PrimaryTo evaluate the safety and tolerability of single and multiple doses of TBAJ-587 in healthy participants.SecondaryTo determine the pharmacokinetics (PK) of single and multiple doses of TBAJ-587 and metabolites M2, M3 and M12. To compare the…
ID
Source
Brief title
Condition
- Mycobacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PK
Part 1: Single Ascending Dose
Noncompartmental PK parameters of AUClast, AUCinf, Cmax, tmax, CL/F, Vz/F, *z,
and t1/2 will be calculated from plasma concentrations of TBAJ-587, M2, M3 and
M12. Additional PK parameters may be calculated if deemed appropriate.
All clinical safety data will be listed by participant. Continuous variables
will be summarized using sample size (N), mean, standard deviation, median,
minimum, and maximum.
Part 2: Multiple Ascending Dose
Multiple ascending dose cohort PK parameters using noncompartmental analysis,
calculated from plasma concentrations of TBAJ-587, M2, M3 and M12 following
doses on Days 1, 14 and 28, will include:
Day 1: AUCtau, Cmax, Tmax. Clast, Tmax. Parameters such as CL/F, Vz/F, *z, and
t1/2 which require extrapolations of the concentration profile to infinity, may
be calculated of PK results from the SAD indicate the feasibility based on 24
hours of sampling; otherwise not. If so, if for any individual participant
AUCtau < 80% of AUCinf, CLss/F, Vz/F, *z, and t1/2 will be flagged as
unreliable in listings and will not be included in summary statistics.
Day 14 and 28 : AUCtau, Cmax, Cmin, Tmax, Ctrough, Cavg, RAUC, RCmax.
Parameters such as CLss/F, Vz/F, *z, and t1/2 may be calculated if feasible.
All clinical safety data will be listed by participant. Continuous variables
will be summarized using sample size (N), mean, standard deviation, median,
minimum, and maximum.
Secondary outcome
Nap.
Background summary
Tuberculosis (TB) is an infectious disease that continues to present a
significant public health problem world-wide. Without treatment TB can be
fatal, while those who survive without treatment can experience long-term
health problems and remain infectious so put others at risk thorough on-going
community transmission.
Current TB treatment regimens are lengthy in duration and involve multi-drug
therapy. High rates of noncompliance are common, which often result in
increased mortality and chronic, infectious, drug-resistant cases. The present
TB epidemic and treatment conditions demonstrate the clear need for new TB
drugs and drug regimens for patients with drug-sensitive or drug-resistant TB
that are safe and well tolerated and will shorten the overall treatment
duration required for cure. In addition, new TB drugs and regimens should be
affordable, easy to adopt and implement, suitable for pediatric use and for co
administration with antiretroviral therapy in individuals co-infected with
Mycobacterium tuberculosis and HIV.
This study is the first time into human study (FTIH) for TBAJ-587. The study
will evaluate the safety, tolerability, and pharmacokinetics (PK) of single
ascending and repeat oral doses of TBAJ-587 in healthy adult volunteers. The
results of this study are intended to be used to identify appropriate and well
tolerated doses of TBAJ-587 to be used in further studies. A food effect
assessment will also be undertaken to investigate the influence of food on the
pharmacokinetics of TBAJ-587.
Study objective
Primary
To evaluate the safety and tolerability of single and multiple doses of
TBAJ-587 in healthy participants.
Secondary
To determine the pharmacokinetics (PK) of single and multiple doses of TBAJ-587
and metabolites M2, M3 and M12.
To compare the rate and extent of absorption of a single oral dose of TBAJ-587
when administered after a high-calorie, high-fat meal versus when it is
administered fasting in healthy adult participants.
Study design
This is a two-part, partially blinded, placebo-controlled, combined single
ascending dose (SAD) trial with a food effect cohort (Part 1) and multiple
ascending dose (MAD) trial (Part 2) to be conducted in one trial centre in
Europe.
Part 1: Has a single ascending dose (SAD) design with up to 6 planned dose
levels with a food effect cohort at one of the dose levels.
The first SAD cohort will be separated into 2 groups. A sentinel group of two
participants (1 active and 1 placebo) will be dosed at least 72 hours before
the remaining 6 participants (5 active and 1 placebo). The other cohorts will
not be separated.
First cohort: current total duration and scheduling of safety and PK sampling
is based on the assumption that the expected t1/2 will be 26 days which will
ensure coverage for PK and safety out to approximately 5 half-lives. Refer to
Section 1.2.1 Schedule of Assessments & Procedures for more details. However,
the sampling schedule may change depending on the observed PK profile.
Other Dose Level cohorts: scheduling of safety and PK sample collection will be
based on the PK data collected from previous cohorts and could require that the
participants return to the clinic for up to 20 weeks or longer after dosing,
depending on what is learned about the half-life of TBAJ-587.
Food Effect Cohort: Based on exposure levels from preceding SAD cohorts, one of
the planned cohorts and the specific dose will be selected for the food effect
(FE) cohort which will study the effect on PK after a high-calorie, high-fat
meal. The food effect on the PK of TBAJ-587 will be studied in one of the
previously completed cohorts using a parallel group design involving two
groups, one group dosed fasted and the other group dosed after a meal.
Additional participants will be recruited to reach a total of 9 active
participants, inclusive of the previously dosed participants, in the fasted
group, and 9 additional active participants will be recruited for the group
dosed with food.
Part 2: Has a multiple ascending dose (MAD) design. Three cohorts are planned
for Part 2 and will be determined based on model predictions of steady state
AUC exposures and safety from Part 1.
In this MAD part, each participant, based on current assumptions, is expected
to be administered TBAJ-587 or matching placebo daily for 28 days with
corresponding PK and safety measurements.
Parts 1 and 2:
Additional cohorts: up to three additional cohorts in Part 1 and one additional
cohort in Part 2 may be enrolled if deemed appropriate by the Sponsor to repeat
a dose level or to study another dose level.
See CSP section 4 for further details.
Intervention
The test product is TBAJ-587 5 mg/mL and 20 mg/mL oral suspension formulation
and TBAJ-587 matching placebo.
Study burden and risks
Since the study is being executed in healthy volunteers, there are no
anticipated benefits of the IMP. Please see the IB for further
information.
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Listed location countries
Age
Inclusion criteria
Provide written, informed consent prior to all trial-related procedures.
Healthy adult male and females of non-childbearing potential, 18-64 years of
age (inclusive) at the time of screening.
Body mass index (BMI) >= 18.5 and <= 32.0 (kg/m2) and a body weight of no less
than 50.0 kg.
Medically healthy with no clinically significant screening results (e.g.,
laboratory profiles normal or up to Grade 1 per FDA Toxicity Tables), medical
histories, vital signs, ECGs, physical examination findings, as deemed by the
Investigator. Lab results within the testing facilities normal range will not
be considered AEs when referenced to the FDA Toxicity Scales (Appendix 2)
assessment/grading scale. If exclusionary lab criteria are met, values may be
confirmed by repeat evaluation
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 toxicity (severe tenderness with marked impairment of
activity) or musculoskeletal toxicity (frank necrosis).
History of any illness that, in the opinion of the Investigator, might confound
the results of the trial or poses an additional risk to the participant by
their participation in the trial.
Surgery within the past 90 days prior to dosing or other previous surgery as
determined by the Investigator to be clinically relevant.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-001935-28-NL |
| CCMO | NL73973.056.20 |