Pain, Peripheral Neuropathy
Conditions
Keywords
Pain, Peripheral Neuropathy
Brief summary
The purpose of this study is to assess the maintenance of effect after long-term treatment of Sativex® in subjects with neuropathic pain.
Detailed description
A five week randomised-withdrawal phase (Part B) for a subset of subjects who took part in a 38 week, multicentre, open label (Part A) follow-on study to evaluate, the maintenance of effect of, the development of tolerance through exposure to, and safety of, Sativex® in the treatment of subjects with neuropathic pain. Subjects returned to the centre for an end of treatment visit at week 38 of Part A (Visit 5, Day 266), followed by Visits 5b (week 39), 5c (week 43) and an end of study visit took place 28 days after Visit 5c or withdrawal from the study.
Interventions
DRUGSativex®
Containing THC (27 mg/ml):CBD (25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavoring. Maximum permitted dose was eight actuations in any three hour period and 24 actuations (THC 65 mg: CBD 60 mg) in 24 hours
DRUGPlacebo
containing peppermint oil, 0.05% (v/v), quinoline yellow, 0.005% (w/v), sunset yellow, 0.0025% (w/v), in ethanol:propylene glycol (50:50) excipient
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Had participated in GWCL0404, was currently ongoing in the study (i.e. still receiving GW-1000-02 treatment) and had completed the study up to Visit 5 * Had complied with all of the study requirements to-date, including the completion of the diary cards * Had shown tolerability to the study medication in this study * Ability (in the investigators opinion) and willingness to comply with all study requirements, including the completion of diary cards and study questionnaires
Exclusion criteria
* Had experienced or was currently experiencing any adverse events or untoward medical occurrences which, in the opinion of the investigator, would prevent them from safely participating in this phase of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Daily Pain Severity on a 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment) | Day 0-35 | The pain severity Numerical Rating Scale was complete at the same time each day, i.e. bedtime in the evening. The patient was asked on a scale of '0 to 10', please indicate the number that best describes your pain severity in the last 24 hours where 0 = no pain and 10 = pain as bad as you can imagine. No pain relates to the time prior to the onset of neuropathic pain. A negative value indicates an improvement in pain score from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Failed Treatment at the End of the Treatment Period | Day 7 to time of last dose | Treatment failure was defined as follows: A. Premature termination of Part B (Randomised-Withdrawal) study medication. All subjects who did not complete at least 28 days on Part B (Randomised-Withdrawal) study medicationOr: B. An increase in pain, i.e. the mean pain 0-10 Numerical Rating Scale over seven consecutive days after Part B (Randomised-Withdrawal) randomisation had increased by at least 20% from the Part B (Randomised-Withdrawal) randomised treatment baseline. |
| Number of Subjects With More Than a 20% Loss of Response at the End of Treatment | Day 0-35 | The percentage change from baseline in mean 0-10 Numerical Rating Scale pain score was calculated. The percentage changes from baseline were classified and the number of subjects with 20% or greater loss of response to treatment (i.e. percent increase from baseline ≥ 20%) is presented. |
| Change From Baseline Neuropathic Pain Score at the End of Treatment | Day 7 to 35 | The Neuropathic Pain Scale score is the 0-100 sum of 10 individual pain scores (0-10 Numerical Rating Scale, 0= no pain to 10 = most pain imaginable). A negative change from baseline indicates an improvement in pain. |
| Subject Global Impression of Change at the End of Treatment | Day 7 to 35 | A 7-point Likert-type scale was used, with the question: 'Please assess the status of your nerve pain since entry into the study using the scale below' with the markers very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse. The number of subjects wo reported an improvement is presented. |
| Incidence of Adverse Events as a Measure of Subject Safety | Day 0 -35 | The number of subjects who experienced an adverse event during the course of the study is presented. |
