A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-42160443 in Subjects With Postherpetic Neuralgia and Post-Traumatic Neuralgia, Followed by a Double Blind Safety Extension and an Open-Label Safety Extension

• Man or woman between 18 and 80 years of age, inclusive
• Subjects who have chronic neuropathic pain (pain persistent for greater than 6 months) that is moderate to severe in the opinion of the investigators) and are currently taking neuropatic pain medication but are not adequately controlled by standard of care (which may include antidepressants, antiepileptics, topical lidocaine, or opiods) or are not currently taking neuropatic pain medications because they are intolerable to, or not willing to use, standard of care.
• Subjects currently taking medications for the treatment of neuropathic pain at Screening have 3 options:
- They may continue taking their current pain medication: Subjects are required to be on a stable dose for at least 4 weeks prior to the first dose of study drug and must remain on this dose for the duration of the double blind efficacy phase. The class, number and doses of medications for the treatment of neuropathic pain are limited to the guidelines provided below (refer to Maximal Neuropathic Pain Medication Allowed). If the number and/or doses of such medications must be reduced to fall within the acceptable limits for this study, then the number and/or doses must be reduced (see next bullet).
- They may reduce the number and/or dose of their current pain medications: If the number and/or dose exceed the limits of allowed neuropathic pain medications (refer to Maximal Neuropathic Pain Medication Allowed), then the number and/or dose must be reduced to fall within acceptable limits. This must be achieved at least 3 days or 5-half lives of the pain medication taken (whichever is longer) prior to the beginning of the Interactive Voice Response System (IVRS) baseline period. Medications with the potential to cause withdrawal symptoms should be tapered using a taper schedule that is determined by the investigator. Subjects must remain on this lowered number/dose of pain medication dose for the duration of the double blind efficacy phase.
- They may discontinue their current pain medication: If they choose to discontinue their neuropathic pain medications, then a washout interval of 3 days or 5 half lives of the pain medication taken, whichever is longer, prior to beginning the IVRS baseline period is required. Medications with the potential to cause withdrawal symptoms should be tapered using a taper schedule that is determined by the investigator.
Maximal pain medication allowed: Use of two or less of the following medications, each one from a different class, is permitted:
- Anticonvulsants: gabapentin (<= 1800 mg/day) or pregabalin (<= 300 mg/day)
- Opioid analgesics (<= 60 mg/day oxycodone equivalent) or tramadol (<= 200 mg/day)
- Antidepressants: tricyclic antidepressants (<= 75 mg/day amitriptyline equivalent), duloxetine (<= 60 mg/day), or venlafaxine (<= 150 mg/day) (sponsor approval is required for use of any other SNRI antidepressant for treatment of neuropatic pain not listed here)
Note: Medications for treatment of neuropathic pain are limited to the guidelines provided above (refer to Maximal Neuropathic Pain Medication Allowed). No other classes of neuropathic pain medications (e.g., topical lidocaine, capsaicin, botulinum toxin) are permitted.
• Subjects must have a mean average pain intensity score of at least 5, but less than 10, over 7 consecutive days on an 11-point numerical rating scale during the IVRS baseline period. Subjects are not permitted to have a pain score of less than 3 on 2 or more days within the 7 consecutive days. During the 7 consecutive days, at least 5 days of scores are required.
• Subjects with PHN:
o Diagnosis of PHN includes a clear history of herpetic (varicella-zoster) rash and persistent pain in a dermatomal distribution area
o Pain must be present for greater than 6 months after the onset of the dermatomal rash
• Subjects with post-traumatic neuralgia are required to have all of the following:
o The persistent pain was related to nerve injury caused by trauma or surgery for longer than 6 months, and is not associated with an ongoing infection. Examples include thoracotomy, inguinal herniorrhaphy, knee or hip replacement, sternotomy, plastic surgery, or traumatic injury.
