A Study of Sativex® for Pain Relief Due to Diabetic Neuropathy

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00710424
• Collaborator: (none)
• Enrollment: 297
• Location: 1
• Arms: 2
• Duration (Months): 11
• Patients Per Site Per Month: 27

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of Sativex® compared with placebo in relieving pain due to Diabetic Neuropathy.

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

Detailed Description

This was a 15 week (one week baseline and fourteen weeks treatment period), multicentre, double blind, randomised, placebo controlled, parallel group study to evaluate the efficacy of Sativex in subjects with pain due to diabetic neuropathy. Subjects were screened to determine eligibility and completed a seven-day baseline period. Subjects then returned to the centre for assessment, randomisation and dose introduction. Visits occurred at the end of weeks two, six, ten and at the end of the study (treatment week 14) or earlier if they withdrew. A follow up visit occurred 28 days after completion or withdrawal. Subjects in this study were given the opportunity to be enrolled in an open label extension study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 297 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Double Blind, Randomized, Placebo Controlled, Parallel Group Study of Sativex in the Treatment of Subjects With Pain Due to Diabetic Neuropathy
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Jun 1, 2006
• Actual Study Completion Date: Jun 1, 2006

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%) flavouring. 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. The Change From Baseline in Mean Diabetic Neuropathy Pain 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment) [Day 0 to Day 98]

   The diabetic neuropathy pain Numerical Rating Scale was complete at the end of every day. The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your nerve pain due to diabetes in the last 24 hours" where 0 = no pain and 10 = worst possible pain. No pain relates to the time prior to the onset of pain due to diabetic neuropathy. For those whose evaluable period ended before Day 7, the mean of the available post-randomisation data was used. Those with no post-baseline diary pain 0-10 Numerical Rating Scale scores were excluded from the analysis.

2. Number of Responders at the 30% Improvement Level at the End of Treatment [Day 0 - Day 98]

   A positive 30% pain response is defined as a reduction of at least 30% in the mean NRS average pain score from baseline to week 14 (last 7 days). The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your pain or average pain 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 pain. The average pain NRS was completed at the same time each day, i.e. bedtime in the evening. Estimates were produced for a one-week period, with the evaluable period finishing at the end of the appropriate seven-day period.

Secondary Outcome Measures

1. Change From Baseline in Mean Neuropathic Pain Scale Score at the End of Treatment [Day 0 to Day 98]

   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. The baseline mean Neuropathic Pain Scale score was to be the mean of the two assessments during the baseline period, with the end of study value as the mean of the last two assessments made during the evaluable period.

2. Change From Baseline in Mean Sleep Quality 0-10 Numerical Rating Scale Score at the End of Treatment [Day 0 - Day 98]

   The sleep quality 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 the number that best describes your sleep quality in the last 24 hours" where 0 = slept extremely well and 10 = unable to sleep at all. A negative value indicates an improvement in pain score from baseline. The analyses were based on the change from baseline for the last assessment falling within the evaluable period (considered the end of treatment).

3. Subject Global Impression of Change at the End of Treatment [Day 0 and Day 98]

   The subject was to assess the change in their nerve pain due to diabetic neuropathy at the end of the study compared to baseline on a 7-point scale from very much worse to very much improved. The number of participants reporting each score is presented.

4. Change From Baseline in Mean Brief Pain Inventory (Short Form)'Pain Severity Composite Score' at the End of Treatment [Day 0 and Day 98]

   The brief pain inventory (short form) is a 14-item questionnaire that asks patients to rate pain over the prior week and the degree to which it interferes with activities on a 0 to 10 scale, where 0=no pain and 10=pain as bad as you can imagine. Severity is measured as worst pain, least pain, average pain, and pain right now. The pain severity composite score was calculated as the arithmetic mean of the four severity items (range 0-10). The minimum value is zero and maximum is 10. A higher score represents a poor outcome.