| Change From Baseline in Sleep Disruption 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment) | Day 0-35 | The sleep disruption Numerical Rating Scale was completed at the same time each day, i.e. bedtime in the evening. The patient was asked on a scale of '0 to 10', please indicate how your pain disrupted your sleep last night? where 0 = did not disrupt sleep and 10 = completely disrupted (unable to sleep at all). A negative value indicates an improvement in sleep disruption score from baseline. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sativex Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 24 actuations (THC 64.8 mg:CBD 60 mg) in 24 hours. | 10 |
| Placebo Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period. | 9 |
| Total | 19 |
Baseline characteristics
| Characteristic | Sativex | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 8 Participants | 18 Participants |
| Age, Continuous | 51.7 years STANDARD_DEVIATION 4.69 | 56.1 years STANDARD_DEVIATION 10.33 | 53.8 years STANDARD_DEVIATION 7.98 |
| Region of Enrollment Czech Republic | 8 participants | 7 participants | 15 participants |
| Region of Enrollment United Kingdom | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 10 | 2 / 9 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 |
Outcome results
Primary
Change From Baseline in Mean Daily Pain Severity on a 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment)
The pain severity Numerical Rating Scale was complete at the same time each day, i.e. bedtime in the evening. The patient was asked on a scale of '0 to 10', please indicate the number that best describes your pain severity in the last 24 hours where 0 = no pain and 10 = pain as bad as you can imagine. No pain relates to the time prior to the onset of neuropathic pain. A negative value indicates an improvement in pain score from baseline.
Time frame: Day 0-35
Population: The efficacy analyses were conducted on data from all subjects who were randomised, received at least one dose of study medication and yielded on-treatment efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline in Mean Daily Pain Severity on a 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment) | 0.57 units on a scale | Standard Deviation 1.06 |
| Placebo | Change From Baseline in Mean Daily Pain Severity on a 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment) | -0.49 units on a scale | Standard Deviation 2.32 |
Comparison: The two groups were compared using Analysis of Covariance (ANCOVA) with baseline severity as a covariate and study centre group and treatment group as factors. Due to the low power of the test for interaction the test was performed at the 10% level of significance and a 95% confidence interval (CI) was presented for the difference between treatments.p-value: 0.27395% CI: [-0.78, 2.56]ANCOVA
Secondary
Change From Baseline in Sleep Disruption 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment)
The sleep disruption Numerical Rating Scale was completed at the same time each day, i.e. bedtime in the evening. The patient was asked on a scale of '0 to 10', please indicate how your pain disrupted your sleep last night? where 0 = did not disrupt sleep and 10 = completely disrupted (unable to sleep at all). A negative value indicates an improvement in sleep disruption score from baseline.
Time frame: Day 0-35
Population: The efficacy analyses were conducted on data from all subjects who were randomised, received at least one dose of study medication and yielded on-treatment efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline in Sleep Disruption 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment) | 0.24 units on a scale | Standard Deviation 1.58 |
| Placebo | Change From Baseline in Sleep Disruption 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment) | 0.12 units on a scale | Standard Deviation 0.97 |
Comparison: The two groups were compared using Analysis of Covariance (ANCOVA) with baseline severity as a covariate and study centre group and treatment group as factors. Due to the low power of the test for interaction the test was performed at the 10% level of significance and a 95% confidence interval (CI) was presented for the difference between treatments.p-value: 0.90295% CI: [-1.45, 1.29]ANCOVA
Secondary
Change From Baseline Neuropathic Pain Score at the End of Treatment
The Neuropathic Pain Scale score is the 0-100 sum of 10 individual pain scores (0-10 Numerical Rating Scale, 0= no pain to 10 = most pain imaginable). A negative change from baseline indicates an improvement in pain.
