A Confirmatory Study of JNS013 in Patients With Chronic Pain

• The mean pain intensity on the Visual Analog Scale for the last 24 hours (VAS24) [ Time Frame: From a week before the first study drug administration to Day 43. ] [ Designated as safety issue: No ]
• Pain intensity (PI) difference (PID) and its time course [ Time Frame: From the first study drug administration to Day 36 ] [ Designated as safety issue: No ]
• Time course of pain relief rating (PAR) [ Time Frame: From the first study drug administration to Day 36 ] [ Designated as safety issue: No ]
• Time course of sum of PID and PAR (PRID) [ Time Frame: From the first study drug administration to Day 36 ] [ Designated as safety issue: No ]
• Sum of PIDs at each assessment point (SPID) [ Time Frame: From the first study drug administration to Day 36 ] [ Designated as safety issue: No ]

The purpose of this study is to evaluate the analgesic effectiveness and safety of JNS013 in patients with chronic pain accompanied by osteoarthritis of the knee or low back pain which cannot be controlled sufficiently with NSAIDs in a placebo-controlled manner.

Since JNS013 is a combination of tramadol hydrochloride (TRAM) acting as a weak opioid with acetaminophen (APAP). It is expected to have an intermediate effect between narcotic analgesics and NSAIDs (non-steroid anti-inflammatory drugs). This study was planned to evaluate the effectiveness and safety of JNS013 patients with chronic pain. To increase the accuracy of the confirmatory study, osteoarthritis of the knee (OA) and low back pain (LBP) were selected as target diseases for the study. This is a multicenter, randomized (patients assigned study drug by chance) - withdrawal (the study design which the patients receive active drug before randomization), double-blind (neither patient nor physician knows the assigned study drug medication name), placebo-controlled, parallel-group study. Patients with lack of analgesic effect of NSAIDs will be enrolled in the study. Patients who meet the criteria for the open-label period will receive JNS013 for 2 weeks, and after that patients who meet the criteria for the double-blind period will be randomized and receive JNS013 or placebo for 4 weeks. The primary efficacy endpoint in this study is time to treatment withdrawal due to lack of effectiveness. In addition, the investigator will assess the safety by handling any untoward medical events (including abnormal changes in laboratory data) that occurred in patients from informed consent through the completion of follow-up period as an adverse event. Besides collection of any untoward medical event information, laboratory data, vital signs and body weight will be measured for safety evaluation. Total Study Period is 11 weeks. Screening Period is 4 weeks. Open-label Period (2 weeks): JNS013 will be administered to patients who meet the criteria for entry into the open-label period. The dose will be selected by each patient, 1 or 2 tablets/times of JNS013, according to the severity of pain and tolerability. JNS013 will orally be administered 4 times daily no less than 4-hour intervals (up to 8 tablets per day) for 2 weeks. During the latter 1 week, the dose will be fixed for each patient. Double-blind Period (4 weeks): Either JNS013 or placebo will be administered to patients who meet the criteria for entry into the double-blind period. The study drug will be administered at the same dose as used for the latter 1 week of the open-label period for up to 4 weeks. It will orally be administered 4 times daily at no less than 4-hour intervals (up to 8 tablets per day). It will be discontinued in patients confirmed to have lack of analgesic effect during the double-blind period. Follow-up Period: 1 week. Safety evaluations: Adverse events reporting, laboratory test values, vital blood/pulse rate, body weight. JNS013 will be orally administered 4 times daily at least 4-hour intervals (up to 8 tablets per day). The dose will be selected by each patient, 1 or 2 tablets of JNS013, according to the severity of pain and tolerability during 2 weeks of the open-label period. During the latter 1 week, the dose will be fixed for each. In the double-blind period, either JNS013 or placebo will be administered at the same dose as used for the latter 1 week of the open-label period for up to 4 weeks.

• Drug: placebo
  the same dose (number of tablets) as that for the second 1 week in the open-label period
• Drug: Tramadol Hydrochloride and Acetaminophen
  1or 2 tablets containing Tramadol Hydrochloride 37.5 mg/Acetaminophen 325 mg 4 times daily(maximum daily dose: 8 tablets) in the open-label period
• Drug: Tramadol Hydrochloride and Acetaminophen
  the same dose (number of tablets) as that for the second 1 week in the open-label period

• Experimental: 001
  Tramadol Hydrochloride and Acetaminophen 1or 2 tablets containing Tramadol Hydrochloride 37.5 mg/Acetaminophen 325 mg 4 times daily(maximum daily dose: 8 tablets) in the open-label period
  Intervention: Drug: Tramadol Hydrochloride and Acetaminophen
• Experimental: 002
  Tramadol Hydrochloride and Acetaminophen the same dose (number of tablets) as that for the second 1 week in the open-label period
  Intervention: Drug: Tramadol Hydrochloride and Acetaminophen
• Experimental: 003
  placebo the same dose (number of tablets) as that for the second 1 week in the open-label period
  Intervention: Drug: placebo

Inclusion Criteria:

• Patients with sustention of chronic pain associated with OA or LBP for at least 3 months
• Patients whose pain cannot be controlled sufficiently with at least 14-day continuous treatment with identical oral NSAIDs at a usual maximum dose during 3 months prior to this study
• Outpatients
• Ambulatory patients without need for any supportive device or assistance during daily life

Exclusion Criteria:

• Patients with conditions for which opioids are contraindicated
• Patients with conditions for which APAP are contraindicated
• Patients with history of convulsion or the possibility of convulsive seizure
• Patients with concurrent, previous, or possible alcohol dependence, drug dependence, or narcotic addiction
• Pregnant patients or those who may be pregnant, lactating mothers, and patients who wish pregnancy during the study period