A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00713817
• Collaborator: (none)
• Enrollment: 19
• Location: 1
• Arms: 2
• Duration (Months): 4
• Patients Per Site Per Month: 4.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pain; Peripheral Neuropathy	Drug: Sativex®; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Multicentre, Open Label, Follow on Study to Assess the Maintenance of Effect, Tolerance and Safety of Sativex® in the Treatment of Subjects With Neuropathic Pain. This Will be Followed by a Randomised-withdrawal Phase (Part B) for a Subset of Patients
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Jul 1, 2007
• Actual Study Completion Date: Jul 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sativex	Drug: Sativex®; 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; Other Names: GW-1000-02
Placebo Comparator: Placebo	Drug: Placebo; 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; Other Names: GW-4001-01

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pain Management Research, Clinical Trials Unit, Netherwood House, Solihull Hospital	Solihull	West Midlands	United Kingdom	B91 2JL,

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Barbara Hoggart, MBBS, FRCA, Pain Management Research, Clinical Trials Unit, Netherwood House, Solihull Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00713817
• Other Study ID Numbers: GWCL0404 Part B
• First Posted: Jul 11, 2008
• Last Update Posted: Aug 16, 2012
• Last Verified: Jul 1, 2012

• Keywords provided by Jazz Pharmaceuticals: Pain; Peripheral Neuropathy
• Additional relevant MeSH terms: Neuralgia; Peripheral Nervous System Diseases; Nabiximols

Study Results

Participant Flow

Arm/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
Period Title: Overall Study
STARTED	10	9
COMPLETED	10	9
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Sativex	Placebo	Total
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.	Total of all reporting groups
Overall Participants	10	9	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	8 88.9%	18 94.7%
>=65 years	0 0%	1 11.1%	1 5.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.7 (4.69)	56.1 (10.33)	53.8 (7.98)
Sex: Female, Male (Count of Participants)
Female	6 60%	4 44.4%	10 52.6%
Male	4 40%	5 55.6%	9 47.4%
Region of Enrollment (participants) [Number]
United Kingdom	2 20%	2 22.2%	4 21.1%
Czech Republic	8 80%	7 77.8%	15 78.9%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
Measure Participants	10	9
Mean (Standard Deviation) [units on a scale]	0.57 (1.06)	-0.49 (2.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.273
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; -0.78 to 2.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline Neuropathic Pain Score at the End of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
Measure Participants	10	9
Mean (Standard Deviation) [units on a scale]	2.56 (5.57)	-2.06 (9.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.296
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	4.62
	Confidence Interval	(2-Sided) 95%; -4.51 to 13.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Subjects Who Failed Treatment at the End of the Treatment Period
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
Measure Participants	10	9
Number [participants]	5 50%	4 44.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.826
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Chi-square
	Estimated Value	0.048
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Subjects With More Than a 20% Loss of Response at the End of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
Measure Participants	10	9
Number [participants]	3 30%	2 22.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments
	Method	Hodges-Lehmann
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-7.14
	Confidence Interval	(2-Sided) 95%; -39.7 to 9.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Sleep Disruption 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
Measure Participants	10	9
Mean (Standard Deviation) [units on a scale]	0.24 (1.58)	0.12 (0.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.902
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimate mean treatment difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -1.45 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Subject Global Impression of Change at the End of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
Measure Participants	10	9
Number [participants]	5 50%	4 44.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.603
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.557
	Confidence Interval	(2-Sided) 95%; 0.293 to 8.261
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Incidence of Adverse Events as a Measure of Subject Safety
Description	The number of subjects who experienced an adverse event during the course of the study is presented.
Time Frame	Day 0 -35

Outcome Measure Data

Analysis Population Description

The safety analysis set comprised all subjects who received at least one dose of study medication.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	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.	Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
Measure Participants	10	9
Number [participants]	3 30%	2 22.2%

Adverse Events

Time Frame	All adverse events (AEs) occurring from the time of consent to post study follow up (63 days) were collected. All deaths and serious adverse events (SAEs) occurring within 28 days of the final dose of study medication were also collected.
Adverse Event Reporting Description	All AEs occurring during the study were reported on the running logs at the back of the study case report form.
Arm/Group Title	Sativex		Placebo
Arm/Group Description	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.		Contains no active drug but colourants and excipients. The maximum permitted dose was 24 actuations in any 24 hour period.
All Cause Mortality
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		2/9 (22.2%)
Eye disorders
Cataract	0/10 (0%)		1/9 (11.1%)
Gastrointestinal disorders
Stomach discomfort	0/10 (0%)		1/9 (11.1%)
General disorders
Fatigue	1/10 (10%)		0/9 (0%)
Infections and infestations
Onychomycosis	0/10 (0%)		1/9 (11.1%)
Investigations
Weight decreased	1/10 (10%)		0/9 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/10 (10%)		0/9 (0%)
Bone pain	1/10 (10%)		0/9 (0%)
Nervous system disorders
Headache	2/10 (20%)		0/9 (0%)
Tremor	1/10 (10%)		0/9 (0%)
Psychiatric disorders
Insomnia	1/10 (10%)		0/9 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/10 (10%)		0/9 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GW will coordinate the dissemination of data from this study and may solicit input and assistance from the principal investigator. All publications, for example manuscripts, abstracts, oral/slide presentations or book chapters based on this study, must be submitted to GW for corporate review before release.