Time frame: Day 7 to 35
Population: The efficacy analyses were conducted on data from all subjects who were randomised, received at least one dose of study medication and yielded on-treatment efficacy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sativex | Change From Baseline Neuropathic Pain Score at the End of Treatment | 2.56 units on a scale | Standard Deviation 5.57 |
| Placebo | Change From Baseline Neuropathic Pain Score at the End of Treatment | -2.06 units on a scale | Standard Deviation 9.87 |
Comparison: The two groups were compared using Analysis of Covariance (ANCOVA) with baseline severity as a covariate and study centre group and treatment group as factors. Due to the low power of the test for interaction the test was performed at the 10% level of significance and a 95% confidence interval (CI) was presented for the difference between treatments.p-value: 0.29695% CI: [-4.51, 13.75]ANCOVA
Secondary
Incidence of Adverse Events as a Measure of Subject Safety
The number of subjects who experienced an adverse event during the course of the study is presented.
Time frame: Day 0 -35
Population: The safety analysis set comprised all subjects who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Incidence of Adverse Events as a Measure of Subject Safety | 3 participants |
| Placebo | Incidence of Adverse Events as a Measure of Subject Safety | 2 participants |
Secondary
Number of Subjects Who Failed Treatment at the End of the Treatment Period
Treatment failure was defined as follows: A. Premature termination of Part B (Randomised-Withdrawal) study medication. All subjects who did not complete at least 28 days on Part B (Randomised-Withdrawal) study medicationOr: B. An increase in pain, i.e. the mean pain 0-10 Numerical Rating Scale over seven consecutive days after Part B (Randomised-Withdrawal) randomisation had increased by at least 20% from the Part B (Randomised-Withdrawal) randomised treatment baseline.
Time frame: Day 7 to time of last dose
Population: The efficacy analyses were conducted on data from all subjects who were randomised, received at least one dose of study medication and yielded on-treatment efficacy data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Number of Subjects Who Failed Treatment at the End of the Treatment Period | 5 participants |
| Placebo | Number of Subjects Who Failed Treatment at the End of the Treatment Period | 4 participants |
Comparison: Time to treatment failure was analysed using Kaplan-Meier Survival analysis methodology. The difference in loss of response cumulative distribution function between treatments was assessed using the Hodges-Lehmann estimate.p-value: 0.826Log Rank
Secondary
Number of Subjects With More Than a 20% Loss of Response at the End of Treatment
The percentage change from baseline in mean 0-10 Numerical Rating Scale pain score was calculated. The percentage changes from baseline were classified and the number of subjects with 20% or greater loss of response to treatment (i.e. percent increase from baseline ≥ 20%) is presented.
Time frame: Day 0-35
Population: The efficacy analyses were conducted on data from all subjects who were randomised, received at least one dose of study medication and yielded on-treatment efficacy data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Number of Subjects With More Than a 20% Loss of Response at the End of Treatment | 3 participants |
| Placebo | Number of Subjects With More Than a 20% Loss of Response at the End of Treatment | 2 participants |
Comparison: The difference in loss of response cumulative distribution functions between treatments was assessed using the Wilcoxon test with an estimate of the median difference between groups in response level (percent change from baseline) provided by the Hodges-Lehmann estimator.p-value: 0.5495% CI: [-39.7, 9.62]Hodges-Lehmann
Secondary
Subject Global Impression of Change at the End of Treatment
A 7-point Likert-type scale was used, with the question: 'Please assess the status of your nerve pain since entry into the study using the scale below' with the markers very much improved, much improved, slightly improved, no change, slightly worse, much worse or very much worse. The number of subjects wo reported an improvement is presented.
Time frame: Day 7 to 35
Population: The efficacy analyses were conducted on data from all subjects who were randomised, received at least one dose of study medication and yielded on-treatment efficacy data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sativex | Subject Global Impression of Change at the End of Treatment | 5 participants |
| Placebo | Subject Global Impression of Change at the End of Treatment | 4 participants |
Comparison: The two treatment groups were compared using ordinal logistic regression and the proportional odds model. The model incorporated the parent Randomised Controlled Trials (RCTs). The interaction between treatment group and parent RCTs was investigated, but was dropped from the model if found to have little influence. The test was performed at the 10% significance level. The final model was then treatment group and parent RCTs, i.e. the treatment effect was adjusted for parent RCTs baseline.p-value: 0.60395% CI: [0.293, 8.261]Regression, Logistic