| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anxiety disorders and depression |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057666 |
| E.1.2 | Term | Anxiety disorder |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether R317573, after multiple dosing over one week in healthy male or female subjects, reduces the intensity of anxiety symptoms induced by breathing air with 7.5% carbon dioxide (CO2) over 20 minutes. |
|
| E.2.2 | Secondary objectives of the trial |
1) To assess the influence of R317573 on CO2 induced changes in blood pressure, heart rate, and adrenocorticotrophic hormone (ACTH)-, vasopressin (AVP)- and cortisol plasma concentrations.
2) To assess the safety and tolerability of multiple oral doses of R317573 in healthy male or female subjects.
3) To assess the effect of a single oral dose of lorazepam (2 mg) on the intensity of anxiety symptoms induced by breathing air with 7.5% CO2 over 20 minutes, as a reference active control.
4) To assess potential relationships between the R317573 pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects, safety and tolerability of R317573.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Healthy males and females
2) Age between 18 and 45 years, inclusive
3) BMI between 18 and 28 kg/m2 inclusive (BMI = weight/height2).
4) For males: Willingness to use an adequate contraception for the duration of the study and for 3 months thereafter.
5) Female subjects must be postmenopausal (for at least 12 months), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study; have a negative urine pregnancy test at screening and at Day 1.
6) A positive response to a 20 minutes CO2 inhalation defined as a score greater than or equal to 2 in at least one of the items: fear of loss of control; anxiety; fear of dying; apprehension/fear in the PSI and/or a score of greater than or equal to 1 of at least 8 of the 34 symptoms in the PSI taken just after the inhalation to assess peak effect.
7) Non-smoker or smokes < 5 cigarettes per day.
8) No abuse of alcohol defined as an average intake of greater than 21 units per week or 3 units per day. One unit is equivalent to a half pint of beer or 1 measure of spirits or 1 glass of wine.
9) Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
10) In order to participate in the pharmacogenomic component, subjects must have signed the informed consent for DNA research indicating whether they do or do not wish to participate in the DNA component of the study (where local regulations permit).
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| E.4 | Principal exclusion criteria |
1) Having cardiovascular disease or a history of cardiovascular disease.
2) Having (a history of) migraine or frequent headache.
3) Having attacks of hyperventilation.
4) Clinically significant abnormal values in TSH measured during the screening period. It is expected that the values will generally be within the normal range for the laboratory, though minor deviations, which are not considered to be of clinical significance, are acceptable.
5) Clinically significant abnormal values for hematology, clinical chemistry or urinalysis. It is expected that laboratory values will generally be within the normal range for the laboratory, though minor deviations, which are not considered to be of clinical significance to both the investigator and to the J&JPRD Safety Physician, are acceptable.
6) Clinically significant abnormal physical examination, vital signs or 12-lead ECG at screening or admission.
7) History of or current significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematological disease, lipid abnormalities, bronchospastic respiratory disease, diabetes mellitus, renal or hepatic insufficiency, thyroid disease, infection, or any other illness that the Investigator considers should exclude the subject.
8) A history or presence of neurological or psychiatric conditions (e.g. stroke, traumatic brain injury, epilepsy, space occupying lesions, multiple sclerosis, Parkinson’s disease, vascular dementia, transient ischemic attack, schizophrenia, major depression, generalized anxiety disorder, panic attacks, claustrophobia or severe anxiety etc.). Psychiatric illness will be assessed by a neuropsychiatric interview and the medical history.
9) Needle or blood phobia.
10) Positive urine screen for drugs of abuse (opiates, barbiturates, cannabis, benzodiazepines, cocaine, amphetamines).
11) A positive alcohol breath test.
12) Serology positive for hepatitis B surface antigen, hepatitis C antibodies or HIV antibodies 1 and 2.
13) Drinks, on average, more than 8 cups of tea/coffee/cocoa/cola per day.
14) Clinically significant acute illness within 7 days prior to first study drug administration.
15) History of relevant drug and/or food allergies.
16) Any treatment with corticosteroids either depot or orally within a month first study drug administration.
17) Donation of 1 or more units (approximately 450 mL) of blood or acute loss of an equivalent amount of blood within 90 days prior to study drug administration.
18) Exposure to any new investigational agent within 90 days prior to the study drug administration.
19) Use of any prescription or over-the-counter medication, herbal medication, vitamins, or mineral supplements within 14 days prior to study drug administration (not including paracetamol). Corticosteroids within 1 month and contraceptives and stable hormone replacement therapy (HRT) are allowed.
20) Psychological and/or emotional problems, which would render the informed consent invalid, or limit the ability of the subject to comply with the study requirements.
21) Any condition that in the opinion of the investigator would complicate or compromise the study, or the well being of the subject.
22) Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy of the CRF-1 receptor antagonist R317573 on CO2 induced anxiety. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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