• To evaluate the safety and tolerability of THB001 in cold induced chronic urticaria patients
ID
Source
Brief title
Condition
- Allergic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Treatment emergent AEs/SAEs
• Laboratory assessments
• ECG, vital signs
Secondary outcome
• Change from baseline in critical temperature threshold (CTT) over time using
the TempTest® system
• Percentage of complete responders (CTT <= 4°C) and partial responders
(> 4°C CTT change from baseline) over time
• Time to complete (partial) response
• Pre- and post-treatment changes in skin mast cell density
• Pre- and post-treatment changes in serum tryptase
• Plasma PK concentration of THB001 over time
• Modeled plasma PK parameters of THB001 including but not limited to Cmax,
Cmin and AUC as appropriate
Background summary
This planned phase 1b trial will be performed to evaluate the safety,
pharmacokinetics, and pharmacodynamics of up to 3 dose levels of THB001 over 12
weeks in the treatment of patients with ColdU. Targeting mast cells with THB001
is expected to provide clinical benefit in ColdU by decreasing the number of
mast cells and their activity. Since mast cells are the primary effector cell
in CIndU and with early clinical data demonstrating reduction of serum
tryptase, THB001 should reduce wheal responses in ColdU measured as change in
critical threshold temperature (CCT). Treatment effects will be evaluated
through Patient Reported Outcome (PRO) measures and skin biopsies for
evaluation of mast cell numbers.
This represents a novel therapeutic approach. Existing therapies generally
target individual mast cell mediators, such as histamine, leukotrienes, and/or
mast cell activation pathways (IgE) and many patients have inadequate response.
THB001 is intended to deplete the mast cells and thereby inhibit multiple
mediators of symptoms of ColdU or other allergic diseases.
Study objective
• To evaluate the safety and tolerability of THB001 in cold induced chronic
urticaria patients
Study design
This is a phase 1b, open label, non-randomized, sequential dose-escalation,
multicenter trial in adult patients with cold induced chronic urticaria.
Intervention
THB001 200 mg BID for 12 weeks
THB001 300 mg BID for 12 weeks
THB001 400 mg BID for 12 weeks
Study burden and risks
Based on clinical and/or nonclinical findings, monitorable potential adverse
effects of THB001 are as follows:
• Changes in hematology laboratory parameters * THB001-related hematologic
effects include reductions in Red Blood Cell (RBC), reticulocytes, and White
Blood cell (WBC) counts that correlate with decreased bone marrow cellularity
in rats and dogs. These changes are considered on target and reversible. In the
first-in-human (FiH) trial, mild reductions in mean WBC and neutrophil count
were observed through 2 weeks of dosing. Mean cohort decreases in reticulocyte
counts were also observed through 2 weeks of dosing.
These effects were fully reversible approximately 7 days after dosing was
stopped.
• Changes in heart rate
• Changes in clinical chemistry * Colony-Stimulating Factor 1 receptor (CSF-1R)
mediated inhibition of Kupffer cells may cause reduced clearance of liver
function enzymes and Creatine Kinase (CK) and result in mild elevations.
Prior clinical experience with targeted CSF-1R inhibitors were considered mild
elevations as on target pharmacology and non-adverse (Genovese et al. 2015).
• Changes in hair color
The following potential non-monitorable effects were observed in nonclinical
studies:
• Depletion of male reproductive germ cells
• Hemorrhage of corpora lutea of ovaries
• Fetal toxicity
Risks to participants in the trial will be minimized by inclusion of
participants fulfilling all eligibility criteria, close clinical monitoring,
individual dose stopping criteria, and dose escalation stopping criteria.
Technology Square, 8th Floor 300
Cambridge MA 02139
US
Technology Square, 8th Floor 300
Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
-Diagnosis of chronic cold urticaria for at least 3 months.
-Participants must be refractory to antihistamine treatment.
-Participants must understand the nature of the trial and must provide signed
and dated written informed consent in accordance with local regulations before
the conduct of any trial-related procedures.
-Participants currently on an antihistamine must be on a stable dose for at
least 2 weeks prior to day 1 and must maintain the same stable dose throughout
the treatment period.
-Positive cold stimulation test assessed by TempTest®
-Healthy as determined by the Investigator
-Men and women, age 18-75 years
-Women of child-bearing potential must not be pregnant or lactating. Women of
child-bearing potential and their non-vasectomized partners must agree to use
two of the following contraceptive methods during the trial and for 90 days
after the (last) trial drug administration: non-hormonal intra-uterine
device/system, condom, diaphragm, cervical cap with spermicide. Hormonal
contraceptives may continue to be used but are not considered a highly
effective form of birth control for this study.
OR Women of child-bearing potential and their vasectomized partners must agree
to use one of the following contraceptive methods during the trial and for 90
days after the (last) trial drug administration: non-hormonal intra-uterine
device/system, condom, diaphragm, cervical cap with spermicide. Hormonal
contraceptives may continue to be used but are not considered a highly
effective form of birth control for this study.
OR Women of child-bearing potential must practice sexual abstinence (when this
is in line with her preferred and usual lifestyle) during the trial and for 90
days after the (last) trial drug administration.
Exclusion criteria
-Participants with acute urticaria and participants with non-cold chronic
inducible urticaria.
-Current/ongoing treatment with immunosuppressant drugs, leukotriene
antagonists, danazol, penicillin, angiotensin-converting inhibitors, and
griseofulvin
-Any previous treatment with CDX-0159.
-A positive test for drugs of abuse at Screening.
-A positive Hepatitis B surface antigen or positive Hepatitis C or human
immunodeficiency virus (HIV) antibody result at Screening.
-Abnormal clinically significant findings on the laboratory examinations at the
Screening (ALT, AST, TBL, greater than 1.5 times the upper limit of normal;
Hbg, platelet count, ANC, reticulocyte count, WBC, below the lower limit of
normal)
-Use of prescription or non-prescription drugs, vitamins, herbal, and dietary
supplements, unless in the opinion of the Investigator and the Medical Monitor
the medication will not interfere with the trial procedures or compromise
participant safety.
-Received or used an investigational product (including placebo) or device
within the following time period prior to the first dosing day in the current
trial: 90 days, 5 half-lives or twice the duration of the biological effect of
the investigational product (whichever is longer).
-A positive pregnancy test or lactation.
-A history or presence of a clinically significant hepatic, renal,
gastrointestinal, cardiovascular, endocrine, pulmonary, ophthalmologic,
immunologic, hematologic, dermatologic (other than chronic urticaria),or
neurologic abnormality.
-A clinically significant vital signs abnormality, as judged by the principal
investigator, at Screening.
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 | EUCTR2021-005360-21-NL |
| CCMO | NL81526.056.22 |