The purpose of this study is to investigate the effect of multiple doses of itraconazole on how quickly and to what extent the new compound PHA-022121 is absorbed into the body and eliminated from the body (this is called pharmacokinetics). It will…
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
The primary PK parameters are Cmax, AUClast, and AUC* of the PHA-022121. All
parameters will be analyzed on a logarithmic scale. AUC* will be rejected as
primary parameter for a treatment if more than half of the subjects do not have
a reliable value for that treatment.
Secondary outcome
NA
Background summary
PHA-022121 is a new compound that may potentially be used for the treatment of
hereditary angioedema. With this disease, swellings occur, most commonly in the
limbs, the face (lips and tongue), the intestinal tract, the area of the
abdomen near the urinary and genital openings, and the airways. These swellings
often lead to discomfort, pain, and nausea, and can become life threatening in
case of airway blockade. It is estimated that hereditary angioedema affects on
average 1 in every 50,000 people. PHA-022121 is able to influence a certain
receptor, called bradykinin B2, and thereby has the ability to treat hereditary
angioedema.
PHA-022121 is broken down by certain enzymes, among others by CYP3A4.
Itraconazole (a medicine against fungi and yeast) is a strong inhibitor of the
enzyme CYP3A4, and may thus have an impact on how long PHA-022121 stays in the
body. Research into the effect of itraconazole on PHA-022121 is therefore
needed.
Study objective
The purpose of this study is to investigate the effect of multiple doses of
itraconazole on how quickly and to what extent the new compound PHA-022121 is
absorbed into the body and eliminated from the body (this is called
pharmacokinetics). It will also be investigated how safe PHA-022121 is and how
well it is tolerated when it is administered to healthy volunteers. PHA-022121
has been administered to humans before. It has furthermore been previously
tested in the laboratory and on animals. Itraconazole is not a new compound; it
is already more than 30 years available on the market as antifungal medication.
This study will be performed in 14 healthy male and female volunteers.
Study design
The study will consist of 1 period during which the volunteer will stay in the
research center for 10 days (9 nights). The volunteer will then return to the
research center for 1 day for a follow-up visit.
Day 1 is the first day of administration of the study compound. The volunteer
is expected at the research center at 2:00 PM in the afternoon prior to the day
of first administration of the study compound, so on Day -1. The volunteer will
leave the research center on Day 9 of the study.
Intervention
PHA-022121 will be given twice as a solution via the mouth using a syringe.
Then the volunteer will be given 240 milliliter (mL) of water which the
volunteer should drink. Itraconazole will be given 7 times as a solution via
the mouth, together with 120 or 240 mL of water. The planned treatments for the
study are as follows:
Day Treatment How often
1 12 mg PHA-022121 Once
2 - -
3 200 mg (20 mL) itraconazole Twice
4 to 6 200 mg (20 mL) itraconazole Once daily
7 12 mg PHA-022121
200 mg (20 mL) itraconazole Once
Once
8 200 mg (20 mL) itraconazole Once
When the volunteer receives both PHA 022121 and itraconazole (Day 7), the
volunteer will first receive itraconazole. One hour later, the volunteer will
receive a breakfast. Half an hour after the volunteer finished the breakfast,
the volunteer will receive PHA-022121.
One of the investigators will inspect the volunteers hands and mouth after each
study compound intake.
Study burden and risks
The study compound may cause side effects.
PHA-022121 has been studied extensively in the laboratory and in animals.
PHA-022121 has furthermore been administered to humans in 1 completed clinical
trial. In total, 52 volunteers have received single doses up to 22 mg of
PHA-022121. Overall, PHA-022121 was considered safe and well tolerated. In this
study, the reported side effects which were considered related to the study
compound were: stomach cramps (once) and nausea (once).
Based on the way PHA-022121 is working, the following side effects may occur:
increased blood pressure, reduced heart rate, and worsening of blood supply.