5. Change From Baseline in Mean Quality of Life EuroQol 5-D Weighted Health State Index Score at the End of Treatment Measured by Visual Analogue Scale [Day 0 and Day 98]

   The EuroQol-5D Health Status Visual Analogue Scale rated the health state on a scale of 0-100 with 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition.

6. Change From Baseline in the Use of Rescue Analgesia at the End of Treatment [Day 0 - Day 98]

   The mean daily number of paracetamol tablets used were calculated for the periods over which the primary endpoint was calculated.

7. Incidence of Adverse Events as a Measure of Subject Safety [Day 0 - Day 133]

   The number of subjects who experienced an adverse event during the course of the study (including the follow-up period i.e 28 days after the end of treatment) is presented.

8. Change From Baseline in Mean Intoxication 0-10 Numerical Rating Scale Score at the End of Treatment [Day 0 - Day 98]

   Subjects rated their intoxication levels on a scale of 0-10, where 0 equals "no intoxication" and 10 equals "extreme intoxication". A negaitve value from baseline indicates and improvement. End of treatment was classed as the last on-treatment visit where data was recorded.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Willing and able to give informed consent.

• Male or female, aged 18 years or above.

• Ability (in the investigators opinion) and willingness to comply with all study requirements.

• Diagnosed with Type 1 or 2 diabetes mellitus as diagnosed according to the World Health Organisation (WHO) criteria.

• Diagnosed with neuropathic pain due to distal symmetrical diabetic neuropathy of at least six months duration, as defined by a NDS score of at least 4, and in who pain is not wholly relieved with their current therapy. The NDS score must be attained from at least two different test parameters and not only the ankle jerk reflex.

• The last six daily diary 0-10 NRS pain scores before randomisation summed to at least

• Stable dose of regular pain medication and non-pharmacological therapies (including TENS) for at least 14 days prior to the screening visit and willingness for these to be maintained throughout the study.

• Agreement for the responsible authorities (as applicable in individual countries), their primary care physician, and their consultant, if appropriate, to be notified of their participation in the study.

Exclusion Criteria:

• Concomitant pain thought by the investigator to be of a nature or severity to interfere with their assessment of their painful diabetic neuropathy.

• Uncontrolled diabetes with HbA1c blood levels of more than 11% at Visit1, Day B1.

• Receiving a prohibited medication and were unwilling to stop or comply for the duration of the study.

• Has used cannabinoid based medications within 60 days of study entry and were unwilling to abstain for the duration for the study.

• Has used cannabis within 30 days of study entry and were unwilling to abstain for the duration for the study.

• History of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition.

• Known or suspected history of alcohol or substance abuse.

• History of epilepsy or recurrent seizures.

• Known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP.

• Postural drop of 20mmHg or more in systolic blood pressure at screening.

• Medical history of gastroparesis.

• Evidence of cardiomyopathy.

• Experienced myocardial infarction or clinically relevant cardiac dysfunction within the last 12 months or had a cardiac disorder that, in the opinion of the investigator would put the subject at risk of a clinically relevant arrhythmia or myocardial infarction.

• QT interval; of > 450 ms (males) or > 470 ms (females) at Visit 1.

• Secondary or tertiary AV block or sinus bradycardia (HR <50bpm) or sinus tachycardia (HR>110bpm) at Visit 1.

• Diastolic blood pressure of <50 mmHg or >105 mmHg in a sitting position at rest for five minutes prior to randomisation.

• Impaired renal function i.e., creatinine clearance is lower than 50 ml/min at Visit 1.

• Significantly impaired hepatic function, at Visit 1, in the investigator's opinion.

• Female subjects of child bearing potential and male subjects whose partner was of child bearing potential, unless they were willing to ensure that they or their partner used effective contraception during the study and for three months thereafter.

• If female, were pregnant or lactating, or were planning pregnancy during the course of the study and for three months thereafter.

• Received an IMP within the 12 weeks before Visit 1.

• Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, may influence the result of the study, or the subject's ability to participate in the study.

• Following a physical exam, the subject had any abnormalities that, in the opinion of the investigator, would prevent the subject from safely participating in the study.

• Intention to donate blood during the study.

• Intention to travel internationally during the study.

• Previous randomisation into this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Hallamshire Hospital	Sheffield	Yorkshire	United Kingdom	S10 2JF

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Solomon Tesfaye, JCHMT FRCP, Royal Hallamshire Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00710424
• Other Study ID Numbers: GWCL0305
• First Posted: Jul 4, 2008
• Last Update Posted: Aug 1, 2012
• Last Verified: Jul 1, 2012

• Keywords provided by Jazz Pharmaceuticals: Pain; diabetic neuropathy
• Additional relevant MeSH terms: Peripheral Nervous System Diseases; Diabetic Neuropathies; 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Period Title: Overall Study
STARTED	149	148
COMPLETED	105	125
NOT COMPLETED	44	23

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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.	Total of all reporting groups
Overall Participants	149	148	297
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	97 65.1%	119 80.4%	216 72.7%
>=65 years	52 34.9%	29 19.6%	81 27.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (10.38)	58.2 (10.57)	59.5 (10.54)
Sex: Female, Male (Count of Participants)
Female	56 37.6%	58 39.2%	114 38.4%
Male	93 62.4%	90 60.8%	183 61.6%
Region of Enrollment (participants) [Number]
United Kingdom	91 61.1%	86 58.1%	177 59.6%
Czech Republic	34 22.8%	37 25%	71 23.9%
Romania	24 16.1%	25 16.9%	49 16.5%

Outcome Measures

1. Primary Outcome

Title	The Change From Baseline in Mean Diabetic Neuropathy Pain 0-10 Numerical Rating Scale Score at the End of Treatment (Average of Last 7 Days Treatment)
Description	The diabetic neuropathy pain Numerical Rating Scale was complete at the end of every day. The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your nerve pain due to diabetes in the last 24 hours" where 0 = no pain and 10 = worst possible pain. No pain relates to the time prior to the onset of pain due to diabetic neuropathy. For those whose evaluable period ended before Day 7, the mean of the available post-randomisation data was used. Those with no post-baseline diary pain 0-10 Numerical Rating Scale scores were excluded from the analysis.
Time Frame	Day 0 to Day 98

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	146	148
Mean (Standard Deviation) [units on a scale]	-1.67 (2.13)	-1.55 (2.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The model used for the analysis of the end of study value was an analysis of covariance (ANCOVA) with baseline value as a covariate and treatment group and centre group as main effect. The test was performed at the 10% significance level as a possible indicator of an interactive effect. The null hypothesis was one of no difference between treatments.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.634
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	estimated treatment effect
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.60 to 0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	A negative difference in treatment effect indicates an improvement in pain in favour of Sativex.

2. Secondary Outcome

Title	Change From Baseline in Mean Neuropathic Pain Scale 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. The baseline mean Neuropathic Pain Scale score was to be the mean of the two assessments during the baseline period, with the end of study value as the mean of the last two assessments made during the evaluable period.
Time Frame	Day 0 to Day 98

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	135	140
Mean (Standard Deviation) [units on a scale]	-13.70 (19.91)	-14.16 (17.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in mean neuropathic pain scale scale score at the end of treatment was to be compared between treatment groups using ANCOVA. The model was to include treatment and centre group as factors and baseline mean usage as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.865
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; -3.87 to 4.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.153
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Mean Sleep Quality 0-10 Numerical Rating Scale Score at the End of Treatment
Description	The sleep quality 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 the number that best describes your sleep quality in the last 24 hours" where 0 = slept extremely well and 10 = unable to sleep at all. A negative value indicates an improvement in pain score from baseline. The analyses were based on the change from baseline for the last assessment falling within the evaluable period (considered the end of treatment).
Time Frame	Day 0 - Day 98

