Chronic Pain
Conditions
Keywords
Chronic Pain, Acetaminophen, Tramadol, JNS013
Brief summary
The purpose of this study is to evaluate the efficacy and safety of tramadol hydrochloride plus acetaminophen (JNS013) with long term administration in participants with chronic pain.
Detailed description
This is an open-label (both physician and participant know the name of the study drug), non-randomized, multicenter (when more than one hospital or medical school team work on a medical research study) and long-term efficacy and safety study of JNS013 (combination of tramadol hydrochloride (TRAM) with acetaminophen \[APAP\]) in participants with chronic pain (aching sensation that persists for more than a few months. It may or may not be associated with trauma or disease, and may persist after the initial injury has healed. Its localization, character, and timing are more vague than with acute pain). This study consists of 4 periods; screening period: 1 week, treatment period I: 4 weeks, treatment period II: 48 weeks and follow-up period: 1 week. During Treatment Period I, restrictions on concomitant treatments will be established and the participants will be treated with one or two tablets of JNS013, four times daily for four weeks. During Treatment Period II, the participants will be treated for 48 weeks using the same dosing method and dose level for JNS013 as was used during Treatment Period I, permitting modifications to the concomitant drugs/therapies as during normal medical care. Throughout both Treatment Period I and Treatment Period II, the decision will be made to permit the participants to select to use either one or two tablets of JNS013 per dose according to the extent of the participant's pain and tolerability. The total duration of treatment period will be of 52 weeks. Efficacy will be assessed using change from baseline in Visual Analogue Scale for pain (VAS24) score at the pre-defined time point until Week 52. Participants safety will be monitored throughout the study.
Interventions
DRUGTramadol Hydrochloride (HCL) plus Acetaminophen (JNS013)
Tramadol hydrochloride 37.5 milligram (mg) plus acetaminophen 325 mg (JNS013) one or two tablets will be given orally four times daily (maximum dose is 8 tablets per day) for 4 weeks during treatment period 1 (restrictions on concomitant treatments will be established) and for 48 weeks during treatment period 2 (permitting modifications to the concomitant drugs/therapies). The dosing interval will be of at least 4 hours.
Sponsors
Janssen Pharmaceutical K.K.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants whose pain cannot be controlled sufficiently with at least 14-day continuous treatment with identical oral non steroid anti inflammatory drugs (NSAIDs) at a usual maximum dose during 3 months prior to this study * Ambulatory participants without need for any supportive device or assistance during daily life * Outpatients * Participants who do not plan to change the therapeutic policy and content of the medications for underlying disease during screening period to the end of Treatment Period I * Sustention of chronic pain due to Osteo Arthritis (OA), Low Back Pain (LBP), Rheumatoid Arthritis (RA), Neck Shoulder Arm Syndrome (NSAS), Diabetic Neuropathy (DN), Post herpetic Neuralgia (PHN) or other for at least 3 months
Exclusion criteria
* Participants with conditions for which opioids are contraindicated * Participants with conditions for which APAP are 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Visual Analogue Scale (VAS24) Score at Week 4 | Baseline and Week 4 | Pain over the last 24 hours was assessed by using VAS score ranges from 0 millimeter (mm)=no pain to 100 mm=worst possible pain. An increase in score from baseline represented disease progression and decrease represented improvement. |
| Change From Baseline in VAS24 Score at Week 52 | Baseline and Week 52 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Relief (PAR) Score at Week 4 | Week 4 | Pain relief was evaluated based on a 5-stage scale from 4 (complete relief) to 0 (no relief). An increase in score represented improvement and decrease represented disease progression |
| Number of Participants With Improvement From Baseline in VAS24 Score | Week 4 and 52 | 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. |
| Change From Baseline in Short Form-36 (SF-36) Score | Baseline, Week 4 and 52 | SF-36 is a metric for general health and Quality of Life (QOL), consists of 8 sub-scale indices related to health and QOL (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health). Each of the sub-scale scores ranged from 0 to 100, where higher values indicate a better health status or a better mental status. |
| Pain Relief Combined With Pain Intensity Difference (PRID) at Week 4 | Week 4 | PRID was sum of the PID and PAR for each participant at each evaluation time point (2 hours after dosing, 4 hours after dosing). Pain Intensity was evaluated on a 4-stage scale ranges from 3=severe pain to 0=no pain and PID ranges from -3 (the worst) to +3 (the most improved). PAR ranges from 0 (no improved) to +4 (the most improved). PRID ranges from -3 (the worst) to +7 (the most improved). |
| Pain Intensity Difference (PID) at Week 4 | Week 4 | PID is defined as the amount of change in the pain intensity at each evaluation time point (at 2 and 4 hours after the study drug dosing) from the baseline for each participant. Pain Intensity was evaluated on a 4-stage scale ranging from 3=severe pain to 0=no pain. PID ranges from -3 (the worst) to +3 (the most improved). |
Countries
Japan
Participant flow
Pre-assignment details
219 participants were enrolled in this study out of which 29 participants did not meet the criteria to transfer to treatment period 1.
