Phase 2 Efficacy Trial of Z160 in Lumbosacral Radiculopathy

• Change in average daily pain score (PI-NRS) [ Time Frame: Baseline to weeks 1,2,3,4,5 ] [ Designated as safety issue: No ]
• Galer Neuropathic Pain Scale (NPS) [ Time Frame: Baseline to weeks 1,2,4,6 ] [ Designated as safety issue: No ]
• Patient Global Impression of Change (PGIC) [ Time Frame: Baseline to week 6 ] [ Designated as safety issue: No ]
• Modified Roland-Morris Disability Scale (RMDQ) [ Time Frame: Baseline to weeks 1,2,4,6 ] [ Designated as safety issue: No ]
• Rescue medication use [ Time Frame: Weeks 1,2,3,4,5,6 ] [ Designated as safety issue: No ]
• Profile of Mood States (POMS) [ Time Frame: Baseline to weeks 1,2,4,6 ] [ Designated as safety issue: No ]
• Daily Sleep Interference Scale [ Time Frame: Baseline to weeks 1,2,3,4,5,6 ] [ Designated as safety issue: No ]
• Short Form 36 (SF-36) [ Time Frame: Baseline to week 6 ] [ Designated as safety issue: No ]
• Safety and tolerability [ Time Frame: Baseline, weeks 1,2,3,4,5,6,7,12 ] [ Designated as safety issue: No ]
  Adverse events, ECG, labs
• Relationship of plasma concentrations [ Time Frame: Baseline to weeks 1,2,3,4,5,6 ] [ Designated as safety issue: No ]
• Time to a 30% reduction in average daily pain score [ Time Frame: Baseline to weeks 1,2,3,4,5,6 ] [ Designated as safety issue: No ]
• Time to a 50% reduction in average daily pain score [ Time Frame: Baseline to weeks 1,2,3,4,5,6 ] [ Designated as safety issue: No ]
• Subjects who have greater than or equal to a 30% reduction in average daily pain score [ Time Frame: Baseline to weeks 1,2,3,4,5,6 ] [ Designated as safety issue: No ]
• Subjects who have greater than or equal to a 50% reduction in average daily pain score [ Time Frame: Baseline to weeks 1,2,3,4,5,6 ] [ Designated as safety issue: No ]

This study will compare Z160 and placebo in patients with Lumbosacral Radiculopathy for safety and efficacy for a period of 6 weeks.

• Drug: z160
  Other Name: Z160
• Drug: Placebo

• Experimental: Z160
  375mg BID
  Intervention: Drug: z160
• Placebo Comparator: placebo
  matching placebo control
  Intervention: Drug: Placebo

Inclusion Criteria:

1. The subject must have a diagnosis of pain due to LSR, with all of the following characteristics:

   • The subject perceives pain in one or both lower limbs at sites that are consistent with the area innervated by the L4, L5, or S1 nerve roots, with or without other sensory symptoms in the affected areas (typically, the pain may be perceived in the buttock, thigh, calf, leg, foot, or toes).
   • The history of the pain suggests that the cause of the LSR is due to injury of the lumbosacral nerve root(s) by degenerative disease of the vertebrae in the lumbosacral spine or associated soft tissues (including the intervertebral discs).
   • The duration of pain since onset is ≥ 12 weeks.
   • Based on clinical history, the intensity of pain has been stable during the 2-week period before screening.

2. In the investigator's opinion, the subject's diagnosis of LSR is supported by all of the following at screening:

   • Based on the StEP instrument:

     • Neurological examination of lower limbs shows impaired muscle power, sensory function, or deep tendon reflexes in the territory of the affected nerve roots.
     • Pain/sensory disturbance in dermatomal/myotomal distribution is precipitated or exacerbated by straight leg raising (the straight-leg-raising test should be performed as specified in StEP).
     • The total StEP score is > 4 (indicative of LSR as the cause of the pain)
   • Magnetic resonance imaging (MRI) studies of the lumbar spine, which indicate the nature of the subject's spinal disease is not due to infection or abscess, hematoma, or malignancy, have been obtained within 1 year before screening or at screening.
3. At screening, the subject is currently receiving treatment for pain with gabapentin (Neurontin) or with pregabalin (Lyrica) and has received such treatment for ≥ 4 weeks at a stable dose.
4. At screening, the subject has an average daily pain score for neuropathic pain due to LSR of ≥ 2 and ≤ 7 on the PI-NRS.
5. If female, the subject must be postmenopausal (defined as no menstruation for at least 12 months), surgically sterilized for ≥3 months before the screening visit, or agree to use 2 reliable methods of contraception (oral, implantable, transdermal, or injectable contraceptives in conjunction with an intrauterine device or a barrier method) during the 6-week treatment period, during the 6 week posttreatment follow-up period, and for an additional 8 weeks after the last study visit (Week 12, Visit 9) to avoid pregnancy if of childbearing potential (defined as biologically capable of becoming pregnant). If male, the subject must agree to use condoms during the 6-week treatment period with the study drug, during the 6-week posttreatment follow up period, and for an additional 8 weeks after the last study visit (Week 12, Visit 9).