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	132	142
Mean (Standard Deviation) [units on a scale]	-2.0 (3.02)	-1.6 (2.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in mean sleep quality numerical rating scale score at the end of treatment was compared between treatment groups using ANCOVA. The model included treatment and centre group as factors and baseline mean usage as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.139
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.45
	Confidence Interval	(2-Sided) 95%; -1.04 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Subject Global Impression of Change at the End of Treatment
Description	The subject was to assess the change in their nerve pain due to diabetic neuropathy at the end of the study compared to baseline on a 7-point scale from very much worse to very much improved. The number of participants reporting each score is presented.
Time Frame	Day 0 and Day 98

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	140	141
Very Much Improved	13 8.7%	14 9.5%
Much Improved	40 26.8%	36 24.3%
Slightly Improved	48 32.2%	35 23.6%
No Change	30 20.1%	45 30.4%
Slightly worse	6 4%	9 6.1%
Much worse	2 1.3%	2 1.4%
Very much worse	1 0.7%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	In the analysis of Subject Global Impression of Change, the two treatment groups were compared using ordinal logistic regression and the proportional odds model. The model incorporated centre group as a factor.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.219
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.301
	Confidence Interval	(2-Sided) 95%; 0.855 to 1.981
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Mean Brief Pain Inventory (Short Form)'Pain Severity Composite Score' at the End of Treatment
Description	The brief pain inventory (short form) is a 14-item questionnaire that asks patients to rate pain over the prior week and the degree to which it interferes with activities on a 0 to 10 scale, where 0=no pain and 10=pain as bad as you can imagine. Severity is measured as worst pain, least pain, average pain, and pain right now. The pain severity composite score was calculated as the arithmetic mean of the four severity items (range 0-10). The minimum value is zero and maximum is 10. A higher score represents a poor outcome.
Time Frame	Day 0 and Day 98

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	137	135
Mean (Standard Deviation) [units on a scale]	-1.2 (1.92)	-1.2 (2.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in mean brief pain inventory (short form) composite score at the end of treatment was compared between treatment groups using ANCOVA. The model included treatment and centre group as factors and baseline mean usage as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.841
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	estimated mean treatment difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Mean Quality of Life EuroQol 5-D Weighted Health State Index Score at the End of Treatment Measured by Visual Analogue Scale
Description	The EuroQol-5D Health Status Visual Analogue Scale rated the health state on a scale of 0-100 with 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition.
Time Frame	Day 0 and Day 98

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	138	135
Mean (Standard Deviation) [units on a scale]	3.3 (22.26)	7.8 (22.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in weighted health state index score at the end of treatment was compared between treatment groups using ANCOVA. The model included treatment and centre group as factors and baseline symptom score as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.523
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.021
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in the Use of Rescue Analgesia at the End of Treatment
Description	The mean daily number of paracetamol tablets used were calculated for the periods over which the primary endpoint was calculated.
Time Frame	Day 0 - Day 98

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	146	148
Mean (Standard Deviation) [Tablets]	-0.53 (2.02)	-0.35 (1.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The model used for the analysis of the end of study value was ANCOVA with baseline value as a covariate and treatment group and centre group as main effect. The test was performed at the 10% significance level as a possible indicator of an interactive effect. The null hypothesis was one of no difference between treatments. A negative difference in adjusted means indicates an improvement in favour of Sativex.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.410
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	estimated mean treatment difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.59 to 0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. 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 (including the follow-up period i.e 28 days after the end of treatment) is presented.
Time Frame	Day 0 - Day 133

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	149	148
All-causality relationship to study medication	120 80.5%	101 68.2%
Plausibly related to study medication	96 64.4%	52 35.1%

9. Secondary Outcome

Title	Change From Baseline in Mean Intoxication 0-10 Numerical Rating Scale Score at the End of Treatment
Description	Subjects rated their intoxication levels on a scale of 0-10, where 0 equals "no intoxication" and 10 equals "extreme intoxication". A negaitve value from baseline indicates and improvement. End of treatment was classed as the last on-treatment visit where data was recorded.
Time Frame	Day 0 - Day 98