Participants by arm
| Arm | Count |
|---|---|
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) Tramadol hydrochloride 37.5 milligram (mg) plus acetaminophen 325 mg (JNS013) one or two tablets was given orally four times daily (maximum dose was 8 tablets per day) for 4 weeks during treatment period 1 (restrictions on concomitant treatments was established) and for 48 weeks during treatment period 2 (permitting modifications to the concomitant drugs/therapies). The dosing interval was of at least 4 hours. | 190 |
| Total | 190 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 43 |
| Overall Study | did not attend hospital appointments | 1 |
| Overall Study | not eligible for Treatment Period I | 22 |
| Overall Study | Physician Decision | 5 |
| Overall Study | violation of eligibility criteria | 2 |
| Overall Study | Withdrawal by Subject | 49 |
Baseline characteristics
| Characteristic | Tramadol Hydrochloride Plus Acetaminophen (JNS013) |
|---|---|
| Age, Continuous | 64.3 years STANDARD_DEVIATION 12.9 |
| Sex: Female, Male Female | 106 Participants |
| Sex: Female, Male Male | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 189 / 190 |
| serious Total, serious adverse events | 24 / 190 |
Outcome results
Primary
Change From Baseline in VAS24 Score at Week 52
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.
Time frame: Baseline and Week 52
Population: Full analysis set included all participants who met the eligibility criteria, received study medication and had at least one post-treatment efiicacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in VAS24 Score at Week 52 | Baseline | 65.80 millimeter | Standard Deviation 11.629 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in VAS24 Score at Week 52 | Change at Week 52 | -36.54 millimeter | Standard Deviation 21.936 |
Primary
Change From Baseline in Visual Analogue Scale (VAS24) Score at Week 4
Pain over the last 24 hours was assessed by using VAS score ranges from 0 millimeter (mm)=no pain to 100 mm=worst possible pain. An increase in score from baseline represented disease progression and decrease represented improvement.
Time frame: Baseline and Week 4
Population: Full analysis set included all participants who met the eligibility criteria, received study medication and had at least one post-treatment efiicacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Visual Analogue Scale (VAS24) Score at Week 4 | Baseline | 65.80 millimeter | Standard Deviation 11.629 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Visual Analogue Scale (VAS24) Score at Week 4 | Change at Week 4 | -22.28 millimeter | Standard Deviation 21.189 |
Secondary
Change From Baseline in Short Form-36 (SF-36) Score
SF-36 is a metric for general health and Quality of Life (QOL), consists of 8 sub-scale indices related to health and QOL (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health). Each of the sub-scale scores ranged from 0 to 100, where higher values indicate a better health status or a better mental status.
Time frame: Baseline, Week 4 and 52
Population: Full analysis set included all participants who met the eligibility criteria, received study medication and had at least one post-treatment efiicacy assessment. 'N' (number of participants analyzed) signifies participants evaluable for this measure and n = the number of participants with measurements for that time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Physical functioning:Baseline | 33.7 units on a scale | Standard Deviation 17.03 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Role-emotional:Baseline | 39.4 units on a scale | Standard Deviation 14.97 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Physical functioning:Change at Week 4 (n=150) | 2.9 units on a scale | Standard Deviation 9.06 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Physical functioning:Change at Week 52 (n=96) | 4.1 units on a scale | Standard Deviation 12 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Role-physical:Baseline | 35.0 units on a scale | Standard Deviation 15.43 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Role-physical:Change at Week 4 (n=150) | 3.2 units on a scale | Standard Deviation 11.51 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Role-physical:Change at Week 52 (n=96) | 6.0 units on a scale | Standard Deviation 13.76 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Bodily pain:Baseline | 33.7 units on a scale | Standard Deviation 6.7 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Bodily pain:Change at Week 4 (n=150) | 5.5 units on a scale | Standard Deviation 7.12 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Bodily pain:Change at Week 52 (n=96) | 9.0 units on a scale | Standard Deviation 8.74 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | General health:Baseline | 42.1 units on a scale | Standard Deviation 10.42 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | General health:Change at Week 4 (n=150) | 1.5 units on a scale | Standard Deviation 7.74 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | General health:Change at Week 52 (n=96) | 3.9 units on a scale | Standard Deviation 8.92 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Vitality:Baseline | 44.0 units on a scale | Standard Deviation 9.82 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Vitality:Change at Week 4 (n=150) | 2.1 units on a scale | Standard Deviation 8.37 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Vitality:Change at Week 52 (n=96) | 4.9 units on a scale | Standard Deviation 9.38 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Social functioning:Baseline | 41.0 units on a scale | Standard Deviation 13.61 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Social functioning:Change at Week 4 (n=150) | 2.7 units on a scale | Standard Deviation 11.36 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Social functioning:Change at Week 52 (n=96) | 6.0 units on a scale | Standard Deviation 11.57 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Role-emotional:Change at Week 4 (n=150) | 2.6 units on a scale | Standard Deviation 12.43 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Role-emotional:Change at Week 52 (n=96) | 5.2 units on a scale | Standard Deviation 14.44 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Mental health:Baseline | 43.9 units on a scale | Standard Deviation 11.5 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Mental health:Change at Week 4 (n=150) | 2.5 units on a scale | Standard Deviation 8.73 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Change From Baseline in Short Form-36 (SF-36) Score | Mental health:Change at Week 52 (n=96) | 5.5 units on a scale | Standard Deviation 10.11 |
Secondary
Number of Participants With Improvement From Baseline in VAS24 Score
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.
