Primary objective:• To investigate the effect of THB001 on the pharmacokinetics (PK) of caffeine, omeprazole and midazolam.Secondary objective:• To evaluate the safety and tolerability of THB001 co-administered with caffeine, omeprazole and…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
allergic mediated diseases
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PK parameters for midazolam, caffeine and omeprazole include, but are not
limited to: Cmax, tmax, AUC0-t, and AUC0-inf.
Secondary outcome
Safety and tolerability parameters include: physical examination, AEes,
clinical laboratory values, vital signs and 12-lead ECGs.
Background summary
Mast cells play a central role in the pathology of allergic-mediated diseases,
providing a strong rationale that depletion of mast cells can benefit patients
diagnosed with allergic mucosal and cutaneous disorders in which mast cell
degranulation plays a role in onset and progression. As a novel therapeutic
approach, mast cell depletion should inhibit multiple mediators of symptoms of
allergic diseases that have inadequate responses to single agents that target
only individual mediators of mast cells or whose off-target toxicity profiles
limit their use.
Mast cell activation, proliferation, and survival depend on the receptor
tyrosine kinase. Studies have shown that KIT mutations and kinase inhibition of
mutant KIT have profound effects on mast cells. Therefore, KIT is a
pharmacologically and genetically validated target to drive mast cell depletion.
THB001 is highly selective for KIT and, therefore, mast cell proliferation and
survival. The exquisite selectivity of THB001 was demonstrated in animals by
limited*to*no off*target toxicity and a defined on-target toxicity with a
reasonable therapeutic window. THB001 is expected to have robust mast cell
depletion and a favorable safety profile that supports clinical investigation.
Study objective
Primary objective:
• To investigate the effect of THB001 on the pharmacokinetics (PK) of caffeine,
omeprazole and midazolam.
Secondary objective:
• To evaluate the safety and tolerability of THB001 co-administered with
caffeine, omeprazole and midazolam.
Exploratory objectives:
• To determine the PK of the CYP substrate metabolites, and metabolite to
parent ratios where appropriate, in the presence and absence of THB001.
• To evaluate the potential effect of genetic CYP2C19 polymorphisms on any
observed variable response in the magnitude of the drug interaction between
THB001 and omeprazole.
Study design
This is an open-label, fixed-sequence, drug-drug interaction (DDI) in healthy
subjects.
One (1) dose of 400 mg THB001 , dosed in the absence and presence of 2 mg
midazolam, 100 mg caffeine, and 10 mg omeprazole, is planned to be tested in 1
cohort of 18 healthy subjects.
Eligibility will be assessed during a screening period of up to 28 days.
Subjects will check into the clinic one day prior to first dosing with the CYP
substrates (Day -1). On Day 1, all subjects will receive midazolam, caffeine
and omeprazole in a fasted state (after an overnight fast of at least 10
hours). From Day 3 up to and including Day 12, all subjects will receive a
single oral dose of THB001 once daily in a fasted state (after an overnight
fast of at least 10 hours). On Day 11, subjects will receive both THB001 and a
second single oral doses of midazolam, caffeine, and omeprazole administered
concurrently. Subjects will be released from the clinic on Day 13 after all
required study procedures are completed and if medically justified.
Subjects will return to the clinic between Day 17 and Day 19 for a follow-up
visit.
Please refer to Table 5-1 for an overview of ambulatory visits and residence in
the clinic.
Intervention
THB001 Drug Product
Caffeine (CYP1A2 substrate)
Omeprazole (CYP2C19 substrate)
Midazolam (CYP3A4 substrate)
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.
300 Technology Square, 8th Floor 300
Cambridge MA 02139
US
300 Technology Square, 8th Floor 300
Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
1. Subjects must understand the nature of the study and must provide signed and
dated written informed consent in accordance with local regulations before the
conduct of any study-related procedures.
2. Healthy as determined by the Investigator, based on a medical evaluation
including medical history, physical examination, laboratory tests and ECG
recording. A subject with a clinical abnormality or laboratory parameters
outside the reference range for the population being studied may be included
only if, in the opinion of the Investigator, the finding is (a) unlikely to
introduce additional risk to the subject, (b) will not interfere with study
procedures or confound study results, and (c) is not otherwise exclusionary
(see Exclusion Criteria).
3. Vasectomized men and women, age 18-65 years inclusive at will be enrolled.
Women of child-bearing potential must agree not to attempt to become pregnant
and to use a highly effective form of hormonal (excluding oral contraceptives)
or non-hormonal birth control, which entails the use of a non-hormonal
intra-uterine device/system in combination with a barrier method (e.g. condom,
diaphragm, cervical cap with spermicide) or abstinence during the study and for
90 days after the (last) study drug administration. Postmenopausal women must
have had >=12 months of spontaneous amenorrhea (with documented
follicle-stimulating hormone (FSH) >=30 mIU/mL). Surgically sterile women are
defined as those who have had a hysterectomy, bilateral ovariectomy, or
bilateral tubal ligation. Women who are surgically sterile must provide
documentation of the procedure by an operative report or by ultrasound. All
women must have a negative pregnancy test result on Day 1 before (first)
administration of study medication. Male subjects must have had a vasectomy at
least 4 months prior to the Screening Visit and must have a documented
post-surgical follow up to confirm success of the vasectomy. They must also
agree to use a condom from Day 1 until 90 days after the last dose of study.
Exclusion criteria
1. A positive urine drug screen/alcohol breath test at Screening or Day -1.
2. A positive Hepatitis B surface antigen or positive Hepatitis C antibody
result at screening.
3. A positive test for human immunodeficiency virus (HIV) antibody at screening.
4. Alanine aminotransferase, aspartate aminotransferase, or total bilirubin
levels greater than the upper limit of normal (ULN) at Screening or Day -1. One
test result up to 1.25 x the ULN is allowed. One retest at Screening and on Day
-1 is allowed. Subjects with Gilbert*s Syndrome are permitted to have total
bilirubin values outside the 1.25 x the ULN, as judged by the Investigator as
long as the AST and ALT are within normal limits (WNL).
5. Hemoglobin, Platelet count, or White blood cell count below the lower limit
of normal LLN at Screening. Hemoglobin, Platelet count, or White blood cell
count below the LLN on Day -1. One retest is allowed at each visit.
6. Serum creatinine greater than the ULN at Screening or Day -1. One retest is
allowed.
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 | EUCTR2021-005997-25-NL |
| CCMO | NL79761.056.21 |