Subjects with failed low back pain syndromes, or spine disease, radiculopathy, or complex regional pain syndrome (CRPS) type I should not be considered as the posttraumatic neuralgia diagnosis for the purpose of this study.
o Neuropathic pain diagnostic questionnaire (Douleur neuropathic 4 questionnaire) score of 4 or more based on investigator*s assessment (Attachment 26; Bouhissira 2005)
o Grading to be at least *probable neuropathic pain* according to *Neuropathic Pain: redefinition and a grading system for clinical and research purposes* (Treede 2008). Probable neuropathic pain requires 1 and 2, plus either 3 or 4 below.
1. Pain with a distinct neuroanatomical plausible distribution (i.e., in a body region corresponding to the innervation territory of one or more peripheral nerves).
2. A history consistent with an injury to the peripheral somatosensory system. For example, for subjects with nerve injury during a surgical procedure, the onset of neuropathic pain is related temporally to the surgical procedure. For subjects with nonsurgical nerve injury, the onset of neuropathic pain is related to the episode of trauma.
3. Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory test (as part of the clinical examination, this test confirms the presence of negative or positive neurologic signs concordant with the distribution of pain).
4. Demonstration of the relevant lesion or disease by at least one confirmatory test
• Subjects who are sexually active must consent to utilize a medically acceptable and highly effective (<1% per year failure rate) method of contraception throughout the entire study from screening through 6 months after the last dose of study drug.
o Medically acceptable, highly effective methods of contraception that may be used by the subject and/or partner include oral, transdermal, progestin implant, or injectable contraception, intrauterine device (IUD), tubectomy or vasectomy (at least 6 months post surgery)
o For all women of childbearing potential, contraception must be consistently used for 3 months before the first dose of study drug through 6 months after the last dose of study drug.
o Subject or partner may also be postmenopausal (states having not experienced a menstrual period for a minimum of 12 months) or surgically sterile. Postmenopausal or surgically sterile women will not be required to use contraception.
o Further, subjects must agree to not donate sperm or eggs or attempt conception (pregnancy) for 6 months after the last dose of study drug
• Women of childbearing potential must have a negative serum b-human chorionic gonadotroping (b-hCG) pregnancy test at screening and a negative urine b-hCG at randomization (Day 1)
• Medically stable on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening.
• Medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel or hematology are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the subject's source documents and initialed by the investigator.
• Negative urine drug screen (including tetrahydrocannabinol (THC), cocaine, and heroin)
• No active or chronic hepatitis due to hepatitis B infection, according to the interpretation of hepatitis B serology test results
• Negative for anti-hepatitis C virus antibody (anti-HCV)
• Mini-mental state exam score of >26 and lack of signs or symptoms of dementia or clinically significant memory loss
• Patient has daily access to a touchtone phone (land-line phone preferred, but cell phone acceptable)
• Willing/able to adhere to the prohibitions and restrictions specified in this protocol
• Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

• A separate pain condition (e.g., joint osteoarthritis) that is more severe than their pain due to their diagnosis of PHN or post-traumatic neuralgia, or, if in the opinion of the Investigator, the chronic pain condition could confound the subject*s assessment of neuropathic pain under this study
• Subjects with post-traumatic neuralgia that are characteristic of complex regional pain syndrome Type I, including: pain out of proportion to the severity of the injury, pain outside the distribution of nerve injury, changes in the skin color and/or temperature in the affected limb or body part, edema or excessive sweating of the affected limb or body part. Note, subjects with Type II CRPS are allowed in the study.
• Subjects with lumbar-sacral radiculopathy, failed low-back surgery, or spinal cord injury.
• Subject whose nerve injury or pain is expected to recover in the next 4 months
• Subjects with evidence of another neuropathic pain not under study, such as pain resulting from diabetic painful neuropathy, sensory neuropathies or pain caused by radiation, chemotherapy, alcohol, HIV infection
• Other peripheral neuropathy, paresthesia, or dysesthesia, or any other previously diagnosed neurologic condition causing the above noted symptoms that is not related with the PHN or posttraumatic neuralgia under the study
• Participation in an analgesia trial within 30 days of the first planned dose of study drug.
