Primary ObjectiveTo assess the tolerability and safety of multiple ascending oral doses of PHA-022121 administered after a standard caloric meal in healthy adult subjects.To assess the PK characteristics of PHA-022121 after administration of…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint, safety:
- All standard safety assessments including physical examination, vital signs,
adverse events, neurological assessment, hematology, chemistry, urinalysis and
ECG
Primary endpoint, pharmacokinetics:
- After the first and second dose on Day 1:
Plasma PK parameters, Cmax, 1, Cmax, 2, tmax, 1, tmax, 2, AUC0-12h, AUC0-24h,
AUClast, AUCinf, t1/2, CL/F and Vz/F of PHA-022121.
The following urinary PK parameters of PHA-021221 will be derived (x-y
represent the different time intervals): Ae x-y, Ae total, Durine,x-y,
Durine,total and CLR.
After the morning dose on Day 10:
Plasma PK parameters Cmax, tmax, AUC0-12h, AUC0-24h, AUClast, t1/2, CL/F and
Vss/F of PHA-022121.
Urinary PK parameters of PHA-021221 will be derived as on Day 1.
Cmin (pre-dose) every morning.
Secondary outcome
- After the first and second dose on Day 1:
Plasma PK parameters for the major metabolite M2-D: Cmax, 1 , Cmax, 2, tmax, 1,
tmax, 2, AUC0-12h, AUC0-24h, AUClast, AUCinf, and t1/2,.
The following urinary PK parameters of M2-D will be derived (x-y represent the
different time intervals): Ae x-y, Ae total, Durine,x-y, Durine,total and CLR.
- After the morning dose on Day 10:
Plasma PK parameters for the major metabolite M2-D: Cmax, tmax, AUC0-12h,
AUC0-24h, AUClast, and t1/2,.
Urinary PK parameters of M2-D will be derived as on Day 1.
- Cmin (pre-dose) every morning.
- 4-βHC plasma levels and urinary 6-βHC / cortisol ratio as biomarkers for
CYP3A4 activity.
- QT, and the corrected QT interval by Fridericia*s formula (QTcF)
Background summary
An oral treatment for HAE attacks is currently not available rendering the
management of this disease difficult: all of the currently approved drugs for
HAE, except for androgens, can only be applied by i.v. or s.c. route, which is
often associated with a delay of drug administration, discomforts, local side
effects and with a reduction in the QoL for the patients. Therefore, there is a
strong unmet medical need for an efficacious orally bioavailable drug for the
treatment and/or prevention of acute HAE attacks.
Of all products available to patients or in development, only one other
antagonizes the B2 receptor, namely icatibant. Extensive clinical experience
has demonstrated the selectivity, safety, and rapid onset of action of this
mechanism to resolve HAE attacks of all causes. PHA-022121 retains these
characteristics through the shared mechanism, as demonstrated preclinically in
the BK challenge model adapted from human clinical experience to monkey.
Study objective
Primary Objective
To assess the tolerability and safety of multiple ascending oral doses of
PHA-022121 administered after a standard caloric meal in healthy adult subjects.
To assess the PK characteristics of PHA-022121 after administration of multiple
ascending oral doses, administered after a standard caloric meal.
Secondary Objectives
To assess the PK characteristics of the major active metabolite M2-D after
administration of multiple ascending doses of PHA-022121.
To explore the potential of PHA-022121 for CYP3A4 enzyme induction.
To assess the concentration-QTc effect of PHA-022121 after repeated ascending
doses.
Study design
This is a randomized, double-blind, placebo-controlled study for PHA-022121 and
will be conducted in healthy subjects at a single study center.
This study will consist of four double-blind, randomised, placebo-controlled,
multiple ascending dose cohorts, in which the safety, tolerability and PK of
PHA-022121 will be assessed when administered B.I.D. for 9 days and a morning
dose on Day 10 (with a 12 h time interval). Within each cohort, 10 subjects
will be randomized to PHA-022121 (N=8) and to matching placebo (N=2).
Accordingly, approximately 40 subjects will be enrolled in this study. Each
cohort must comprise of at least 3 female subjects .
Safety and PK data of the corresponding single dose from the SAD extension
study and the previous lower multiple dose will be available and submitted to
the Safety Monitoring Committee (SMC) and Ethics Committee (EC), which will
decide on predefined safety and PK decision criteria whether the next higher
multiple dose can be administered.
Intervention
PHA-022121 will be made available as an oral self-micro emulsifying drug
delivery system (SMEDDS) solution containing 50 mg/mL PHA-022121.
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.
Leiden Bio Science Park, J.H. Oortweg 21
Leiden 2333 CH
NL
Leiden Bio Science Park, J.H. Oortweg 21
Leiden 2333 CH
NL
Listed location countries
Age
Inclusion criteria
Healthy male and female subjects of non-childbearing potential
Between 18 and 65 years of age, inclusive.
Body Mass Index (BMI) between 18.0 and 30 kg/m2 (inclusive).
Healthy on the basis of physical examination, medical history, vital signs,
clinical laboratory tests, and 12-lead ECG performed at screening. If any of
the results are abnormal, the subject may be included only if the investigator
judges that the abnormalities or deviations from normal are not clinically
significant. This determination must be recorded in the subject's source
documents and initialled by the investigator.
A resting heart/pulse rate (supine position for 5 minutes) between 40 and 100
beats per minute (bpm). If heart/pulse rate is out of range, up to 2 repeated
assessments are permitted.
A resting blood pressure (supine position for 5 minutes) between 90 and 140
mmHg systolic, inclusive, and between 40 to 90 mmHg diastolic. If blood
pressure requirements are out of range, up to 2 repeated assessments are
permitted.
Exclusion criteria
Clinically relevant allergy (except for untreated, asymptomatic, seasonal
allergies at time of dosing) or drug hypersensitivity.
Known hypersensitivity to the drug substance, or any inactive ingredient(s) of
the investigational product (refer to investigator's Brochure).
History of any medical condition or prior surgery of the GI-tract that could
alter the absorption of orally administered drugs (does not apply to history of
appendectomy).
History or current evidence of any form of angioedema.
History or current evidence of any form of bronchial asthma.
History of postural disorders, i.e. labile blood pressure or symptomatic
orthostatic hypotension, faintings, or blackouts) and/or treatment requiring
hypotension
Design
Recruitment
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 | EUCTR2020-001533-12-NL |
| CCMO | NL73626.056.20 |