The purpose of the study is to investigate how quickly and to what extent ACT-132577 is absorbed, distributed, metabolized (broken down) and eliminated from the body (this is called pharmacokinetics). ACT-132577 to be administered will be labeled…
ID
Source
Brief title
Condition
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Clinically relevant change from baseline to each time point of measurement in
vital signs (supine blood pressure and pulse rate) after study treatment
administration.
- Clinically relevant change from baseline to each time point of measurement in
ECG variables: HR, and the intervals: PR, QRS, QT, RR, QTcB, and QTcF after
study treatment administration.
- Clinically relevant change from baseline to EOS in clinical laboratory tests
(clinical chemistry and hematology).
- Clinically relevant treatment-emergent ECG abnormalities from the study
treatment administration up to EOS.
- Treatment-emergent AEs from the study treatment administration up to EOS.
- Treatment-emergent SAEs from the study treatment administration up to EOS.
- Mass balance (Cumulative excretion of radioactivity in urine and feces.)
- PK of 14C-radioactivity in whole blood and plasma
- PK of ACT-132577 and its metabolites in plasma
- Metabolic profiling (Profiles, identification, and quantification of
metabolites in plasma, urine, and feces.)
Secondary outcome
Not applicable
Background summary
ACT-132577 is a new investigational compound that may eventually be used for
the treatment of high blood pressure that is hard to treat (also called
resistant hypertension). ACT-132577 is a metabolite of macitentan. Macitentan
is registered under the tradename Opsumit® as a drug to
treat pulmonary arterial hypertension (PAH) (high blood pressure in the
arteries of the lungs). In the body, macitentan is metabolized (broken down)
into ACT-132577. Macitentan and ACT-132577 are both active in the body. They
act by binding to certain proteins on the cells that form the inside of blood
vessels (the so-called endothelial cells).
ACT-132577 is in development and is not registered as a drug but has been given
to humans before.
Study objective
The purpose of the study is to investigate how quickly and to what extent
ACT-132577 is absorbed, distributed, metabolized (broken down) and eliminated
from the body (this is called pharmacokinetics). ACT-132577 to be administered
will be labeled with 14-Carbon (14C) and is
thus radioactive (also called radiolabeled). In this way ACT-132577 can be
traced in blood, urine and feces. It will also be investigated to what extent
ACT-132577 is safe and tolerated.
Study design
The actual study will consist of 1 period during which you will stay in the
clinical research center for 16 days (15 nights). You are expected at the
clinical research center at 14:00 h in the afternoon prior to the day of
administration of the study compound (Day -1; Day 1 is the day of
administration of study compound). You will leave the clinical research center
on Day 15.
You should take into account that it is possible that after your first 16-days
stay in the clinical research center you may have to return for at most 2
additional stays of 24 hours each. In this study this is called the extended
observation period. Whether you have to participate in the extended observation
period will depend on the amount of radioactivity that is still present in your
urine and feces at the end of your stay in the clinical research center (Day
15). On Day 15 it is determined whether enough radioactivity has been recovered
in urine and feces during the preceding 14 days. Also the amount of
radioactivity excreted in urine and feces during the preceding 2 days (Day 13
and Day 14) is determined. If on Day 15 one of these results does not meet the
predefined criteria, you will have to return on Day 18 (departure on Day 19)
for a 24-hour stay. If on Day 18 the amount of radioactivity excreted still
does not meet the predefined criteria, you will have to return again on Day 21
(departure on Day 22) for a 24-hour stay. You will be required not to have
consumed any food or drinks (with the exception of water) during the 6 hours
prior to arrival in the clinical research center on Day 18 and Day 21.
The post-study screening visit (the last time you will come to the clinical
research center) will take place 1 to 2 days after your last stay in the
clinical research center. You will be required not to have consumed any food or
drinks (with the exception of water) during the 6 hours prior to arrival in the
clinical research center. The appointment for the post-study screening visit
will be made as soon as it is known when the study will end for you.
You will be contacted by telephone for a last safety follow-up call, 30 to 32
days after administration of the investigational compound. During this phone
call you will be asked how you are feeling and if anything happened to you
since the post-study screening visit.
Intervention
The volunteer will receive a single dose of 25 mg/3.7 MBq radiolabeled
ACT-132577 as an oral capsule.
Study burden and risks
All drugs in development can potentially cause adverse effects; the extent to
which this occurs differs. In medical practice, humans are being exposed to
ACT-132577 as a metabolite of macitentan after administration of Opsumit®.
Opsumit® is an approved drug at a dose level of 10 mg once daily.
ACT-132577 itself has been given to 56 healthy volunteers in a previous
clinical study. In this study, ACT-132577 was given as single doses of 5, 25,
100, 300, and 600 mg and as multiple doses of 5, 25, and 100 mg once daily for
10 days. ACT-132577 was well tolerated in this study at all dose levels tested.
The most frequently reported adverse effects following a single dose were
headache, nausea, and a strong increase in heart rate upon standing up after
sitting or lying down (orthostatic tachycardia). The most frequently reported
adverse effect following multiple doses was headache. In addition, volunteers
that participated in the multiple dose part of the study reported sleepiness
(somnolence), nasal congestion, nausea, upper respiratory tract infection, rash
and a strong increase in heart rate upon standing up. All adverse effects were
mild to moderate in intensity (this is the degree of discomfort caused by these
adverse effects) and most had resolved by the end of the study visit.
In studies where rats and dogs were exposed to ACT-132577, the side effects
included findings in the heart (only dogs), liver (rats and dogs), kidney (dogs
only), nasal cavity (dogs only), and testes (rats and dogs). ACT-132577 belongs
to a class of drugs that has been associated with decreases in blood laboratory
parameters related to liver function and the amount of oxygen in the blood.
In this study radiolabeled ACT-132577 will be used. The amount of radioactivity
in this dose will be approximately 3.7 MBq (MBq = megaBecquerel, this is a unit
to express the amount of radioactivity in the study compound). The average
environmental background radiation burden in The Netherlands is approximately 2
mSv per year (mSv = milliSievert, this unit indicates the burden on the human
body; thus the effect on the human body of the amount of radioactivity
administered). The additional radiation burden in this study due to the
administration of approximately 3.7 MBq radiolabeled ACT-132577 is calculated
to be 0.17 mSv. This is approximately 9% of the average annual radiation
burden.
Gewerbestrasse 16
Allschwil CH-4123
CH
Gewerbestrasse 16
Allschwil CH-4123
CH
Listed location countries
Age
Inclusion criteria
- Healthy male volunteers
- 45-65 years, inclusive
- BMI: 18.0-28.0 kg / m2, inclusive
- SBP: 100-145 mmHg
- DBP: 50-90 mmHg
- HR: 45-90 bpm
Exclusion criteria
Suffering from hepatitis B, hepatitis C, cancer or HIV/AIDS. Treatment with another investigational drug within 3 months prior to screening or participation in more than 4 investigational drug studies within 1 year prior to screening. Loss of 250 mL or more of blood within 3 months prior to
screening. A radiation burden of > 0.1 milliSievert (mSv) and <= 1.0 mSv in the period of 1 year prior to screening; a radiation burden of >= 1.1 mSv and <= 2.0 mSv in the period of 2 years prior to screening, etc. (add 1 year per 1 mSv).
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 | EUCTR2016-004175-44-NL |
| CCMO | NL60698.056.17 |