Spinal Disorders
Conditions
Keywords
spinal disorders
Brief summary
Study Objectives: 1. Primary objective \- To assess the pain reduction after 8 weeks treatment from baseline (week 0) 2. Secondary objectives * To assess the pain reduction after 4 weeks treatment from baseline (week 0) * To assess the EQ-5D * To assess physician's overall satisfaction * To assess subject's overall satisfaction * To assess safety
Detailed description
Study Design (Methodology): This will be a multicenter, phase IV, interventional study to assess the efficacy and safety of TARGIN(R)(Oxycodone/Naloxone) in Korean patients who are dissatisfied with their current analgesic medication (WHO step II analgesics). Upon providing written informed consent, subject will be screened in the study and assessment will be performed at that time such as safety laboratory assessments, physical examination, vital sign, medical history taking, 24 hours pain intensity score, EQ-5D, physician's overall satisfaction and subject's overall satisfaction. If patient is eligible in inclusion/exclusion criteria at the time of visit 1, the patient will receive treatment with TARGIN(R). Re-screening, study drug dose interruption is not allowed. The duration of study drug dose interruption is defined as for 1 week. Treatment with TARGIN(R) will be started at 5/2.5mg b.i.d.,and proper titration (up titration) will be allowed at each visit or at unscheduled visit according to the investigator's decision. On-site visit or phone call will be allowed for visit 2(wk 1).The up titration will be considered by investigator's judgement as followings; (1) if the rescue medication was used more than 2 times per day, on average or (2) based on the daily average numerical rating scale , if the numerical rating scale was changed to worsen since the previous visit, (3) Investigator's judgement by considering any titration needed situation (e.g. dose, frequency of rescue medication). Pain assessment by investigator at each visit will be used for analysis and criteria for uptitration. Daily pain diary will be used for only criteria for uptitration. Safety laboratories will be obtained at baseline (visit 1) and study end (visit 4) in a local laboratory. The laboratory values within 4 weeks prior to baseline (visit 1) will be allowed to use at study visit 1. The rescue medication is the IRcodon(R). Patients will be withdrawn from the study if the following circumstance require study drug discontinuation: * Failure of pain control (Failure of pain control will be decided by investigators judgement, e.g. there is poor pain control or lack of efficacy despite 2\ 3 times of titration.) * Adjustment of the other analgesics due to Adverse event except TARGIN(R) or IRcodon(R) * Adjustment of the other major pain management modality (e.g. surgery, non-surgical interventional therapy, etc.) * Withdrawal of informed consent * Pregnancy * Any other significant risk to the patient's safety in the clinical judgement of the investigator
Interventions
Targin 5mg, 10mg, 20mg up to 40mg b.i.d
Sponsors
Mundipharma Korea Ltd
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female ≥ 20 and \<80 years of age * Patients who have spinal disorders related pain for over 90days * Patients who have moderate to severe pain intensity which is not controlled with weak opioids or NSAIDs: NRS ≥ 4 * Naïve patients for Oxycodone/Naloxone * Naïve patients for strong opioid * Patients who signed a written informed consent form
Exclusion criteria
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive urine pregnancy test * Patients with known hypersensitivity to Oxycodone/Naloxone or to any of the excipients * Patients with severe respiratory depression with hypoxia and/or hypercapnoea * Patients with severe chronic obstructive pulmonary disease * Patients with cor pulmonale * Patients with severe bronchial asthma * Patients who have been diagnosed or is suspected of having paralytic or obstructive ileus.Patients with moderate to severe hepatic impairment * Targin(R) product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take * Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels (\>2.5 times the upper limit of normal, it is allowed \>5 times the upper limit of normal in case of transition in liver) or an abnormal total bilirubin and/or creatinine level (s)(greater than 1.5 times the upper limit of normal), gamma glutamyl transpeptidase (GGT or GGTP) ≥ 3 times the upper limit of normal * Patients with uncontrolled seizures * Requiring interventional treatment for pain such as neurodestructive procedure or regional infusion * Patients with increased intracranial pressure * In the investigator's opinion, subjects who are receiving hypnotics or central nervous system (CNS) depressants that may pose a risk of additional CNS depression with opioid study medication * Patients with myxodema, not adequately treated hypothyroidism or Addisons disease * Patients receiving opioid substitution therapy for opioid addiction (e.g. methadone or buprenorphine) * Clinically significant impairment of cardiovascular, respiratory and renal function * Major surgery within 1 month prior to screening or planned surgery * Mainly pain originated other than spinal disorders disease * Non-malignant patients or cancer patients who are receiving any oncology treatment that could affect the measure of pain control * Patients with uncontrolled constipation regardless of laxative use and/or laxative type * With a disability that may prevent the patient