Side effects of icatibant (another medication that influences the receptor
bradykinin B2) which could potentially also occur for PHA-022121, include:
dizziness, headache, nausea, rash, redness of the skin, itching, fever, and
increased enzymes involved in the production of amino acids.
The study compound may also have side effects that are still unknown. In
addition to unknown side effect, there is a (small) chance that an allergic
reaction will occur. This can be caused by the study compound or the
excipients.
If during the study more information becomes available regarding side effects
that may be related to the study compound, the responsible doctor will inform
the volunteer about this.
J.H. Oortweg 21
Leiden 2300 CH
NL
J.H. Oortweg 21
Leiden 2300 CH
NL
Listed location countries
Age
Inclusion criteria
1. Subject must be a healthy male or female subject, between 18 to 60 years of
age, extremes included, at screening.
2. Subject must have a body mass index between 18.0 and 30.0 kg/m2, extremes
included, and a body weight not less than 50.0 kg, inclusive, at screening.
3. Subject must sign an ICF indicating that he understands the purpose of the
study including the procedures required, and is willing to participate in the
study, including that he agrees to provide DNA samples for research, before
starting of any screening activities.
4. During the study and for a minimum of 1 spermatogenesis cycle (defined as
approximately 90 days) after receiving the last dose of study drug, a male
subject: - who is sexually active with a woman of child-bearing potential and
has not had a vasectomy, must agree to use a barrier method of contraception
(eg, condom or partner with occlusive cap [diaphragm or cervical/vault caps]).
In addition, their female partner should also use a highly effective method of
birth control (eg, hormonal contraception) for at least the same duration. -
Who is sexually active with a woman who is pregnant must use a condom. - Must
agree not to donate sperm.
5. A female subject must be of non-childbearing potential at screening, defined
as: - Postmenopausal. A postmenopausal state is defined as no menses for 12
months without an alternative medical cause. A high follicle stimulating
hormone (FSH) level at screening (>33.4 IU/L ) in the postmenopausal range may
be used to confirm a postmenopausal state in woman not using hormonal
contraception or hormonal replacement therapy, however in the absence of 12
months of amenorrhea, a single FSH measurement is insufficient. - Permanently
sterile. Permanent sterilization methods include hysterectomy, bilateral
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral
oophorectomy.
Exclusion criteria
1. Subject has a history of current clinically significant medical illness
including (but not limited to) cardiac arrhythmias or other cardiac disease,
hematologic disease, lipid abnormalities, significant pulmonary disease,
including bronchospastic respiratory disease, diabetes mellitus, hepatic or
renal insufficiency (estimated creatinine clearance <90 mL/min at screening,
calculated by MDRD formula), thyroid disease, neurologic or psychiatric
disease, infection, or any other illness, that in the investigator*s and/or
sponsor*s medical monitor opinion should exclude the subject or that could
interfere with the interpretation of the study results.
2. Subject has one of the following laboratory abnormalities at screening as
defined by the World Health Organization (WHO) Toxicity Grade Scale and in
accordance with the normal ranges of the clinical laboratory if no gradings are
available. - Serum creatinine elevation grade 1 or greater (>1.1 x upper limit
of normal range [ULN])- Hemoglobin lowering grade 1 or greater (<=6.5 mmol ;
<=109 g/L); - Platelet count below LLN; - Absolute neutrophil count lowering
grade 1 or greater (<=1,5 109/ ); - Aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) >= ULN; - Total bilirubin >= ULN; - Any other toxicity
grade 2 or above, except for grade 2 elevations for triglycerides, low density
lipoprotein (LDL) cholesterol and/or cholesterol.
3. Clinically significant abnormal values for hematology, clinical chemistry or
urinalysis at screening or at admission to the clinical site on Day -1 as
deemed appropriate by the investigator.
4. Subject has a positive test of human immunodeficiency virus (HIV) 1 and 2
antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C antibodies.
5. Subject has a history of heart arrhythmias, tachycardia at rest, or history
of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family
history of long QT syndrome).
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 | EUCTR2019-005001-49-NL |
CCMO | NL72719.056.20 |