Exclusion Criteria:

1. The subject has:

   • Neuropathic pain due to causes other than that specified in the inclusion criteria (e.g., postherpetic neuralgia; painful diabetic neuropathy; mononeuritis multiplex; central poststroke pain; failed back surgery in relation to the presenting episode of radiculopathy; spinal abscess, infection, hematoma, or malignancy; phantom limb pain; peripheral neuropathy due to alcoholism, malignancy, human immunodeficiency virus [HIV], syphilis; drug abuse; vitamin B12 deficiency; hypothyroidism; liver disease; toxic exposure).
   • Pain that is associated with a substantial somatic pain component (e.g., non-neuropathic/musculoskeletal pain in lower limbs or other parts of the body apart from the back) or more than one cause or potential cause for pain symptoms.
   • Any painful concurrent rheumatic disease such as, but not limited to, fibromyalgia, rheumatoid arthritis, or significant osteoarthritis.

   Any question regarding the acceptability of the etiology of the neuropathic pain should be discussed with the Zalicus medical monitor.

2. In the investigator's opinion, the subject is unable to reliably delineate or assess his or her own pain by anatomical location/distribution (e.g., the subject cannot reliably tell the difference between his or her back pain and lower limb pain and cannot rate the intensity of each separately).
3. The subject has pain in the lower limbs solely upon walking and not at rest.
4. The subject has undergone surgery for LSR within the last 6 months or has received treatment with epidural injections, nerve blocks, or acupuncture for LSR within 6 weeks before screening.

5. The subject has:

   • A history of seizure, excluding pediatric febrile seizures, or currently has seizures
   • A history of or a current diagnosis of schizophrenia or bipolar disorder
   • Had a stroke ≤ 6 months before the screening visit
   • Has uncontrolled major depression or generalized anxiety disorder with onset ≤ 6 months before the screening visit.
   • Subjects who are on stable doses of SSRIs for depression or benzodiazepines for anxiety are eligible for the study.

6. The subject has a history of or currently has any of the following conditions that, in the investigator's opinion, may interfere with the study procedures or compromise the subject's safety:

   • Cardiovascular disease
   • Gastrointestinal disease
   • Hepatic disease
   • Respiratory disease
   • Renal disease
   • Any condition that is known to interfere with the absorption, distribution, metabolism, or excretion of drugs

7. The subject has a history of or currently has:

   • Any clinically significant vital sign, ECG, or laboratory abnormalities.
   • Illness within 30 days before screening, which, in the investigator's opinion, may interfere with the study procedures or the pain or safety assessments or compromise the subject's safety.
8. The subject had a malignancy other than basal cell carcinoma of the skin, unless the lesion was surgically removed or has not been recurrent ≤1 year before the screening visit.
9. The subject has had a positive test for HIV antibody or a history of HIV.
10. The subject has had a positive test for hepatitis B surface antigen or hepatitis C antibody.
11. The subject has a history of hypersensitivity to calcium channel blockers.
12. The subject has a history of multiple drug allergies (≥ 2 kinds) that, in the investigator's opinion, may place him or her at greater risk during participation in the study.
13. The subject has participated in a previous clinical study of Z160 or has received another investigational drug ≤ 30 days before the screening visit.
14. The subject has taken a prohibited medication ≤ 30 days before the screening visit.
15. The subject has a history of alcohol or narcotic substance abuse, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), ≤ 1 year before the screening visit.
16. The subject has a positive urine drug test at screening.
17. The subject is female and is pregnant or breastfeeding at the time of the screening visit or plans to become pregnant during the study period.