Outcome Measure Data

Analysis Population Description

The primary population for analysis was the full analysis set, which included all randomised subjects who 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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	142	145
Mean (Standard Deviation) [units on a scale]	0.8 (2.73)	-0.3 (1.96)

10. Primary Outcome

Title	Number of Responders at the 30% Improvement Level at the End of Treatment
Description	A positive 30% pain response is defined as a reduction of at least 30% in the mean NRS average pain score from baseline to week 14 (last 7 days). The patient was asked "on a scale of '0 to 10', please indicate the number that best describes your pain or average pain 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 pain. The average pain NRS was completed at the same time each day, i.e. bedtime in the evening. Estimates were produced for a one-week period, with the evaluable period finishing at the end of the appropriate seven-day period.
Time Frame	Day 0 - Day 98

Outcome Measure Data

Analysis Population Description

All subjects who were randomised and received at least one actuation of study medication were included in the analysis. Subjects with no data during the primary period (i.e. unknown response) were included in the analysis, and were classed as non-responders.

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 65 mg: CBD 60 mg) in 24 hours	Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
Measure Participants	149	148
Number [participants]	54 36.2%	59 39.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The numbers of responders were to be analysed using the difference in proportions and the odds ratio comparing the treatment groups with the provision of 95% CIs for the difference and odds ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.521
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.857
	Confidence Interval	(2-Sided) 95%; 0.537 to 1.370
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All adverse events occurring from the time of consent to post study follow up i.e. 19 weeks were collected. All deaths and serious adverse events occurring within 28 days of the final dose of study medication were also collected.
Adverse Event Reporting Description	All adverse events 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 65 mg: CBD 60 mg) in 24 hours		Contains no active drug but colourants and excipients. Maximum permitted dose was 24 actuations in 24 hours.
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	14/149 (9.4%)		12/148 (8.1%)
Cardiac disorders
ACUTE CORONARY SYNDROME	1/149 (0.7%)		0/148 (0%)
BRADYCARDIA	1/149 (0.7%)		0/148 (0%)
MYOCARDIAL INFARCTION	1/149 (0.7%)		1/148 (0.7%)
Eye disorders
EYE HAEMORRHAGE	0/149 (0%)		1/148 (0.7%)
Gastrointestinal disorders
GASTROINTESTINAL INFLAMMATION	1/149 (0.7%)		0/148 (0%)
PERIODONTITIS	1/149 (0.7%)		0/148 (0%)
ABDOMINAL PAIN	0/149 (0%)		1/148 (0.7%)
GASTRITIS	0/149 (0%)		1/148 (0.7%)
HAEMATEMESIS	0/149 (0%)		1/148 (0.7%)
IMPAIRED GASTRIC EMPTYING	0/149 (0%)		1/148 (0.7%)