from completing all study requirements and in particular, interfere with 24hrs pain intensity score * Patients known to have, or suspected of having a history of drug abuse * Patients with history of opioid or drug dependence * Any situation where opioids are contraindicated * Patient who needs acute dose titration or whose pain intensity fluctuate significantly in a short period according to investigator's judgment * Having used other investigational drugs at the time of enrollment No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pain Intensity of Patient With Spinal Disorder as Measured by NRS. | Baseline, 8 week | NRS-Pain scale assessed the severity of a subject's pain of mean pain over the past 24 hours prior to the visit on a scale of 0 (No pain) and 10 (Worst possible pain). Change = mean score at Week 8/ET minus mean score at Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change in Quality of Life (EQ-5D) at Week 8 of Treatment With the Study Drug From Baseline | Baseline, 8 week | EQ-5D to measure of health related quality of life should be answered as one of 3 levels about current condition for 5 dimensions and was calculated total average by giving a weighting on 3 level of answers (EQ-5D levels into 'no problems' (level 1) and 'problems' (level 2 and 3)). Table of scores by each level for EQ-5D items: mobility(level 1=0, level2=0.069,level 3=0.314), self care(level 1=0, level2=0.104,level 3=0.214), usual activities(level 1=0, level2=0.036,level 3=0.094), pain/discomfort (level 1=0, level2=0.,level 3=0.386) and anxiety/depression(level 1=0, level2=0.071,level 3=0.2) \*EQ-5D Total = 1 - 0.081 - (the score of the each level) - 0.269 (if at least one of level 3 presents) EQ-5D total score could be 0.919 in maximum and -0.594 in minimum if case all index indicates the level 3. So, if EQ-5D total score closed by 1 means that the healthy condition and high quality of life. |
| Clinical Global Impression of Change(CGIC) | Baseline, 8 week | The number of patients who choose the best opinion of overall satisfaction among Clinical Global Impression of Change Scale(CGIC) among 7 point scale. Missing data was imputed by LOCF. Very much improved much improved minimally improved no change minimally worse much worse very much worse |
| Change of Pain Intensity in Patient With Spinal Disorder at Week 4 of Treatment With the Study Drug From Baseline | Baseline, 4 week | NRS-Pain scale assessed the severity of a subject's pain of mean pain over the past 24 hours prior to the visit on a scale of 0 (No pain) and 10 (Worst possible pain). Change = mean score at Week 4/ET minus mean score at Baseline. |
| Change From Baseline in Health-related Quality of Life Assessed by EuroQol Visual Analog Scale (EQ-5D VAS) | Baseline, 8 weeks | The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' (score = 100) and 'Worst imaginable health state' (score = 0). Higher points were positive results and positive points of difference gap means improvement results. |
| Patient Global Impression of Change(PGIC) | Baseline, 8week | Number of participants with categorical change in overall satisfaction. PGIC: a participant-rated instrument assessing change in participant's overall satisfaction from baseline, on a scale ranging from 1 (very much improved) to 7 (very much worse). |
Participant flow
Recruitment details
The 10 general hospitals were recruited patients from 26 Sep. 2012 to 02 Aug. 2013.
Participants by arm
| Arm | Count |
|---|---|
| Oxycodone/Naloxone Single-arm study
Oxycodone/Naloxone: 8 weeks treatment with Oxycodone/Naloxone | 220 |
| Total | 220 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 25 |
| Overall Study | Lack of Efficacy | 4 |
| Overall Study | Protocol Violation | 4 |
| Overall Study | subject refused study medication | 6 |
| Overall Study | Withdrawal by Subject | 42 |
Baseline characteristics
| Characteristic | Oxycodone/Naloxone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 134 Participants |
| Age, Categorical Between 18 and 65 years | 86 Participants |
| Age, Continuous | 62.25 years STANDARD_DEVIATION 10.42 |
| Region of Enrollment Korea, Republic of | 220 participants |
| Sex: Female, Male Female | 136 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 | 77 / 220 |
| serious Total, serious adverse events | 3 / 220 |
Outcome results
Primary
Change From Baseline in Pain Intensity of Patient With Spinal Disorder as Measured by NRS.
NRS-Pain scale assessed the severity of a subject's pain of mean pain over the past 24 hours prior to the visit on a scale of 0 (No pain) and 10 (Worst possible pain). Change = mean score at Week 8/ET minus mean score at Baseline.
Time frame: Baseline, 8 week
Population: The 209 is IIT set population. ITT set included all subjects who participated in the study and had at least one dose of the study drug and had at least one primary efficacy endpoint data available.~Missing values were imputed by LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxycodone/Naloxone | Change From Baseline in Pain Intensity of Patient With Spinal Disorder as Measured by NRS. | -1.69 scores on a scale | Standard Deviation 2.18 |
p-value: <0.05t-test, 2 sided
Secondary
Change From Baseline in Health-related Quality of Life Assessed by EuroQol Visual Analog Scale (EQ-5D VAS)
The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' (score = 100) and 'Worst imaginable health state' (score = 0). Higher points were positive results and positive points of difference gap means improvement results.
