A Double Blind, Placebo- and Active-Controlled, Randomized, Sequential Group, Multiple Dose Study to Examine the Effect of the CRF1-Receptor Antagonist R317573 on 7.5% CO2-Inhalation Induced Anxiety in Healthy Subjects

INTERVENTION: Product Name: R317573 10mg Product Code: F008 Pharmaceutical Form: Tablet INN or Proposed INN: N/A CAS Number: 724471‐25‐4 Current Sponsor code: R317573, JNJ‐19567470 Other descriptive name: Please see IB for compound name Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Product Name: R317573 50mg Product Code: F007 Pharmaceutical Form: Tablet INN or Proposed INN: N/A CAS Number: 724471‐25‐4 Current Sponsor code: R317573, JNJ‐19567470 Other descriptive name: Please see IB for compound name Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Trade Name: Temesta 1mg Product Name: N/A Product Code: F320 Pharmaceutical Form: Capsule* INN or Proposed INN: N/A CAS Number: N/A Current Sponsor code: N/A Other descriptive name: N/A Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 2‐ Pharmaceutical form of the placebo: Capsule* Route of administration of the placebo: Oral use CONDITION: Anxiety disorders and depression ; MedDRA version: 8.1 Level: LLT Classification code 10057666 Term: Anxiety disorder PRIMARY OUTCOME: Main Objective: 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. Primary end point(s): Efficacy of the CRF‐1 receptor antagonist R317573 on CO2 induced anxiety. Secondary Objective: 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.; 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 o