Primary Part 1: To investigate the effect of multiple oral doses of rifampicin on the pharmacokinetics (PK) of a single oral dose of RO7017773 in healthy participants.Part 2: To investigate the effect of multiple oral doses of gemfibrozil on the PK…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Autism Spectrum Disorder
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1 and Part 2:
RO7017773 plasma concentrations and RO7017773 PK parameters.
Secondary outcome
Part 1 and 2:
•Incidence and severity of adverse events (AEs).
•Changes in vital signs, physical findings, electrocardiogram (ECG) parameters,
and clinical laboratory results during and after RO7017773 administration alone
and in combination with rifampicin (Part 1) or gemfibrozil (Part 2).
Part 1:
Concentrations and PK parameters for rifampicin.
Part 2:
Concentrations and PK parameters for gemfibrozil and its metabolite
(gemfibrozil 1-O-β-glucuronide).
Background summary
RO7017773 is a new compound that may potentially be used for the treatment of
Autism Spectrum Disorder (ASD). Autism Spectrum Disorders refer to a range of
developmental conditions that affect the way that people think, feel, and
behave. Patients with ASD have challenges with communication and speech, social
skills, and repetitive or unusual behavior. In addition to these challenges,
patients suffer from a range of other limitations, such as irritability,
depression or anxiety, issues with attention (i.e., inability to concentrate
for longer periods of time), seizures, and sleep disturbances.
It is not certain what causes ASD or its symptoms, but it has been linked to
changes in levels of substances that carry messages in the brain, of a natural
brain chemical, known as GABA (gamma-aminobutyric acid). GABA is a
neurotransmitter, an agent which transmits messages from one brain cell
(neuron) to another. RO7017773 increases the activity in the brain of GABA by
binding to specific sites in the brain known as gamma-aminobutyric acid type A
(GABAA) alpha (α) 5 receptors. Enhancing the GABA activity could result in
reducing excitatory messaging in the brain: it tells the neurons that it
contacts to slow down or stop firing, which is thought to be beneficial in ASD.
Rifampicin is an antibiotic for the treatment of tuberculosis and gemfibrozil
is a medication for the treatment of dyslipidemia. Both compounds are often
used to investigate interactions between drugs as they influence important
breakdown processes.
Study objective
Primary
Part 1: To investigate the effect of multiple oral doses of rifampicin on the
pharmacokinetics (PK) of a single oral dose of RO7017773 in healthy
participants.
Part 2: To investigate the effect of multiple oral doses of gemfibrozil on the
PK of a single oral dose of RO7017773 in healthy participants.
Secondary
Part 1 and 2: To assess the safety and tolerability of a single oral dose of
RO7017773 alone and in combination with multiple doses of rifampicin (Part 1)
or gemfibrozil (Part 2) in healthy participants.
Part 1: To assess the PK of rifampicin following multiple oral doses of
rifampicin alone and in combination with a single oral dose of RO7017773 to
ensure adequate CYP3A induction.
Part 2: To assess the PK of gemfibrozil following multiple oral doses of
gemfibrozil alone and in combination with a single oral dose of RO7017773 to
ensure adequate CYP2C8 inhibition.
Study design
Volunteers participation from screening until the follow-up visit will last
about 11 weeks.
The actual study will consist of 2 periods during which the volunteer will stay
in the research center for 9 days (8 nights) (Period 1) and 14 days (13 nights)
(Period 2).
Day 1 is the first day of administration of the study compound. In Period 1,
the volunteer will be expected to arrive at the research center at 14:00h , 2
days prior to the day of first administration of the study compound. Volunteer
will leave the research center on Day 7 of Period 1. There are 10 to 14 days
between Day 1 of Period 1 and Day 1 of Period 2. In Period 2, the volunteer
will be expected to arrive at 14:00 h prior to the day of administration of
rifampicin (part 1) or gemfibrozil (part 2). The volunteer will be allowed to
leave the research center on Day 13 of Period 2.
Volunteer will be tested for the presence of coronavirus upon admission to the
research center. Until the test results are available, volunteer will be
separated from other participants and only have very limited contact with study
staff. This is to avoid virus spread from potentially infected participants to
other participants or to the study staff because, until the results are
available, it is not certain whether volunteer is infected or not and can thus
potentially infect others. The test results will be available within one hour.
