Omnitram Safety and Efficacy in the Treatment of Diabetic Neuropathy

A multi-centered, randomized, double-blind, placebo-controlled, two-period cross-over study
to compare the safety and efficacy of Omnitram (30 mg to 120 mg daily) and placebo in
patients with painful diabetic polyneuropathy. For subjects receiving treatment for
neuropathic pain prior to study enrollment, their treatment will be tapered and stopped at
least 2 weeks before they will be enrolled. Approximately fifty subjects will be randomized
in a double-blind manner to a 4-week treatment period of Omnitram or placebo. After a washout
of at least one week, patients will cross-over to the other treatment for a second 4 week
treatment period with Omnitram or placebo.

During the first two weeks of each treatment period, guided by efficacy and tolerability, the
dose will be increased from 3 tablets to 12 tablets per day given in three equal doses at
approximately at 8 am, 2 pm and 8 pm (i.e., if the tablet is Omnitram, 30, 60, 90 or 120
mg/day). During the final two weeks of the treatment period, the doses will be kept constant
at the highest tolerated titrated dose. Up to six tablets daily of 500 mg oral acetaminophen
can be used as rescue medication except on the last 4 days of each treatment segment (Days
26, 27, 28, and 29).

Inclusion Criteria:

1. Male or female between the ages of 18 and 75 years of age.

2. Diabetes mellitus diagnosis for at least 6 months.

3. Total glycosylated hemoglobin of <=12%.

4. Antidiabetic therapy used at screening will not be changed during the study.

5. Clinical diagnosis, confirmed by the Investigator, of painful diabetic neuropathy with
symptoms and signs for at least 6 months.

6. Lower extremity pain, from diabetic neuropathy, present daily for the previous 3
months.

7. Patients currently requiring opioid treatment must be taking daily doses of an
opioid-based analgesic equivalent to <=160mg of oral morphine.

8. Average neuropathic pain intensity over last 3 days before randomization (Segment 1,
Study Day 1) of at least 4 on a 0-10 scale (0 = no pain; 10 = the worst possible
pain).

9. Diabetic neuropathy confirmed by 1 of the following:

- Clinical signs (distal sensory disturbance/lack of distal deep tendon reflexes).

- Electrophysiological tests (slowing of nerve conduction or reduction of amplitude
of sensory action potential).

- Abnormal quantitative sensory testing (reduction or absence of pin sensibility
and/or vibration sensibility on Total Neuropathy Score - Nurse (TNSn) examination
in lower and/or upper extremities at screening.

10. Able and willing to give informed consent.

11. Able to comply with all study procedures.

12. 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 dosing: 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); or abstinence; or bilateral
tubal ligation (if no conception post-procedure).

13. Complete blood count (CBC) within normal range for the testing facility or not
clinically significant.

14. Electrocardiogram (ECG), AST, ALT, and urinalysis values within the normal range for
the testing facility or not clinically significant.

15. Normal renal function: Glomerular filtration rate (GFR) calculated by Cockcroft-Gault
formula > 60 ml/min.

16. Negative pregnancy test within 1 week of Segment 1, Study Day 1.

17. Negative urine test for substances of abuse per CRU standards.

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

19. Body Mass Index (BMI) 19.0 to 40 kg/m.

Exclusion Criteria:

1. Clinically significant abnormal vital signs including oral temperature > 38°C or
history of current illness.

2. Inability to exclude other causes of polyneuropathy including: alcoholism, vitamin B12
deficiency, endocrinopathies, vasculitides, heavy metal exposure, drug use, and
malignancy (direct or paraneoplastic).

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

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

5. Use of serotonergic drugs and drugs that impair serotonin metabolism (e.g.,
mirtazapine, trazodone); monoamine oxidase inhibitors, including linezolid, methylene
blue; serotonin and norepinephrine reuptake inhibitors, except fluoxetine, within 14
days of Segment 1, Study Day 1 or during the study, use of fluoxetine within 28 days
of Segment 1, Study Day 1, or during the study; and selective serotonin re-uptake
inhibitors. Use of tricyclic antidepressants and other tricyclic drugs including
cyclobenzaprine and promethazine; triptans; 5-HT3 receptor antagonists; neuroleptics.
Use of benzodiazepines or other central nervous system depressants including
non-benzodiazepine sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants,
general anesthetics, antipsychotics within 14 days of Segment 1, Study Day 1, or
during the study. Use of opiates, including tramadol, within 28 days of Segment 1,
Study Day 1, or during the study. Use of all other analgesics, except acetaminophen,
within 14 days of Segment 1, Study Day 1, or during the study.

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

7. Contraindication to use of opioids, tramadol, or acetaminophen.

8. Use of non-pharmacological pain therapy.

9. 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's Medical Monitor.

10. Currently pregnant or breast-feeding a child.

11. Unlikely to comply with the study protocol.

12. Known or suspected alcohol or drug abuse within the past 12 months.

13. Received another investigational agent within 4 weeks before screening visit, or
receiving any other investigational agent during this study.

14. 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's data.