The primary objectives are:- To investigate the safety and tolerability of JNJ-61393215 after multiple consecutive dose administrations;- To characterize the pharmacokinetics (PK) of JNJ-61393215 in plasma after multiple consecutive dose…
ID
Source
Brief title
Condition
- Anxiety disorders and symptoms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Safety and tolerability of JNJ-61393215 after multiple consecutive dose
administrations;
2. Pharmacokinetics (PK) of JNJ-61393215 in plasma after multiple consecutive
dose administrations;
3. The effect of JNJ-61393215 on subjective fear and anxiety symptoms elicited
by 35% CO2 double breath inhalation challenge.
Secondary outcome
1. Effect of JNJ-61393215 on physiological response on 35% CO2 double breath
inhalation challenge (i.e. changes in blood pressure and heart rate);
2. Effect of JNJ-61393215 on the startle potentiation in the unpredictable
shock condition during the fear potentiated startle test;
3. Effect of JNJ-61393215 on Alertness/Sedation Through the Bond & Lader Visual
Analogue Scale.
Background summary
JNJ-61393215 is a novel, selective, high affinity/potent orexin-1 receptor
(OX1R) antagonist and is a potential first in class therapy for the treatment
of anxiety and stress disorders. The role of OX1Rs in complex emotional
behavior is emerging. There is evidence for the overactivation of the OX1R
pathway in hyper-arousal states (for example panic attacks), and consequently a
selective OX1R antagonist might normalize overexcited networks without inducing
sedation.
Study objective
The primary objectives are:
- To investigate the safety and tolerability of JNJ-61393215 after multiple
consecutive dose administrations;
- To characterize the pharmacokinetics (PK) of JNJ-61393215 in plasma after
multiple consecutive dose administrations;
- To investigate if JNJ-61393215 decreases subjective fear and anxiety symptoms
elicited by a 35% CO2 double breath inhalation challenge.
The secondary objectives are:
- To investigate if JNJ-6139325 modulates the physiological responses elicited
by 35% CO2 double breath inhalation challenge (i.e, changes in blood pressure
and heart rate);
- To investigate if JNJ-61393215 decreases the startle potentiation in the
unpredictable shock condition during the fear potentiated startle test;
- To characterize the effect of JNJ-61393215 on alertness/sedation through the
Bond & Lader Visual Analogue Scale.
Study design
This study will be a multiple dose phase to establish the anxiolytic
pharmacodynamic (PD) properties of JNJ-61393215. For this purpose, a single CO2
inhalation challenge and the fear potentiated startle (FPS) paradigm will be
applied as pro-anxiogenic stimuli to investigate whether JNJ-61393215 decreases
the subjective fear response and the fear-potentiated startle response,
respectively. Two doses of JNJ-61393215 are tested; a high dose in the range of
45 to 90 mg and a low dose in the range of 15 to 30 mg.
Intervention
JNJ-613932, alprazolam or placebo.
Study burden and risks
This study is the first time in humans that multiple doses of JNJ-61393215 will
be administered.
This will be the second study with JNJ-61393215 in humans. Nonclinical data and
blinded clinical single dose data (study 61393215EDI1001) are available
supporting the administration of multiple doses of JNJ-61393215 to humans.
Healthy young male subjects who will receive no therapeutic benefits from study
participation will be enrolled in this study. These healthy male subjects will
be exposed to an investigational drug, early in clinical development. Women of
childbearing potential will not be included, as segment II studies have not
been performed yet.
Doses may only be escalated following thorough review of all relevant data
collected at lower dose levels. Subjects will be under constant supervision
while in the clinic. Subjects will be confined to the clinical until the
morning of Day 8, with ambulant visits on Days 9 and 10 for PK sampling.
At high JNJ-61393215 doses changes in coagulation parameters were detected
preclinically, as well as an increase in liver weight. Importantly, all
observed changes were reversible and can be monitored in the clinic. To address
these findings, coagulation and liver parameters will be monitored during all
parts of the study to identify potential risks early.
JNJ-61393215 is not genotoxic.
Potential subjects will be fully informed of the risks and requirements of the
study and, during the study, subjects will be given any new information that
may affect their decision to continue participation. They will be told that
their consent to participate in the study is voluntary and may be withdrawn at
any time with no reason given and without penalty or loss of benefits to which
they would otherwise be entitled. Only subjects who are fully able to
understand the risks, benefits, and potential adverse events of the study, and
provide their consent voluntarily will be enrolled.
The total blood volume to be collected will not exceed 450 mL, which is
considered to be safe and acceptable in comparison to a Red Cross blood
donation.
The acute inhalation of CO2 has been developed, validated and technically
innovated over the past years as a reliable challenge model to induce an acute
panic reaction that adequately resembles PAs. CO2 and O2 are harmless
physiological substances that are inhaled according to a standardized challenge
protocol that has been developed by Maastricht University. Numerous studies in
several hundred healthy volunteers and patients suffering from panic disorder,
social anxiety disorder, post-traumatic stress disorder and major depressive
disorder have been conducted according to this protocol over the past 30 years.