Time frame: Week 4 and 52
Population: Full analysis set included all participants who met the eligibility criteria, received study medication and had at least one post-treatment efiicacy assessment. Last Observation Carried Forward (LOCF) method was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Number of Participants With Improvement From Baseline in VAS24 Score | Improvement of 30 percent or more at Week 4 | 76 participants |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Number of Participants With Improvement From Baseline in VAS24 Score | Improvement of 50 percent or more at Week 4 | 51 participants |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Number of Participants With Improvement From Baseline in VAS24 Score | Improvement of 30 percent or more at Week 52 | 110 participants |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Number of Participants With Improvement From Baseline in VAS24 Score | Improvement of 50 percent or more at Week 52 | 77 participants |
Secondary
Pain Intensity Difference (PID) at Week 4
PID is defined as the amount of change in the pain intensity at each evaluation time point (at 2 and 4 hours after the study drug dosing) from the baseline for each participant. Pain Intensity was evaluated on a 4-stage scale ranging from 3=severe pain to 0=no pain. PID ranges from -3 (the worst) to +3 (the most improved).
Time frame: Week 4
Population: Full analysis set included all participants who met the eligibility criteria, received study medication and had at least one post-treatment efiicacy assessment. Participants showing a Pain Intensity (PI) value of 0 prior to dosing at each evaluation time point were not included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Pain Intensity Difference (PID) at Week 4 | 2 hours after dosing at Week 4 | 0.1 units on a scale | Standard Deviation 0.35 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Pain Intensity Difference (PID) at Week 4 | 4 hours after dosing at Week 4 | 0.1 units on a scale | Standard Deviation 0.44 |
Secondary
Pain Relief Combined With Pain Intensity Difference (PRID) at Week 4
PRID was sum of the PID and PAR for each participant at each evaluation time point (2 hours after dosing, 4 hours after dosing). Pain Intensity was evaluated on a 4-stage scale ranges from 3=severe pain to 0=no pain and PID ranges from -3 (the worst) to +3 (the most improved). PAR ranges from 0 (no improved) to +4 (the most improved). PRID ranges from -3 (the worst) to +7 (the most improved).
Time frame: Week 4
Population: Full analysis set included all participants who met the eligibility criteria, received study medication and had at least one post-treatment efiicacy assessment. Participants showing a Pain Intensity (PI) value of 0 prior to dosing at each evaluation time point were not included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Pain Relief Combined With Pain Intensity Difference (PRID) at Week 4 | 2 hours after dosing at Week 4 | 1.3 units on scale | Standard Deviation 1.06 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Pain Relief Combined With Pain Intensity Difference (PRID) at Week 4 | 4 hours after dosing at Week 4 | 1.4 units on scale | Standard Deviation 1.2 |
Secondary
Pain Relief (PAR) Score at Week 4
Pain relief was evaluated based on a 5-stage scale from 4 (complete relief) to 0 (no relief). An increase in score represented improvement and decrease represented disease progression
Time frame: Week 4
Population: Full analysis set included all participants who met the eligibility criteria, received study medication and had at least one post-treatment efiicacy assessment. Participants showing a Pain Intensity (PI) value of 0 prior to dosing at each evaluation time point were not included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Pain Relief (PAR) Score at Week 4 | 2 hours after dosing at Week 4 | 1.3 units on a scale | Standard Deviation 0.91 |
| Tramadol Hydrochloride Plus Acetaminophen (JNS013) | Pain Relief (PAR) Score at Week 4 | 4 hours after dosing at Week 4 | 1.3 units on a scale | Standard Deviation 0.99 |