Effects of SRX246, a Vasopressin Receptor (V1a) Antagonist, on an Experimental Model of Fear and Anxiety in Humans

Objective: The objective of this proposal is to determine the effects of SRX246, a candidate
anxiolytic and investigational new drug, on fear and anxiety based on fear-potentiated
startle in humans. Additionally, the effects of the compound on emotion recognition will be
explored. The compound is a first-in-class, highly selective, orally available, CNS
penetrating vasopressin (V1a) receptor antagonist developed by Azevan Pharmaceuticals Inc.
The anti-fear and anti-anxiety activity twice daily dosing for 10-14 doses over 5-7 days of
SRX246 will be evaluated in healthy male and female subjects using a behavioral paradigm of
phasic (fear) and sustained (anxiety) aversive states derived from experimental models in
humans and pre-clinical studies in rodents. Subjects will also undergo a computerized
behavioral task assessing neurocognitive processing of emotions.

Study population: The study population will consist of up to 47 healthy male and female
volunteers between the ages of 21-50 with diverse racial and ethnic backgrounds.

Design: The study will use a double-blind, cross-over design in which each subject will
receive placebo and 180 mg every morning/120 mg every evening (total 300mg every day) of
SRX246 for a total of 10-14 doses over 5-7 days before testing (given in counter-balanced
order). We will examine the effect of the drug on the potentiation of startle using a
well-established paradigm that involves anticipation of no-shock, predictable shock, and
unpredictable shock. Drug effects on emotion recognition will also be explored.

Outcome measures: The main outcome measures for the startle potentiation task are the
magnitude of the startle reflex and retrospective anxiety during each condition; secondary
measures are skin conductance and subjective anxiety. Latency and accuracy of emotion
recognition will be measured in the Emotional Expression Multimorph Task.

- INCLUSION CRITERIA:

- Healthy male and female volunteers, ages 21-50, inclusive.

- Subjects able to give their consent and have signed informed consent forms indicating
that they understand the purpose and procedures of the study and are willing to
participate in the study procedures and restrictions.

- Body mass index (BMI) of 18.5 to 34.0 kg/M(2), inclusive, and a total body weight of
>50kg (110 pounds).

EXCLUSION CRITERIA:

- Non-English speakers

- Current or history of Axis I psychiatric disorder(s) as identified with the Structured
Clinical Interview for DSM-IV-TR, non-patient edition (SCID-np) and clinical
evaluation.

- Active or history of active suicidal ideation.

- Lifetime alcohol or drug dependence according to the Structured Clinical Interview for
DSM-IV-TR, non-patient edition (SCID-np).

- All prescription and non-prescription medications and herbal remedies are prohibited
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study
medication and until at least 7 days or 5 half-lives (whichever is longer) after last
dose of study medication, except hormonal contraceptives in females.

- Subject is currently participating in another clinical trial in which (s)he is or will
be exposed to an investigational or non-investigational drug or device, or has been
exposed to an investigational or non-investigational drug or device within the
preceding 14 days or 5 half-lives of the investigational or non-investigational drug
(whichever is longer).

- Current evidence or history of significant medical illness or organic brain
impairment, including syndrome of inappropriate antidiuretic hormone secretion
(SIADH), diabetes insipidus (DI), stroke, epilepsy, CNS tumor, demyelinating disease,
cardiac, pulmonary, gastrointestinal, renal or hepatic impairment that would likely
interfere with the action, absorption, distribution, metabolism, or excretion of
SRX246, or influence psychophysiological responses.

- Any laboratory abnormality that in the investigators judgment is considered to be
clinically significant (ECG, TSH, LFT, etc.).

- Abnormal urine specific gravity (below 1.00 or above 1.03) as documented by urine
sample refractometry.

- Subject who has resting blood pressure outside of a systolic blood pressure range of
90-140 mmHg or a diastolic blood pressure outside a range of 50-90 mmHg on two
consecutive measurements taken up to 10 minutes apart.

- Subject who has resting pulse rate greater than 100 bpm or less than 50 bpm on two
consecutive measurements taken up to 10 minutes apart.

- Pregnancy, lactating/breastfeeding, or positive pregnancy test.*

- A history of anaphylaxis, or any known/suspected hypersensitivity to SRX246, or
allergy to gelatin.

- Lack of measurable startle response (3 times the baseline EMG activity) for at least 5
of 9 startles used during the habituation visit.

- Subjects who would be noncompliant with the visit schedule or study procedures.
Possible noncompliance may include planned vacations or planned hospitalizations
during the study.

- Participants who are physically able to get pregnant and those who are able to father
a child, unwillingness to use at least two effective birth control methods or remain
completely abstinent from heterosexual Intercourse for 15 days prior to the time they
enroll in the study, until 15 days after their last exposure to the study drug.
Effective methods of contraception for this study include:

1. hormonal contraception (birth control pills, injected hormones or vaginal ring),

2. intrauterine device,

3. barrier methods (condom or diaphragm) combined with spermicide, and

4. surgical sterilization (hysterectomy, tubal ligation, or vasectomy).

- Employee of NIMH or an immediate family member who is a NIMH employee.

- A urine pregnancy test is performed at each visit. Since this test might not
detect the very early stage of pregnancy (i.e. maximum of 10 day period between
fertilization and implantation), women of child-bearing age are excluded from the
study if they do not agree to above contraceptive measures.