If volunteer test positive for coronavirus, he/she cannot participate in the
study.
Each period, when volunteer enter the research center, two samples will be
collected at the same time to test if volunteer is a carrier of SARS-CoV-2.
This test will be repeated on the day after dosing and at follow-up. It may be
decided that more tests are needed (eg, if volunteer has COVID-19 symptoms).
Intervention
Part 1:
RO7017773 will be given as oral tablets with 240 milliliters (mL) of water.
Rifampicin will be given as oral capsules with 240 mL of water.
The planned treatments are as follows:
Day Treatment
How How often
Day 1, Period 1 RO7017773 180 mg oral tablets once
Day 1 to Day 11, Period 2 Rifampicin 600 mg oral capsules once daily
Day 8, Period 2 RO7017773 180 mg oral tablets once
RO7017773 and rifampicin will be administered after volunteer has fasted for at
least 10 hours. One of the investigators will inspect volunteers hands and
mouth after the study compound intake. Four hours after administration of
RO7017773, on Day 1 of Period 1 and on Day 8 of Period 2 volunteer will be
given a lunch.
Part 2:
RO7017773 will be given as oral tablets with 240 milliliters (mL) of water.
Gemfibrozil will be given as oral tablets with 240 mL of water
The planned treatments are as follows:
Day Treatment
How How often
Day 1, Period 1 RO7017773 60 mg oral tablets once
Day 1 to Day 10, Period 2 Gemfibrozil 600 mg oral tablets twice
daily
Day 5, Period 2 RO7017773 60 mg oral tablets once
RO7017773 will be administered with water in the morning 30 minutes after
starting a standardized breakfast. This breakfast should be consumed within 30
minutes or less. Gemfibrozil will be administered in the morning and evening
approximately 30 minutes before starting a meal.
Study burden and risks
RO7017773 has been studied extensively in the laboratory and in animals.
Furthermore, RO7017773 has been administered to humans in 4 completed medical
trials. In total, 126 volunteers have received RO7017773 in single doses up to
375 mg or multiple doses up to 200 mg for up to 7 or 14 days. In these studies,
the most frequently reported side effects by more than 1 volunteer across the
dose levels which were related to the study compound were: somnolence (feeling
sleepy), headache, fatigue (feeling tired), sudden onset of sleep, nausea,
dizziness and dizziness postural, myalgia, disturbance in attention, feeling
cold, neck pain, back pain, abnormal dreams, depressed mood, and hepatic enzyme
increased. These side effects were mainly mild in intensity with the exception
of one moderate event of headache, one moderate event of somnolence and one
moderate event of hypotension. For the side effect of somnolence (feeling
sleepy), the majority started within less than one hour and up to 6.5 hours
after dosing, and resolved within 24 hours. A single dose of 375 mg RO7017773
was not well tolerated by 1 participant who received this dose with drowsiness
(severe), nausea (moderate) and fasciculation (muscle twitch; moderate).
Overall, RO7017773 was safe and well tolerated.
In the study with healthy participants treated with multiple doses of 20 and 50
mg RO7017773, mild increases of liver test values were observed in 2 out of the
8 participants in each dose group. These elevations of liver tests were not
observed in groups at higher doses (100 mg and 200 mg). Participants did not
experience any associated signs or symptoms and the liver function was not
changed. The affected liver enzymes slowly returned to normal values within 20
days after the study. This means that there is no irreversible damage to the
liver. It is not clearly proven that the increase of the liver enzymes was
caused by RO7017773. Nonetheless, the liver enzymes will be monitored.
The study compound may also have 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.
Available data from studies in humans do not show is a risk for side effects
concerning the gastrointestinal tract; however volunteer should inform the
study doctor if volunteer experience any gastrointestinal events during the
study.
An ECG change (prolongation of the QT interval) which could cause an abnormal
heart rhythm has also been seen in the study with one or multiple doses of
RO7017773. Volunteers ECG recordings will be monitored during the study.
The volunteer will receive a package leaflet for information about rifampicin
or gemfibrozil.