Time frame: Baseline, 8 weeks
Population: ITT set, Missing values were imputed by LOCF. Difference (Visti 4(8w)-Baseline)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxycodone/Naloxone | Change From Baseline in Health-related Quality of Life Assessed by EuroQol Visual Analog Scale (EQ-5D VAS) | 10.57 scores on a scale | Standard Deviation 22.11 |
Secondary
Change of Pain Intensity in Patient With Spinal Disorder at Week 4 of Treatment With the Study Drug From Baseline
NRS-Pain scale assessed the severity of a subject's pain of mean pain over the past 24 hours prior to the visit on a scale of 0 (No pain) and 10 (Worst possible pain). Change = mean score at Week 4/ET minus mean score at Baseline.
Time frame: Baseline, 4 week
Population: IIT set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxycodone/Naloxone | Change of Pain Intensity in Patient With Spinal Disorder at Week 4 of Treatment With the Study Drug From Baseline | -1.36 units on a scale | Standard Deviation 2.04 |
Secondary
Clinical Global Impression of Change(CGIC)
The number of patients who choose the best opinion of overall satisfaction among Clinical Global Impression of Change Scale(CGIC) among 7 point scale. Missing data was imputed by LOCF. Very much improved much improved minimally improved no change minimally worse much worse very much worse
Time frame: Baseline, 8 week
Population: ITT Population. Below results : Visit 4(8week)(LOCF): n(%)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oxycodone/Naloxone | Clinical Global Impression of Change(CGIC) | Very much improved | 20 participants |
| Oxycodone/Naloxone | Clinical Global Impression of Change(CGIC) | Much improved | 49 participants |
| Oxycodone/Naloxone | Clinical Global Impression of Change(CGIC) | Minimally improved | 70 participants |
| Oxycodone/Naloxone | Clinical Global Impression of Change(CGIC) | No change | 57 participants |
| Oxycodone/Naloxone | Clinical Global Impression of Change(CGIC) | Minimally worse | 6 participants |
| Oxycodone/Naloxone | Clinical Global Impression of Change(CGIC) | much worse | 5 participants |
| Oxycodone/Naloxone | Clinical Global Impression of Change(CGIC) | Very much worse | 2 participants |
Secondary
Patient Global Impression of Change(PGIC)
Number of participants with categorical change in overall satisfaction. PGIC: a participant-rated instrument assessing change in participant's overall satisfaction from baseline, on a scale ranging from 1 (very much improved) to 7 (very much worse).
Time frame: Baseline, 8week
Population: IIT set, Missing values were imputed by LOCF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oxycodone/Naloxone | Patient Global Impression of Change(PGIC) | Very much improved | 16 participants |
| Oxycodone/Naloxone | Patient Global Impression of Change(PGIC) | Much improved | 49 participants |
| Oxycodone/Naloxone | Patient Global Impression of Change(PGIC) | Minimally improved | 69 participants |
| Oxycodone/Naloxone | Patient Global Impression of Change(PGIC) | Minimally worse | 6 participants |
| Oxycodone/Naloxone | Patient Global Impression of Change(PGIC) | Much worse | 6 participants |
| Oxycodone/Naloxone | Patient Global Impression of Change(PGIC) | Very much worse | 3 participants |
| Oxycodone/Naloxone | Patient Global Impression of Change(PGIC) | No change | 60 participants |
Secondary
The Change in Quality of Life (EQ-5D) at Week 8 of Treatment With the Study Drug From Baseline
EQ-5D to measure of health related quality of life should be answered as one of 3 levels about current condition for 5 dimensions and was calculated total average by giving a weighting on 3 level of answers (EQ-5D levels into 'no problems' (level 1) and 'problems' (level 2 and 3)). Table of scores by each level for EQ-5D items: mobility(level 1=0, level2=0.069,level 3=0.314), self care(level 1=0, level2=0.104,level 3=0.214), usual activities(level 1=0, level2=0.036,level 3=0.094), pain/discomfort (level 1=0, level2=0.,level 3=0.386) and anxiety/depression(level 1=0, level2=0.071,level 3=0.2) \*EQ-5D Total = 1 - 0.081 - (the score of the each level) - 0.269 (if at least one of level 3 presents) EQ-5D total score could be 0.919 in maximum and -0.594 in minimum if case all index indicates the level 3. So, if EQ-5D total score closed by 1 means that the healthy condition and high quality of life.
Time frame: Baseline, 8 week
Population: ITT set included all subjects who participated in the study and had at least one dose of the study drug and had at least one primary efficacy endpoint data available.Missing values were imputed by LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxycodone/Naloxone | The Change in Quality of Life (EQ-5D) at Week 8 of Treatment With the Study Drug From Baseline | 0.15 scores on a scale | Standard Deviation 0.37 |
p-value: <0.0595% CI: [0, 1.12]t-test, 2 sided