In the majority of these studies, a mixture of 35% CO2/65% O2 had been
administered as either single or double vital capacity inhalation. In all
performed studies neither acute nor chronic adverse events have been reported.
Also, no serious adverse events have occurred. To guarantee identical
safeguards for the current study, the same absolute and relative
contra-indications will be maintained and are incorporated into the in- and
exclusion criteria of the protocol.
Maastricht Instruments in collaboration with Maastricht University has recently
developed the CO2 tolerance tester (CTT). The CTT is a research instrument that
safely and reliably induces PA*s by the protocolized administration of inhaled
35% CO2. In addition, the CTT simultaneously measures physiological changes
associated with CO2-induced ANS activation such has heart rate and blood
pressure. In contrast to previous experimental CO2 set ups, the CTT yields
integrated real time information on ANS panic-related parameters following
acute CO2 inhalation which can be readily combined with subjective assessments
such as fear intensity. The CTT is particularly relevant to research in the
field fear-related psychiatric disorders and is a potentially useful tool in
CNS drug development with novel anxiolytic compounds.
The Fear Potentiated Startle is a completely safe method in use for over
numerous years in research. Volunteers are subjected to loud noises (120 dB for
50 ms). Due to the restricted time frame, no hearing damage is expected. The
applied shocks are a nuisance, but not painful.
Turnhoutseweg 30
Beerse 2340
BE
Turnhoutseweg 30
Beerse 2340
BE
Listed location countries
Age
Inclusion criteria
1. Healthy male subjects between 18 and 55 years of age, inclusive.;2. Subjects must have a body mass index (BMI) between 18.0 and 30.0 kg/m2, inclusive
(BMI = weight/height2).;3. Subject must be healthy on the basis of physical examination, medical history, vital signs, and 12-lead ECG [incl. QTcF <= 450 msec for males and <= 470 msec for females] performed at screening and admission to the clinical unit. Minor abnormalities in ECG, which are not considered to be of clinical significance by the investigator, are acceptable. The presence of Left Bundle Branch Block (LBBB), AV Block (second degree or higher), or a permanent pacemaker or implantable cardioverter defibrillator [ICD] will lead to exclusion.;4. Subjects must be healthy on the basis of clinical laboratory tests performed at screening.
If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the investigator.;5. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of contraception e.g., either condom with spermicidal foam/gel/film/cream/suppository during the study and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study drug. All men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug. In addition, their female partner should also use a highly effective method of contraception for at least the same duration. Examples of highly effective contraceptives include implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); vasectomized partner; sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.), combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable.;6. Subjects must be willing to adhere to the prohibitions and restrictions specified in this protocol.;7. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study.;Specific exclusion criteria Part 2:
- Healthy male and female subjects of non-childbearing potential between 18 and 55 years of age, inclusive.;- Before randomization, female subjects must be of non-childbearing potential, 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 (>40 IU/L or mIU/mL) in the postmenopausal range may be used to confirm a postmenopausal state in women 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.;- Subjects must show sensitivity to a 35% CO2 double breath inhalation challenge at screening or within 12 weeks prior to study drug administration, which is defined as a change in PSL-IV score >=4 with at least 1-point increase for at least 4 of the symptoms specified in the PSL-IV and an increase of at least 25mm on the VAS for anxiety related symptoms.
Exclusion criteria
1. Subject has a history of or current liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances, any inflammatory illness or any other illness, though minor deviations, which are not considered to be of clinical significance to both the investigator and to the Janssen Safety Responsible Physician, are acceptable.;2.1 Current or past history of any psychiatric disorder as classified according to DSM-IV or DSM-V.;3.1 Subject has any liver function test (including ALT, AST, gGT, ALP and bilirubin) at screening exceeding 1.5 times the upper limit of normal.;4. Subject has estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 at screening (provided by the local laboratory).;5. Subject has a heart rate < 50 bpm or > 100 bpm or systolic blood pressure >= 150 mmHg at screening or at admission to the clinical unit.;Specific exclusion criteria Part 2:
- Contraindications to the use of alprazolam per local prescribing information.;- Subject has a personal or family history of sickle cell anaemia.;- Subject has a history of benzodiazepines abuse and/or dependence.;- Subject has a significant cardiovascular history, or suspicion of infarct, cardiomyopathy, cardiac failure, transient ischaemic attack, angina pectoris, cardiac arrhythmias, cerebrovascular accident.;- Subject has a history of significant respiratory conditions, including asthma, lung fibrosis and non-invalidating Chronic Obstructive Pulmonary Disease.;- Subject has a personal or familial history of cerebral aneurysm.;- Subject has hypertension (i.e. systolic pressure >180 and/or diastolic pressure >100mmHg).;- Subject has epilepsy.
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 | EUCTR2016-003894-16-NL |
| ClinicalTrials.gov | NCT03007693 |
| CCMO | NL59843.056.16 |