NAUSEA	0/149 (0%)		1/148 (0.7%)
VOMITING	0/149 (0%)		1/148 (0.7%)
General disorders
OEDEMA PERIPHERAL	0/149 (0%)		1/148 (0.7%)
PYREXIA	0/149 (0%)		1/148 (0.7%)
Infections and infestations
CELLULITIS	1/149 (0.7%)		0/148 (0%)
LOWER RESPIRATORY TRACT INFECTION	1/149 (0.7%)		0/148 (0%)
Investigations
BLOOD GLUCOSE INCREASED	0/149 (0%)		1/148 (0.7%)
Metabolism and nutrition disorders
DIABETIC KETOACIDOSIS	1/149 (0.7%)		0/148 (0%)
HYPERGLYCAEMIA	1/149 (0.7%)		0/148 (0%)
KETOACIDOSIS	1/149 (0.7%)		0/148 (0%)
DIABETES MELLITUS INADEQUATE CONTROL	0/149 (0%)		1/148 (0.7%)
Musculoskeletal and connective tissue disorders
BACK PAIN	1/149 (0.7%)		0/148 (0%)
EXOSTOSIS	1/149 (0.7%)		0/148 (0%)
MUSCULOSKELETAL CHEST PAIN	0/149 (0%)		1/148 (0.7%)
RHABDOMYOLYSIS	0/149 (0%)		1/148 (0.7%)
Nervous system disorders
ISCHAEMIC STROKE	1/149 (0.7%)		0/148 (0%)
SYNCOPE	1/149 (0.7%)		0/148 (0%)
TRANSIENT ISCHAEMIC ATTACK	0/149 (0%)		1/148 (0.7%)
Renal and urinary disorders
RENAL FAILURE	0/149 (0%)		1/148 (0.7%)
Vascular disorders
ESSENTIAL HYPERTENSION	1/149 (0.7%)		0/148 (0%)
PERIPHERAL OCCLUSIVE DISEASE	1/149 (0.7%)		0/148 (0%)
ACCELERATED HYPERTENSION	0/149 (0%)		1/148 (0.7%)
Other (Not Including Serious) Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	120/149 (80.5%)		101/148 (68.2%)
Cardiac disorders
Palpitations	4/149 (2.7%)		1/148 (0.7%)
Ear and labyrinth disorders
Vertigo	6/149 (4%)		3/148 (2%)
Gastrointestinal disorders
Nausea	25/149 (16.8%)		15/148 (10.1%)
Vomiting	14/149 (9.4%)		11/148 (7.4%)
Dry mouth	12/149 (8.1%)		4/148 (2.7%)
Diarrhoea	10/149 (6.7%)		14/148 (9.5%)
Oral pain	7/149 (4.7%)		0/148 (0%)
Abdominal pain upper	5/149 (3.4%)		2/148 (1.4%)
Mouth ulceration	4/149 (2.7%)		2/148 (1.4%)
Oral discomfort	4/149 (2.7%)		4/148 (2.7%)
General disorders
Fatigue	10/149 (6.7%)		4/148 (2.7%)
Feeling abnormal	4/149 (2.7%)		0/148 (0%)
Oedema peripheral	4/149 (2.7%)		2/148 (1.4%)
Infections and infestations
Nasopharyngitis	8/149 (5.4%)		6/148 (4.1%)
Lower respiratory tract infection	6/149 (4%)		8/148 (5.4%)
Urinary tract infection	2/149 (1.3%)		8/148 (5.4%)
Metabolism and nutrition disorders
Hypoglycaemia	9/149 (6%)		5/148 (3.4%)
Musculoskeletal and connective tissue disorders
Pain in extremity	4/149 (2.7%)		4/148 (2.7%)
Back pain	3/149 (2%)		5/148 (3.4%)
Arthralgia	2/149 (1.3%)		4/148 (2.7%)
Muscle spasms	2/149 (1.3%)		4/148 (2.7%)
Nervous system disorders
Dizziness	42/149 (28.2%)		7/148 (4.7%)
Somnolence	11/149 (7.4%)		7/148 (4.7%)
Headache	9/149 (6%)		11/148 (7.4%)
Lethargy	5/149 (3.4%)		1/148 (0.7%)
Amnesia	4/149 (2.7%)		2/148 (1.4%)
Dysgeusia	4/149 (2.7%)		1/148 (0.7%)
Memory impairment	4/149 (2.7%)		1/148 (0.7%)
Psychiatric disorders
Disorientation	8/149 (5.4%)		1/148 (0.7%)
Depression	5/149 (3.4%)		2/148 (1.4%)
Insomnia	0/149 (0%)		4/148 (2.7%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	6/149 (4%)		4/148 (2.7%)
Cough	2/149 (1.3%)		4/148 (2.7%)
Skin and subcutaneous tissue disorders
Pruritus	1/149 (0.7%)		5/148 (3.4%)

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.