Omnitram Pharmacokinetic and Analgesic Study Following CY2D6 Inhibition With Paroxetine In Healthy Volunteers

A randomized, double-blind, placebo-controlled study to investigating the steady-state oral
pharmacokinetics and hypoalgesic effects of overencapsulated: 20 mg Omnitram (2x10 mg
tablets), 50 mg tramadol (1x50 mg Ultram tablet), and placebo in male and female subjects
made CYP2D6 deficient by paroxetine coadministration.

Sixty participants in normal health, 18 to 50 years of age, who meet the entry criteria, will
be randomized to one of the three treatments in treatment segment 1. Each arm will ingest
three consecutive 20 mg daily doses of paroxetine. Twelve hours after the first paroxetine
dose, subjects will be randomized to one of the treatment sequences to ingest a total of 9
doses of Omnitram, tramadol, or placebo (one dose every 6 hours). Immediately before the 9th
dose a blood sample will be collected to quantify plasma Omnitram, tramadol, and paroxetine.
After the 9th study drug dose, six blood samples will be collected (1.0, 1.5, 2.0, 2.5, 4.0,
and 8.0 hours after the 9th dose is administered) to quantify the Omnitram and tramadol.
After the 9th dose, pain tolerance will be assessed with a cold pressor test (immersion of
hand in ice cold water). Participants will washout for 11-15 days after treatment 1 and
treatment 2. The study will analyze treatment side effects, the pharmacokinetics, and pain
tolerance.

Inclusion Criteria:

1. Healthy males and females with normal vital signs: systolic blood pressure > 90 mm Hg
and < 140 mm Hg; diastolic blood pressure > 45 mm Hg and < 90 mm Hg; pulse 40 to 100
beats per minute; respiratory rate 10 to 20 breathes per minute.

2. Between the ages of 18 and 50 years of age.

3. Able and willing to give informed consent

4. Able to comply with all study procedures.

5. If female, must not be of childbearing potential or must agree to use one or more of
the following forms of contraception during screening and for 30 days following study
drug administration: hormonal (e.g., oral, transdermal, intravaginal, implant or
injection); double barrier (i.e., condom, diaphragm with spermicide); intrauterine
device (IUD) or system (IUS); vasectomized partner (6 months minimum); abstinence; or
bilateral tubal ligation.

6. Have adequate hematologic function as evidenced by the following screening results:

WBC >3,500/mm3 and < 12,000/mm3 Platelet Count > 150,000/mm3 and < 540,000/mm3
Hemoglobin > 12.0 gm/dL and < 20.5 gm/dL

Have adequate liver function as evidenced by the following screening results:

AST (SGOT) ≤ 60 IU/L ALT (SGPT) men ≤ 83 IU/L women < 60 IU/L Alkaline Phosphatase ≤
200 IU/L Total Bilirubin ≤ 1.2 mg/dL PT and PTT < 1.2 ULN

7. Electrocardiogram (ECG) without clinically significant findings as determined by the
PI.

8. Have adequate renal function as evidenced by the following screening result:

Glomerular filtration rate (GFR) calculated by Cockcroft-Gault formula >60 ml/min.

Urinalysis demonstrating < +1 glucose, +1 ketones, and +1 protein.

9. Negative pregnancy test within 1 week of study day 1 (women of childbearing potential
only).

10. Negative urine test for substances of abuse, including opiates, per CRU standards.

11. Negative serology tests for HIV, hepatitis B surface antigen, and hepatitis C virus
antibody.

12. Body Mass Index (BMI) 18.0 to 32 kg/m.

13. Cold pressor screening results as follows: 1) pain tolerance of > 20 seconds and <120
seconds.

14. Cytochrome P450 2D6 (CYP2D6) genotype by Genelex consistent with intermediate
metabolizer phenotype or normal metabolizer phenotype.

Exclusion Criteria:

1. Oral temperature > 38°C or history of current illness.

2. History of seizures, epilepsy, or recognized increase risk of seizure (e.g., head
trauma, metabolic disorders, alcohol or drug withdrawal).

3. History of cirrhosis or laboratory evidence of liver disease.

4. Use of alcohol within 24 hours of day -1 until the end of the study; and grapefruit,
grapefruit-related citrus fruits (e.g., Seville oranges, pomelos), or grapefruit juice
or grapefruit-related juices, or other medication, within 7 days of study drug
administration and until the end of the study.

5. History of previous anaphylaxis, severe allergic reaction to paroxetine, tramadol,
codeine, or other opioid drugs.

6. Use of MAO Inhibitors (including linezolid), Serotonin Reuptake Inhibitors,
Serotonin-Norepinephrine Reuptake Inhibitors, and prescription or over-the counter
(OTC) medications known to induce or inhibit drug metabolism, including CYP2D6, and
other drugs that may affect the serotonergic neurotransmitter systems including, but
not limited to, triptans, dextromethorphan, tricyclic antidepressants, bupropion,
lithium, tramadol, dietary supplements such as tryptophan and St. John's Wort, and
antipsychotics or other dopamine antagonists. These restrictions are to be maintained
from 14 days before study day -1, until the subject completes the study.

7. Any other unstable acute or chronic disease that could interfere with the evaluation
of the safety of the study drug as determined by the principal Investigator in
dialogue with the Sponsor Medical Monitor.

8. Currently pregnant or breast feeding.

9. Unlikely to comply with the study protocol.

10. Known or suspected alcohol or drug abuse within the past 6 months.

11. Received another investigational agent within 4 weeks of Day 1, or receiving any other
investigational agent during this study.

12. Any concurrent disease or condition that in the opinion of the investigator impairs
the subject's ability to complete the trial. Psychological, familial, sociological,
geographical or medical conditions which, in the Investigator's opinion, could
compromise compliance with the objectives and procedures of this protocol, or obscure
interpretation of the trial data.