• Major surgeries (general or regional anesthesia), trauma, and nonhealing wounds/ulcers within 3 months prior to study drug
• History (within 1 year) of seizure, intrathecal therapy and ventricular shunts, radiotherapy to the cerebral area, mild or moderate traumatic brain injury, transient ischemic attack, or stroke, or meningitis
• History of severe traumatic brain injury within the past 15 years (consisting of 1 or more of the following: brain contusion, intracranial hematoma, either unconsciousness or post-traumatic amnesia lasting more than 24 hours) or with residual sequelae suggesting ongoing transient changes in consciousness
• History of epilepsy or multiple sclerosis
• In the investigator*s opinion, in consultation with the medical neurologist, any other conditions that could compromise the blood-brain barrier
• History of a malignancy (within the past 5 years) or current malignancy with the exception of basal cell carcinoma that has been treated and is no longer present
• Received an investigational drug (including vaccines) or used an investigational medical device within 30 days before the planned start of treatment (or 5 half-lives of the investigational drug, whichever is longer) or are currently enrolled in an investigational study.
• Women who are pregnant or breast-feeding
• Significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric (e.g., schizophrenia, bipolar disorder, dementia), immunological (e.g., immune deficiency), or metabolic disturbances
• Type I or Type II diabetes, based on medical history or laboratory results consistent with diabetes mellitus (i.e. fasting plasma glucose >=126 mg/dl or >=7 mmol/L)
• Alanine aminotransaminase (ALT) or aspartate aminotransaminase (AST) >= 2.5 times the upper limit of normal (ULN).
• Serum creatinine of >= 1.8 mg/dL
• Active, major depression or generalized anxiety disorder, recent episode of either disorder within the past 3 months, and subjects with a BDI II score >= 29 (Attachment 1).
• History of suicide attempts or suicidal ideation in the past year
• Clinical diagnosis of human immunodeficiency virus (HIV) infection or clinical diagnosis of acquired immunodeficiency syndrome (AIDS) or any immune deficiency.
Subjects with HIV infection, according to the interpretation of the Screening serology test results, will be excluded.
• Known allergies, hypersensitivity, or intolerance to JNJ-42160443 or its excipients, including mammalian cell-derived (ie., Chinese hamster ovary) products
• Use of disallowed therapies:
o As needed use of analgesics (e.g., non-steroidal anti-inflammatory drugs, cyclooxygenase-II inhibitors, topical capsaicin, topical lidocaine, and short acting opioids) must be discontinued at least 5 half-lives (of the analgesic medication) prior to the start of the IVRS baseline period and are prohibited during the double-blind efficacy phase.
o Corticosteroids, other than topical and inhalation steroids, should not be taken during the trial or within the following periods prior to the start of the IVRS baseline period: Within 4 weeks (oral); within 8 weeks (intramuscular or soft tissue administration); within 3 months (intra articular administration); within 6 months (injection of depot steroids)
• Prior treatment with other experimental NGF-inhibitor therapy
• Pending litigation due to chronic pain or disability
• Subject who consumes excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [284 mL/10 ounces], wine [125 mL/4 ounces], or distilled spirits [25 mL/1 ounce]) per day on a regular basis.
• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.
• History of ocular herpes simplex, HSV pneumonia, or HSV encephalitis
• Primary HSV infection or prophylactic therapy for HSV within the past 2 years
• Recurrent HSV reactivation during the past 2 years consisting of >=4 episodes/year or requiring antiviral treatment
• Currently receiving chronic systemic immunosuppressive therapy
• Any condition that, in the opinion of the investigator, would compromise the well being of the subject or the study or prevent the subject from meeting or performing study requirements
• Subjects unable or unwilling to read or write
• Unresolved or ongoing insurance claims for chronic pain or disability (e.g. workman*s compensation)