An Efficacy and Safety Study of Acetaminophen Plus Tramadol Hydrochloride (JNS013) in Participants With Chronic Pain

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of tramadol hydrochloride plus acetaminophen (JNS013) in participants with chronic pain accompanied by osteoarthritis (a progressive and degenerative joint disease, in which the joints become painful and stiff) of the knee or low back pain (acute or chronic pain in the lumbar or sacral regions) which cannot be controlled sufficiently with non-steriodal anti-inflammatory drugs (NSAIDs).

Detailed Description
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This is a multi-center (when more than one hospital or medical school team work on a medical research study), double-blind (test or experiment in which neither the person giving the treatment nor the participant knows which treatment the participant is receiving), placebo-controlled (an inactive substance; a pretend treatment [with no drug in it] that is compared in a clinical trial with a drug to test if the drug has a real effect), parallel group comparison study. The total duration of the study will be 11 weeks and consists of 4 periods; a pre-observation period (4 weeks), open-label period (2 weeks), double-blind period (4 weeks) and follow-up period (1 week). Participants will receive tramadol hydrochloride plus acetaminophen tablets orally 4 times daily for 2 weeks with no less than 4-hour intervals (up to 8 tablets per day) during the open-label period and the dose will be fixed for each participant in the latter 1 week. During the double-period participants will receive tramadol hydrochloride plus acetaminophen tablets or placebo at the same dose as used for the latter 1 week of the open-label period for up to 4 weeks. Efficacy will be primarily evaluated by number of participants with insufficient pain relief after the start of double-blind period. Participant's safety will be monitored throughout the study.

Official Title
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A Phase 3 Study of JNS013 in Patients With Chronic Pain

Conditions
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Pain

Intervention / Treatment
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* Drug: Tramadol Hydrochloride Plus Acetaminophen (Open-Label)
* Drug: Tramadol Hydrochloride Plus Acetaminophen (Double-Blind)
* Drug: Placebo (Double-Blind)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with sustention of chronic pain associated with OA or LBP for at least 3 months Participants 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 participants without need for any supportive device or assistance during daily life Exclusion Criteria: Participants with conditions for which opioids are contraindicated Participants with conditions for which acetaminophen is contraindicated Participants with history of convulsion or the possibility of convulsive seizure Participants with concurrent, previous, or possible alcohol dependence, drug dependence, or narcotic addiction Pregnant participants or those who may be pregnant, lactating mothers, and participants who wish pregnancy during the study period