Drawing blood and/or insertion of the indwelling cannula (tube in an arm vein)
may be painful or cause some bruising.
In total, about 180 milliliters (mL) of blood will be collected. 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 (small, plastic patches) will be pasted at
specific locations on the arms, chest and legs. To monitor the heart rate,
electrodes (small, plastic patches) will be pasted at specific locations on the
chest and abdomen. Prolonged use of these electrodes can cause skin irritation
(rash and itching).
A sample for the coronavirus test will be taken from the back of the nose and
throat using a swab. Taking the sample only takes a few seconds, but can cause
discomfort and can give an unpleasant feeling. Taking a sample from the back of
the throat may cause volunteer to gag. When the sample is taken from the back
of the nose, volunteer may experience a stinging sensation and the eyes may
become watery.
Grenzacherstrasse 124
Basel 4070
CH
Grenzacherstrasse 124
Basel 4070
CH
Listed location countries
Age
Inclusion criteria
1. Able and willing to provide written informed consent and to comply with the
study protocol according to International Conference on Harmonisation Good
Clinical Practice (ICH-GCP) and local regulations.
2. Participant must be 18 to 54 years of age inclusive, at the time of signing
the ICF.
3. Healthy, as judged by the Investigator. Healthy status will be defined as
the absence of evidence of any active or chronic disease following a detailed
medical and surgical history, a complete physical examination, vital signs,
12-lead ECG, hematology, blood chemistry, serology, and urinalysis.
4. Body mass index (BMI) within the range 18 to 30 kg/m2 (inclusive at
Screening).
5. Male and female participants
•In Part 1: only male participants
•In Part 2: male and female participants
The contraception is intended to prevent exposure of an embryo to the study
treatment. Total abstinence, in accordance with the lifestyle of the
participant, is also acceptable.
The reliability of sexual abstinence for male and/or female enrollment
eligibility needs to be evaluated in relation to the duration of the clinical
study and the preferred and usual lifestyle of the participant. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation
methods) and withdrawal are not acceptable methods of preventing drug exposure.
a) Female participants (Part 2 only)
A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
• Women of non childbearing potential (WONCBP).
Women are considered to be of non-child bearing potential if postmenopausal at
least 12 months of amenorrhea and confirmed by follicle-stimulating hormone
(FSH), or surgically sterile (absence of ovaries and/or uterus; has undergone
bilateral tubal ligation).
• Women of childbearing potential (WOCBP)
Women of childbearing potential must agree to use one highly effective
contraceptive method that result in a failure rate of <1% per year from
screening until 90 days after the last dose of study drug (see Appendix 5 of de
protocol).
b) Male participants
During the treatment period and for at least 90 days after the last dose of
study drug, agreement to:
• Remain abstinent (refrain from heterosexual intercourse) or use a condom with
a female partner of childbearing potential (WOCBP), or pregnant female partner,
to avoid exposing the embryo.
• Refrain from donating sperm for at least 90 days after last dose.
Exclusion criteria
1. Any condition or disease detected during the medical interview/physical
examination that would render the participant unsuitable for the study, place
the participant at undue risk or interfere with the ability of the participant
to complete the study, as determined by the Investigator.
2. History or evidence of any medical condition potentially altering the
absorption, metabolism, or elimination of drugs. This includes a surgical
history of the gastrointestinal tract affecting gastric motility or altering
the gastrointestinal tract.
3. History of any clinically significant gastrointestinal, renal, hepatic,
bronchopulmonary, neurological, psychiatric, cardiovascular, endocrinological,
hematological, or allergic disease, metabolic disorder, cancer, or cirrhosis.
4. Use of any psychoactive medication, or medications known to have effects on
the central nervous system (CNS) or blood flow taken within 4 weeks prior to
first dosing (or within 5 times the elimination half-life of the medication
prior to first dosing, whichever is longer).
5. History of convulsions (other than benign febrile convulsions of childhood)
including epilepsy, or personal history of significant cerebral trauma or CNS
infections (e.g. meningitis).
Further criteria apply.
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 | EUCTR2020-000943-30-NL |
| CCMO | NL73779.056.20 |