male sex at birth who are not sterilized and sexually active with a female partner of childbearing potential: agreement to use condoms from Day -1 through 90 days after the last dose and not donate sperm during the trial and for 90 days after the last dose.
Exclusion criteria
* Current or past clinically significant cardiovascular, cerebrovascular, respiratory, gastrointestinal, haematologic, renal, hepatic, immunologic, metabolic, urologic, neurologic, dermatologic, psychiatric, or other major disease. * Current or past condition expected to require treatment during the trial with medication known to inhibit or induce CYP3A4. * Clinically relevant cardiovascular disorder or symptoms suggestive of such disorder. * Prior history of TB infection or TB disease. * Current cough lasting more than 2 weeks, fever, night sweats, or unexplained weight loss. * Close household or repeated living/workspace contact with an individual with active TB in the preceding 12 months. * Active malignancy within 5 years of Screening, except basal cell or squamous cell skin cancers; any history of breast cancer or melanoma is exclusionary. * History of drug abuse within 1 year before Screening or use of specified hard drugs within 1 year before Screening, unless limited to prescribed opioid or amphetamine medication not currently being taken. * Surgical or medical condition that may alter absorption, metabolism, or excretion of trial treatment. * Use of prohibited medications, vitamins, dietary supplements, herbal products, or vaccination within the protocol-defined windows. * Contraindication to trial interventions or excipients, or clinically significant allergic/anaphylactic reaction to any medication. * Participation in another investigational drug, vaccine, or device study within 30 days or 5 half-lives, whichever is longer, before Screening and during this trial. * Any condition that may interfere with informed consent, compliance, interpretation of results, or place the participant at undue risk. * Blood donation within 2 months before Screening or planned blood donation during the trial or within 12 weeks after the final visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events | Cohort 1: Day 1 through Day 19. Cohort 2 Arm A: Period 1, Day 1 through Day 8; Period 2, Day -4 through Day 16. Cohort 2 Arm B: Period 1, Day 1 through Day 8; Period 2, Day -10 through Day 8. Cohort 3: Day 1 through Day 92. | Number of participants with one or more treatment-emergent adverse events, summarized overall and by severity, Investigator-assessed relationship to trial intervention, System Organ Class, and Preferred Term. |
| Number of Participants With Serious Adverse Events | Cohort 1: Day 1 through Day 19. Cohort 2 Arm A: Period 1, Day 1 through Day 8; Period 2, Day -4 through Day 16. Cohort 2 Arm B: Period 1, Day 1 through Day 8; Period 2, Day -10 through Day 8. Cohort 3: Day 1 through Day 92. | Number of participants with one or more serious adverse events, summarized overall and by severity, Investigator-assessed relationship to trial intervention, System Organ Class, and Preferred Term. |
| Number of Participants With Adverse Events Leading to Trial Intervention Interruption | Cohort 1: Day 1 through Day 19. Cohort 2 Arm A: Period 1, Day 1 through Day 8; Period 2, Day -4 through Day 16. Cohort 2 Arm B: Period 1, Day 1 through Day 8; Period 2, Day -10 through Day 8. Cohort 3: Day 1 through Day 92. | Number of participants with one or more adverse events resulting in temporary interruption of trial intervention, summarized overall and by severity, Investigator-assessed relationship to trial intervention, System Organ Class, and Preferred Term. |
| Number of Participants With Adverse Events Leading to Trial Intervention Discontinuation | Cohort 1: Day 1 through Day 19. Cohort 2 Arm A: Period 1, Day 1 through Day 8; Period 2, Day -4 through Day 16. Cohort 2 Arm B: Period 1, Day 1 through Day 8; Period 2, Day -10 through Day 8. Cohort 3: Day 1 through Day 92. | Number of participants with one or more adverse events resulting in permanent discontinuation of trial intervention, summarized overall and by severity, Investigator-assessed relationship to trial intervention, System Organ Class, and Preferred Term. |
| Number of Participants With Treatment-Emergent Clinical Chemistry Abnormalities | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Number of participants with treatment-emergent clinical chemistry abnormalities, summarized by visit, worst post-baseline grade, and grade shift from baseline using the protocol-specified toxicity grading criteria. |
| Number of Participants With Treatment-Emergent Hematology Abnormalities | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Number of participants with treatment-emergent hematology abnormalities, summarized by visit, worst post-baseline grade, and grade shift from baseline using the protocol-specified toxicity grading criteria. |
| Number of Participants With Treatment-Emergent Coagulation Abnormalities | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Number of participants with treatment-emergent coagulation abnormalities, summarized by visit, worst post-baseline grade, and grade shift from baseline using the protocol-specified toxicity grading criteria. |
| Number of Participants With Treatment-Emergent Urinalysis Abnormalities | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Number of participants with treatment-emergent urinalysis abnormalities, summarized by visit, worst post-baseline grade, and grade shift from baseline using the protocol-specified toxicity grading criteria. |