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tramadol Hydrochloride Plus Acetaminophen (Open-Label)<br> | Drug: Tramadol Hydrochloride Plus Acetaminophen (Open-Label)<br>* Fixed dose combination of tramadol 37.5 milligram (mg)/acetaminophen 325 mg, 1 or 2 tablets 4 times daily will be given for one week; dose level will be fixed for each participant during the second week based on analgesic efficacy and tolerability (maximum daily dose will be 8 tablets).<br>|
| Experimental: Tramadol Hydrochloride Plus Acetaminophen (Double Blind)<br> | Drug: Tramadol Hydrochloride Plus Acetaminophen (Double-Blind)<br>* Fixed dose combination of tramadol 37.5 mg/acetaminophen 325 mg, 1 or 2 tablets (same dose [number of tablets] as that for the second week in the open-label period) will be given 4 times daily up to 4 weeks.<br>|
| Placebo Comparator: Placebo (Double-Blind)<br> | Drug: Placebo (Double-Blind)<br>* Matching placebo will be given up to 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Insufficient Pain Relief After the Start of Double-Blind Period | The pain relief was regarded as insufficient, if either of the following was met, a) the value of average pain intensity felt in daily living during the past 24 hours (Visual analog scale 24 [VAS24] ) on 2 consecutive days in double-blind period worsened greater than 15 millimeter (mm) compared with the average VAS24 during 3 days before the end of open-label period, b) when the participant asked for discontinuation of treatment with the study drug because of insufficient pain relief. | Day 28 of double-blind period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Visual Analog Scale for the Last 24 Hours (VAS24) Value at the Start of the Double-Blind Period From the Baseline Value at the Start of the Open-Label Period | Pain over the last 24 hours was assessed by using VAS score ranges from 0 mm=no pain to 100 mm=worst possible pain. An increase in score from Baseline represented disease progression and decrease represented improvement. | Day 1 of open-label period and Day 1 of double-blind period | 
| Change in the VAS24 Value From the Baseline at the Final Time Point of the Double-Blind Period | Pain over the last 24 hours was assessed by using VAS score ranges from 0 mm=no pain to 100 mm=worst possible pain. An increase in score from Baseline represented disease progression and decrease represented improvement. | Day 1 and Day 28 of double-blind period | 
| Mean Pain Intensity (PI) Score During Open-Label Period | PI was evaluated on a 4-stage scale with a score ranging from 0 to 3, wherein 0=no pain and 3=severe pain. | Pre-dose and post-dose at 2 hours, 4 hours on Day 1, and Day 8 of open-label period | 
| Mean PI Score During Double-Blind Period | The PI was evaluated on a 4-stage scale with a score ranging from 0 to 3, wherein 0=no pain and 3=severe pain. | Pre-dose and post-dose at 2 hours, 4 hours on Day 1, 8, 15, 22 and 28 of double-blind period | 
| Mean Pain Intensity Difference (PID) During the Open-Label Period | The PID was calculated as PI at pre-dose on Day 1, 8 minus PI at post-dose time point (i.e., 2 hours and 4 hours) on Day 1, 8 respectively. Baseline PI score ranges from 1=minor to 3=severe, post-baseline PI score ranges from 0=none to 3=severe. Total possible score range for PID: -2=worst to 3=best. | Pre-dose, and post-dose at 2 hours, 4 hours on Day 1, and Day 8 of open-label period | 
| Mean PID During the Double-Blind Period | The PID was calculated as PI at pre-dose on Day 1, 8, 15, 22, 28 minus PI at post-dose time point (i.e., 2 hours and 4 hours) on Day 1, 8, 15, 22, 28 respectively. Baseline PI score ranges from 1=minor to 3=severe, post-baseline PI score ranges from 0=none to 3=severe. Total possible score range for PID: -2=worst to 3=best. | Pre-dose, and post-dose at 2 hours, 4 hours on Day 1, 8, 15, 22 and 28 of double-blind period | 
| Mean Pain Relief (PAR) Score During the Open-Label Period | PAR was evaluated based on 5-stage scale with a score ranging from 0 to 4, wherein, 0=no relief and 4=complete relief. | 2 hours, 4 hours post-dose on Day 1, and Day 8 of open-label period | 
| Mean PAR Score During the Double-Blind Period | PAR was evaluated based on 5-stage scale with a score ranging from 0 to 4, wherein, 0=no relief and 4=complete relief. | 2 hours, 4 hours post-dose on Day 1, 8, 15, 22 and 28 of double-blind period | 
| Pain Intensity Difference and Pain Relief Scores (PRID) During the Open-Label Period | The PRID is defined as sum of PID and PAR Scores for each participant at each evaluation time point (at 2 and 4 hours after the dosing). The overall possible score ranges for PRID is -2=worst to 7=best. The PID was calculated as PI at pre-dose on Day 1, 8 minus PI at post-dose time point (i.e., 2 hours and 4 hours) on Day 1, 8 respectively. Baseline PI score ranges from 1=minor to 3=severe, post-baseline PI score ranges from 0=none to 3=severe. Total possible score range for PID: -2=worst to 3=best and PAR was evaluated based on a 5-stage scale score ranges from 0=no relief and 4=complete relief. | 2 hours, 4 hours post-dose on Day 1, and Day 8 of open-label period | 
| Pain Intensity Difference and Pain Relief Scores (PRID) During the Double-Blind Period | The PRID is defined as sum of PID and PAR Scores for each participant at each evaluation time point (at 2 and 4 hours after the dosing). The overall possible score range for PRID is -2=worst to 7=best. The PID was calculated as PI at pre-dose on Day 1, 8, 15, 22, 28 minus PI at post-dose time point (i.e., 2 hours and 4 hours) on Day 1, 8, 15, 22, 28 respectively. Baseline PI score ranges from 1=minor to 3=severe, post-baseline PI score ranges from 0=none to 3=severe. Total possible score range for PID: -2=worst to 3=best and PAR was evaluated based on a 5-stage scale score ranges from 0=no relief and 4=complete relief. | 2 hours, 4 hours post-dose on Day 1, 8, 15, 22 and 28 of double-blind period | 
