The main purpose of this study is to investigate the effect of multiple doses of PHA-022121 on how quickly and to what extent a drug cocktail (a combination of agents consisting of caffeine, omeprazole, and midazolam) is absorbed, distributed,…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to determine the potential
inhibitory/inducing effects of multiple doses of PHA 022121 on the single-dose
pharmacokinetics (PK) of a cocktail, containing selective probe substrates of
cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C19 and CYP3A4) in healthy adult
subjects.
Secondary outcome
The secondary objectives of this study are to evaluate the safety and
tolerability of PHA 022121 after multiple doses in the presence of a drug
cocktail in healthy adult subjects and to assess steady-state PK of PHA-022121
and its active metabolite M2-D in the presence of a drug cocktail in healthy
adult subjects.
Background summary
PHA-022121 is a new compound that may potentially be used for the treatment of
hereditary angioedema. With this disease, swellings occur (called edema), 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.
Study objective
The main purpose of this study is to investigate the effect of multiple doses
of PHA-022121 on how quickly and to what extent a drug cocktail (a combination
of agents consisting of caffeine, omeprazole, and midazolam) is absorbed,
distributed, metabolized and eliminated from the body.
It will also be investigated how safe PHA-022121 is and how well it is
tolerated after multiple doses in the presence of the drug cocktail.
Furthermore, the effect of the genetic information on the body*s response to
PHA-022121 will be investigated. This part of the study is mandatory.
PHA-022121 has been administered to humans before. Caffeine, omeprazole, and
midazolam are already available on the market in several dosages and
formulations.
This study will be performed in 14 healthy male and female volunteers.
Study design
The actual study will consist of 1 period during which the volunteers will stay
in the research center for 15 days (14 nights). Day 1 is the first day of
administration of the study compound. They are expected at the research center
at 14:00 h in the afternoon prior to the day of first administration of the
study compound. The time of entry may be changed. If this happens the
volunteers will be informed about it in advance. They will leave the research
center on Day 14 of the study.
On Day 1, the drug cocktail will be given as an oral tablet of caffeine, an
oral capsule of omeprazole, and an oral solution of midazolam together with 240
mL of non-carbonated water, after an overnight fast of at least 10 hours.
On Day 3 until Day 12, PHA-022121 will be given twice daily as oral capsules
with 240 mL of non-carbonated water, 0.5 hours after finishing a standard meal
(Day 4 until Day 11) or after an overnight fast (in the morning of Day 3 and
Day 12) as explained above.
On the morning of Day 3 and Day 12, a combination of PHA-022121 and drug
cocktail will be given. PHA-022121 will be given first with 120 mL of
non-carbonated water and 30 minutes later, the drug cocktail will be given with
120 mL of non-carbonated water. The study compounds will be given after an
overnight fast of at least 10 hours.
Intervention
Day Treatment How often
1 drug cocktail consisting of 50 mg caffeine, 10 mg omeprazole, and 1 mg
midazolam once
3 20 mg PHA-022121 twice daily
drug cocktail consisting of 50 mg caffeine, 10 mg omeprazole, and 1 mg
midazolam once
(30 minutes after PHA-022121)
4 to 11 20 mg PHA-022121 twice daily
12 20 mg PHA-022121 twice daily
drug cocktail consisting of 50 mg caffeine, 10 mg omeprazole, and 1 mg
midazolam once
(30 minutes after PHA-022121)
Study burden and risks
The study compound may cause side effects.
The following side effects are most commonly observed:
• Sore throat/throat irritation
• Dizziness when standing
• Nausea
• Dry skin
• Diarrhea
• Abdominal pain
The study compound may also have (serious) side effects that are still unknown.
In addition to unknown side effects, 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 volunteers about this.
Possible discomforts due to procedures
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising.
In total, we will take about 350 milliliters of blood from the volunteer. This
amount does not cause any problems in adults. To compare: a blood donation
involves 500 mL of blood being taken each time. Based on the discretion of the
responsible doctor, extra samples might be taken to guarantee the safety of the
participants. If this happens, the total amount of blood drawn will be more
than this.
To make a heart tracing, electrodes will be pasted at specific locations on the
arms, chest and legs. Prolonged use of these electrodes can cause skin
irritation.
Samples for the coronavirus test will be taken from the back of your nose and
throat using swabs. Taking the samples only takes a few seconds, but can cause
discomfort and can give an unpleasant feeling. Taking a sample from the back of
your throat may cause the volunteer to gag. When the sample is taken from the
back of the nose, the volunteer may experience a stinging sensation and the
eyes may become watery.
J.H. Oortweg 21
Leiden 2333 CH
NL
J.H. Oortweg 21
Leiden 2333 CH
NL
Listed location countries
Age
Inclusion criteria
1. Subject must be a healthy male or female subject, between 18 to 65 years of
age, extremes included, at screening.
2. Subject must have a body mass index (BMI; weight in kg divided by the square
of height
in meters) 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 or she understands the purpose
of the study including the procedures required, and is willing to participate
in the study, including that he /she 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 , intra-uterine device) 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 until 90 days after receiving the last study
drug administration.
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/1.73m2 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 National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) version 4. 14, 2010 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 below LLN ( reference of site applies for male and female,
respectively) lowering grad 1 or greater (<=6.5 mmol ; <=109 g/L );
- Platelet count below LLN ;
- Absolute neutrophil count lowering grade 1 or greater (<=1,5 109/L );
- 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 total
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.
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 | EUCTR202000413038-NL |
| CCMO | NL75390.056.20 |