Omnitram Pharmacokinetic Study In Healthy Volunteers

A Phase 1, single-center, randomized, double-blind, placebo-controlled, three-period
cross-over study to compare the safety, steady-state oral pharmacokinetics, and clinical
activity of overencapsulated: 20 mg Omnitram (2x10 mg tablets), 50 mg Tramadol (1x50 mg
Ultram tablet), and placebo.

Forty male subjects in normal health, 21 to 55 years of age, will be randomized to three
parallel arms (N=~13 each) to ingest a total of 9 doses of Omnitram, Tramadol, or placebo in
a first treatment segment (one dose every 6 hours). Around the 9th dose blood samples are
collected to quantify plasma Tramadol and Metabolite 1 (M1) enantiomers. After the 9th
dose, pain tolerance is assessed with a cold pressor test (ice cold water immersion).
After the 7th dose abuse liability measures and pupil diameter will be assessed. Subjects
will washout for 7 days after the first treatment segment and second treatment segment.

Inclusion Criteria:

1. Healthy male with normal vital signs: systolic blood pressure > 90 mm Hg and < 140 mm
Hg; diastolic blood pressure > 50 mm Hg and < 90 mm Hg; pulse 50 to 100 beats per
minute; respiratory rate 12 to 20 breathes per minute

2. Between the ages of 21 and 55 years of age

3. Able and willing to give informed consent

4. Able to comply with all study procedures

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

- White Blood Cell (WBC) >3,500/mm3 and < 12,000/mm3;

- Platelet Count > 150,000/mm3 and < 540,000/mm3;

- Hemoglobin > 12.5 gm/dL and < 20.5 gm/dL.

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

- Aspartate transaminase (AST) ≤ 60 IU/L;

- Alanine transaminase (ALT) ≤ 83 IU;

- Alkaline Phosphatase ≤ 150 IU/L;

- Total Bilirubin ≤ 1.2 mg/dL;

- Prothrombin Time (PT) < 1.2 upper limit of normal (ULN); Partial
Thromboplastin Time (PTT) < 1.2 ULN.

6. Electrocardiogram (ECG) within normal limits as determined by the PI

7. 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

8. Negative urine test for substances of abuse, including opiates, per clinical research
unit (CRU) standards

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

10. Body Mass Index (BMI) 19.0 to 32 kg/m

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

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 Tramadol, codeine, or
other opioid drugs

6. Use of monoamine oxidase (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 cytochrome P450 2D6 (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. Unlikely to comply with the study protocol

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

10. Received another investigational agent within 4 weeks of Day 0, or within five
half-lives of Day 0, whichever is longer; or receiving any other investigational
agent during this study

11. 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