Efficacy & Safety Study of Nonracemic Methadone for the Relief of Chronic Peripheral Neuropathic Pain

Pilot Study to Evaluate Efficacy, Tolerability and Safety Nonracemic Methadone HCl in Patients With Chronic Peripheral Neuropathic Pain: Double-Blind, Placebo-Controlled, Crossover Study Followed by Open-Label, Single-Arm Extension

There is a growing evidence that the d-isomer of methadone is effective in treating neuropathic pain while the l-isomer of methadone is the only effective isomer of methadone for treating somatic pain. This study will examine a combination of different amounts of the d- and l-isomers of methadone specifically tailored to the chronic peripheral neuropathic pain. Non-racemic mixture of methadone isomers will be tested in this pilot efficacy and safety study.

This study will evaluate effect of the three doses of the non-racemic mixture of methadone hydrochloride patients with chronic peripheral neuropathic pain compared with a placebo. The study will also examine the minimally effective and maximally tolerated doses of the non-racemic mixture of methadone. Finally, the safety and tolerability of the non-racemic methadone therapy will be evaluated.

Objectives:

• To evaluate effect of the three doses of the non-racemic methadone HCl on the metrics of pain intensity in comparison to placebo.
• To determine minimally effective and maximally tolerated doses of non-racemic methadone HCl for the treatment of diabetic peripheral neuropathic pain.
• To evaluate safety and tolerability of non-racemic methadone HCl therapy.

Study Design:

This is a pilot efficacy and safety study comprised of two parts.

Part I is a double-blind, placebo-controlled, crossover study of three daily doses (15 mg, 30 mg and 40 mg) of non-racemic methadone compared with placebo. Two lower doses (15 mg and 30 mg) will be administered for 1 week. The final dose (40 mg) will be administered for 2 weeks. After receiving three consecutive doses of the assigned drug the subjects will be switched to another regimen. Two 28-day treatment periods will be separated by a 14-day washout (drug-free) interval.

Subjects will be randomly assigned to one of the two treatment sequences:

Sequence 1: non-racemic methadone HCl (Period 1) followed by Placebo (Period 2); Sequence 2: Placebo (Period 1) followed by non-racemic methadone HCl (Period 2).

Subjects completing Part I will be enrolled into the open-label, single-arm extension. Subjects discontinuing the study while on placebo may also be eligible for the enrollment. During the 6-week extension phase (Part II of the study) subjects will be treated with non-racemic methadone HCl with continuous dose titration driven by the clinical response (degree of pain relief) and reported adverse events. The Parts I and II will be separated by a 14-day washout (study drug-free) interval.

Number of Patients:

Up to fifty (50) subjects diagnosed with neuropathic pain associated with diabetic peripheral neuropathy will be enrolled in the study; approximately 30 subjects are expected to complete Study Part I. Enrollment will be terminated when this completion target is achieved.

Study Duration:

The duration of Study Part I is approximately 12 weeks, the duration of Study Part II is approximately 6 weeks. A total study duration (including screening and final evaluations) is expected to be approximately 20 weeks.

Inclusion Criteria:

• Male or female 18 years of age or older;
• Female with a negative serum βhCG pregnancy test
• Female of non-childbearing potential (postmenopausal or surgically sterile) OR female of child-bearing potential agreed to use the protocol-approved contraceptive method
• Documented diagnosis of neuropathic pain associated with diabetic peripheral neuropathy for at least 6 months
• Average daily pain severity score >=4 for the seven days prior to randomization (based on an 11-point numerical rating scale where 0= no pain and 10=worst possible pain)
• Score >= 40 mm on the VAS of the Short Form McGill Pain Questionnaire (SF-MPQ) at screening and randomization visits
• Stable doses (for at least three weeks) of non-opioid analgesics including NSAIDS, corticosteroids, gabapentin, pregabalin or antidepressants prescribed for the purposes of pain control or pain treatment naïve
• Willing to refrain from any pain-relieving drugs other than the protocol-approved rescue medications (acetaminophen, <= 3 g daily or aspirin <= 325 mg daily) during the screening phase and the course of the study
• Willing to limit alcohol consumption during the study according to protocol requirements
• Able to understand and complete study diary and questionnaires
• Willing to give informed consent prior to entry into the study

Exclusion Criteria:

• A documented neuropathy of any cause other than diabetic peripheral neuropathy
• A severe intermittent pain for reasons other than radiculopathy (e.g., migraine attacks)
• History of head injury and/or increased intracranial pressure
• Any neurologic disorder unrelated to diabetic peripheral neuropathy
• Non-adequate renal and/or hepatic function as follows: Serum creatinine > 1.5 x ULN (upper limit of normal range) Liver enzymes (ALT and AST) > 2 x ULN
• Any other know laboratory abnormality that, in the investigator's opinion, would contraindicate study participation
• Chronic hepatitis B, hepatitis C, or HIV infection
• Abnormal cognition defined as obvious clinical findings of state of arousal, confusion and memory or concentration deficit.
• Recent history (within the previous 12 months) of respiratory depression, acute bronchial asthma or hypercarbia, or any other severe pulmonary or respiratory disease
• Recent history (within the previous 12 months) of sleep apnea
• Any hemostatic disorders or a current treatment with anticoagulants;
• Unstable cardiovascular disease or symptomatic peripheral vascular disease
• Hypotension: sitting or standing systolic blood pressure <= 90 mmHg and/or diastolic blood pressure <= 60 mmHg at screening and/or orthostatic hypotension (defined as a difference between sitting and standing systolic blood pressure >20 mmHg and/or a difference between sitting and standing diastolic blood pressure >10 mmHg)
• Any clinically important ECG abnormality (including QT interval exceeding 450 ms)
• Recent history (within the last 12 months) of risk factors for development of prolonged QT interval, including cardiac hypertrophy, concomitant diuretic use, hypocalcemia, hypomagnesemia