| Sum of Pain Intensity Difference (SPID) Score During the Open-Label Period | The SPID is defined as sum of the PID at 2 and 4 hours after dosing on each evaluation day. The overall possible score ranges for SPID is -4=worst to 6=best. The PID was calculated as PI at pre-dose on Day 1, 8 minus PI at post-dose time point (i.e., 2 hours and 4 hours) on Day 1, 8 respectively. Baseline PI score ranges from 1=minor to 3=severe, post-baseline PI score ranges from 0=none to 3=severe. Total possible score range for PID: -2=worst to 3=best. | Day 1, and Day 8 of open-label period | 
| Sum of Pain Intensity Difference (SPID) Score During the Double-Blind Period | The SPID is defined as sum of the PID at 2 and 4 hours after dosing on each evaluation day. The overall possible score ranges for SPID is -4=worst to 6=best. The PID was calculated as PI at pre-dose on Day 1, 8, 15, 22, 28 minus PI at post-dose time point (i.e., 2 hours and 4 hours) on Day 1, 8, 15, 22, 28 respectively. Baseline PI score ranges from 1=minor to 3=severe, post-baseline PI score ranges from 0=none to 3=severe. Total possible score range for PID: -2=worst to 3=best. | Day 1, 8, 15, 22 and 28 of double-blind period | 
| Total Pain Relief (TOTPAR) Score During the Open-Label Period | The TOTPAR is defined as sum of PAR at 2 hours after dosing and the PAR at 4 hours after dosing on each evaluation day. Pain relief as evaluated on 5-stage scale with a score ranging from 0=no relief and 4=complete relief. Total possible score range for TOTPAR is 0=no relief to 8=complete relief. | Day 1 and Day 8 of open-label period | 
| Total Pain Relief (TOTPAR) Score During the Double-Blind Period | The TOTPAR is defined as sum of PAR at 2 hours after dosing and the PAR at 4 hours after dosing on each evaluation day. Pain relief as evaluated on 5-stage scale with a score ranging from 0=no relief and 4=complete relief. Total possible score range for TOTPAR is 0=no relief to 8=complete relief. | Day 1, 8, 15, 22 and 28 of double-blind period | 
| Sum of Pain Relief Combined With Pain Intensity Difference (SPRID) Score During the Open-Label Period | The SPRID is defined as sum of PID and PAR Scores at 2 hours and 4 hours after the dosing on each evaluation day. The overall possible score ranges for SPRID is -4=worst to 14=best. The PID was calculated as PI at pre-dose on Day 1, 8 minus PI at post-dose time point (i.e., 2 hours and 4 hours) on Day 1, 8 respectively. Baseline PI score ranges from 1=minor to 3=severe, post-baseline PI score ranges from 0=none to 3=severe. Total possible score range for PID: -2=worst to 3=best and PAR was evaluated based on 5-stage scale with a score ranging from 0=no relief to 4=complete relief. | Day 1, and Day 8 of open-label period | 
| Sum of Pain Relief Combined With Pain Intensity Difference (SPRID) Score During the Double-Blind Period | The SPRID is defined as sum of PID and PAR Scores at 2 hours and 4 hours after the dosing on each evaluation day. The overall possible score ranges for SPRID is -4=worst to 14=best. The PID was calculated as PI at pre-dose on Day 1, 8, 15, 22, 28 minus PI at post-dose time point (i.e., 2 hours and 4 hours) on Day 1, 8, 15, 22, 28 respectively. Baseline PI score ranges from 1=minor to 3=severe, post-baseline PI score ranges from 0=none to 3=severe. Total possible score range for PID: -2=worst to 3=best and PAR was evaluated based on 5-stage scale with a score ranging from 0 to 4, wherein, 0=no relief and 4=complete relief. | Day 1, 8, 15, 22 and 28 of double-blind period | 
| Change From Baseline in Roland Morris Disability Questionnaire (RDQ) Total Score at Day 14 of Open-Label Period | The RDQ is self-administered measure of disability caused by low back pain and consists of 24 statements. The total score ranges from 0=no disability to 24=severe disability. The higher scores indicate greater physical disability. | Day 1 and Day 14 of open-label period | 
| Change From Baseline in RDQ Total Score at Day 28 of Double-Blind Period | The RDQ is self-administered measure of disability caused by low back pain and consists of 24 statements. The total score ranges from 0=no disability to 24=severe disability. The higher scores indicate greater physical disability. | Day 1 and Day 28 of double-blind period | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Questionnaire Score at Day 14 of Open-Label Period | The WOMAC questionnaire is an activity of daily living (ADL) indicator for Knee Osteoarthritis and designed to capture the elements of pain, stiffness, extent of obstruction to daily activities (EODA) and general index. The score for each element ranges from 0=better ADL to 10=worse ADL. | Day 1 and Day 14 of open-label period | 
| Change From Baseline in WOMAC Questionnaire Score at Day 28 of Double-Blind Period | The WOMAC questionnaire is an activity of daily living (ADL) indicator for knee osteoarthritis and designed to capture the elements of pain, stiffness, extent of obstruction to daily activities (EODA) and general index. The score for each element ranges from 0=better ADL to 10=worse ADL. | Day 1 and Day 28 of double-blind period | 
| Change From Baseline in Short Form-36 (SF-36) Score at Day 14 of Open-Label Period | The SF-36 is a survey of participant health and quality of life. It consists of 8 sub-scales, which are the weighted sums of the questions in their section. The 8 sub-scales are: physical functioning, role-physical, role-emotional, general health, social functioning, bodily pain, vitality, mental health. Each item is scored on a scale ranging from 0-100. Higher score defines a more favorable health status or a better mental status. | Day 1 and Day 14 of open-label period | 
| Change From Baseline in SF-36 at Day 28 of Double-Blind Period | The SF-36 is a survey of participant health and quality of life. It consists of 8 sub-scales, which are the weighted sums of the questions in their section. The 8 sub-scales are: physical functioning, role-physical, role-emotional, general health, social functioning, bodily pain, vitality, mental health. Each item is scored on a scale ranging from 0-100. Higher score defines a more favorable health status or a better mental status. | Day 1 and Day 28 of double-blind period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic pain, Acetoaminophen, Tramadol, Osteoarthritis of the knee, Low back pain