| Number of Participants With Treatment-Emergent Lipid Profile Abnormalities | Baseline and scheduled post-baseline assessments from Day 1 through Day 92 for Cohort 3. | Number of Cohort 3 participants with treatment-emergent lipid profile abnormalities, summarized by visit, worst post-baseline grade, and grade shift from baseline. |
| Change From Baseline in Systolic Blood Pressure | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change from baseline in systolic blood pressure, measured in millimeters of mercury (mmHg). |
| Change From Baseline in Diastolic Blood Pressure | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change from baseline in diastolic blood pressure, measured in millimeters of mercury (mmHg) |
| Change From Baseline in Heart Rate | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change from baseline in heart rate, measured in beats per minute (bpm) |
| Change From Baseline in Body Temperature | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change from baseline in body temperature, measured in degrees Celsius (°C) |
| Change From Baseline in 12-Lead ECG Heart Rate | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change From Baseline in 12-Lead ECG Heart Rate Change from baseline in 12-lead ECG heart rate, measured in beats per minute (bpm) |
| Change From Baseline in RR Interval | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change From Baseline in RR Interval Change from baseline in RR interval, measured in milliseconds (ms). |
| Change From Baseline in PR Interval | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change From Baseline in PR Interval Change from baseline in PR interval, measured in milliseconds (ms). |
| Change From Baseline in QRS Duration | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change From Baseline in QRS Duration Change from baseline in QRS duration, measured in milliseconds (ms). |
| Change From Baseline in QT Interval | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change From Baseline in QT Interval Change from baseline in QT interval, measured in milliseconds (ms). |
| Change From Baseline in QTcF Interval | Cohort 1, Day 1 through Day 19; Cohort 2 Arm A, Period 1 Day 1 through Day 8 and Period 2 Day -4 through Day 16; Cohort 2 Arm B, Period 1 Day 1 through Day 8 and Period 2 Day -10 through Day 8; Cohort 3, Day 1 through Day 92. | Change from baseline in QT interval corrected for heart rate using Fridericia's formula (QTcF), measured in milliseconds (ms). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration of TBD11 | Cohort 1: Day 1 and Day 14. Cohort 3: Day 1 and Day 84. | Maximum observed plasma concentration (Cmax) of TBD11 following single-dose and multiple-dose administration, measured in nanograms per milliliter (ng/mL). |
| Time to Maximum Observed Plasma Concentration of TBD11 | Cohort 1: Day 1 and Day 14. Cohort 3: Day 1 and Day 84. | Time to reach the maximum observed plasma concentration (Tmax) of TBD11, measured in hours (h). |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for TBD11 | Cohort 1: Day 1. Cohort 3: Day 1 | Area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24), measured in hour-nanograms per milliliter (h·ng/mL). |
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Concentration for TBD11 | Cohort 1: Day 14. Cohort 3: Day 84. | Area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast), measured in hour-nanograms per milliliter (h·ng/mL). |
| Minimum Plasma Concentration of TBD11 | Cohort 1: Day 14. Cohort 3: Day 84 | Minimum plasma concentration (Cmin) of TBD11 after multiple-dose administration, measured in nanograms per milliliter (ng/mL). |
| Accumulation Ratio for TBD11 Based on AUC Over the Dosing Interval | Cohort 1: Day 14 compared with Day 1. Cohort 3: Day 84 compared with Day 1. | Accumulation ratio calculated as AUCtau following multiple-dose administration divided by AUC0-24 following the Day 1 dose. |
| Geometric Mean Ratio of TBD11 Cmax With and Without Itraconazole | Cmax derived from plasma PK samples collected from pre-dose through 12 hours after TBD11 administration on Day 1 of Period 1 and Day 1 of Period 2. | Geometric mean ratio and corresponding two-sided 90% confidence interval for TBD11 Cmax, where Test is TBD11 co-administered with itraconazole and Reference is TBD11 administered alone. |
| Geometric Mean Ratio of TBD11 AUC0-inf With and Without Itraconazole | AUC0-inf derived from plasma PK samples collected from pre-dose through 168 hours after TBD11 administration in Period 1 and through 360 hours after TBD11 administration in Period 2. | Geometric mean ratio and corresponding two-sided 90% confidence interval for TBD11 area under the plasma concentration-time curve from time zero extrapolated to infinity, where Test is TBD11 co-administered with itraconazole and Reference is TBD11 administered alone. |
| Geometric Mean Ratio of TBD11 Cmax With and Without Rifampicin | Cmax derived from plasma PK samples collected from pre-dose through 12 hours after TBD11 administration on Day 1 of Period 1 and Day 1 of Period 2. | Geometric mean ratio and corresponding two-sided 90% confidence interval for TBD11 Cmax, where Test is TBD11 co-administered with rifampicin and Reference is TBD11 administered alone. |
| Geometric Mean Ratio of TBD11 AUC0-inf With and Without Rifampicin | AUC0-inf derived from plasma PK samples collected from pre-dose through 168 hours after TBD11 administration in each treatment period. | Geometric mean ratio and corresponding two-sided 90% confidence interval for TBD11 area under the plasma concentration-time curve from time zero extrapolated to infinity, where Test is TBD11 co-administered with rifampicin and Reference is TBD11 administered alone. |
Countries
South Africa
Contacts
CONTACTGates MRI
STUDY_DIRECTORGates MRI
Gates Medical Research Institute
Outcome results
None listed