A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00710554
• Collaborator: (none)
• Enrollment: 246
• Location: 1
• Arms: 2
• Duration (Months): 14
• Patients Per Site Per Month: 17.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of Sativex® compared with placebo in relieving peripheral neuropathic pain associated with allodynia.

Condition or Disease	Intervention/Treatment	Phase
Pain; Peripheral 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 PNP, associated with allodynia. 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: 246 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 Peripheral Neuropathic Pain, Associated With Allodynia
• Study Start Date: Aug 1, 2005
• Actual Primary Completion Date: Oct 1, 2006
• Actual Study Completion Date: Oct 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. Change From Baseline in Mean Peripheral Neuropathic Pain on a 0-10 Numerical Rating Scale (NRS) Score at the End of Treatment (15 Weeks) [Day 7 to Day 98]

   The peripheral neuropathic pain NRS 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 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. A negative value indicates an improvement in pain score from baseline.

Secondary Outcome Measures

1. Change From Baseline in Neuropathic Pain Scale Score at the End of Treatment (15 Weeks) [Day 7 to Day 98]

   The NPS score is 0-100 sum of 10 individual pain scores (0-10 NRS, 0= no pain to 10 = most pain imaginable). A negative change from baseline indicates an improvement in pain.

2. Change From Baseline in Sleep Quality 0-10 Numerical Rating Scale Scores at the End of Treatment (15 Weeks) [Day 7 to Day 98]

   The sleep disruption NRS 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.

3. Change in Baseline Mean Dynamic Allodynia Test Score at the End of Treatment (15 Weeks) [Day 7 and Day 98]

   Dynamic allodynia was assessed by stroking the skin over the affected area five times with a standardised brush, designed specifically for sensory testing at 5 s intervals, and recording the pain severity on a 0-10 point scale (0= no pain to 10 = most pain imaginable). All strokes were of the same length, minimum 2 cm. Each dynamic allodynia score was calculated as the average of the five strokes.A negative change from baseline indicates an improvement in score.

4. Change in Baseline Mean Punctate Allodynia Test Scores at the End of Treatment (15 Weeks) [Day 7 and Day 98]

   Punctate allodynia was measured using an in-house built pressure algometer comprising a strain gauge connected to a metal filament with a diameter of 1 mm and blunt tip at baseline and end of study. The filament was manually directed against the skin at an angle of 90 degrees and a steadily increasing pressure applied until the patient verbally indicated that they perceived pain (punctate pressure pain threshold). Patients were asked to verbally rate the intensity of the pain elicited, choosing a number between 0 (no pain)and 10 (most intense pain imaginable).

5. Subject Global Impression of Change [Day 98]

   A 7-point Likert-type scale was used, with the question: 'Please assess the status of your pain due to peripheral neuropathy 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". At Visit 2 (Baseline) patients wrote a brief description of their pain caused by peripheral neuropathy which was used at end of treatment to aid their memory regarding their symptoms at study start. For each of above markers the number of participants were reported.

6. Change From Baseline in Brief Pain Inventory (Short Form) Scores at the End of Treatment [Day 7 and Day 98]

   The BPI-SF 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 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.

7. Change From Baseline in Quality of Life EuroQol 5-D (Health Status Index) Score at the End of Treatment (15 Weeks) [Day 7 and Day 98]

   The EQ-5D questionnaire provided two outcomes:(1)A weighted health state index visual analogue scale (VAS); (2) A self-rated health status VAS. EQ-5D Health Status VAS Scale: 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition.The weighted health state index used the same VAS as above but was calculated for each assessment without imputation to account for missing values i.e., if one or more individual items was missing then the whole index was missing.

8. Change From Baseline in Quality of Life EuroQol 5-D (Health Status Visual Analogue Scale) Score at the End of Treatment (15 Weeks) [Day 7 and Day 98]

   The EQ-5D questionnaire provided two outcomes:(1)A weighted health state index visual analogue scale (VAS); (2) A self-rated health status VAS. EQ-5D Health Status VAS Scale: 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition.

9. Change From Baseline in the Use of Rescue Analgesia at the End Treatment (15 Weeks) [Days 0-7 and Days 92-98]

   Use of break through medication was recorded daily during the study as the number of paracetamol tablets taken. The change in mean daily quantities of tablets used was calculated from baseline to the last seven days of treatment.

10. Incidence of Adverse Events as a Measure of Subject's Safety. [19 weeks]

    The number of subjects that reported an adverse event in this 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:

• 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 PNP of at least six months duration and in who pain is not wholly relieved with their current therapy.

• Presence of mechanical allodynia within the territory of the affected nerve(s) which has been confirmed by either a positive response to stroking the allodynic area with a SENSELABTM Brush 05 or to force applied by a 5.07 gram Semmes-Weinstein monofilament.

• Had at least one of the following underlying conditions, which caused their peripheral neuropathic pain; post herpetic neuralgia, peripheral neuropathy, focal nerve lesion, radiculopathy or Complex Regional Pain Syndrome (CRPS) type 2.

• The daily diary 0-10 NRS pain scores on days B2 - B7 of the baseline period were completed and summed to at least 24.

• 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. Where subjects were taking a medication containing paracetamol further instructions were provided, refer to Section 9.4.7.

• In the opinion of the investigator the subject has received or was currently receiving the appropriate PNP treatments for their condition.

• 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 the subject's assessment of their PNP.

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

• Had CRPS type 1, cancer related neuropathic pain or neuropathic pain resulted from diabetes mellitus.

• Has used either cannabis (either for recreational or medical purposes) or cannabis based medications within the last year 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 study medication.

• 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 unless physiological) or sinus tachycardia (HR>110bpm) at Visit 1.

• Diastolic blood pressure of <50 mmHg or >105 mmHg in a sitting position at rest for 5 minutes prior to randomisation.

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

• 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 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	Pain Clinic Office, Gartnavel General Hospital,	Glasgow	West Lothain	United Kingdom	G12 0YN

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Mick Serpell, MB ChB, FRCA, Pain Clinic Office

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00710554
• Other Study ID Numbers: GWCL0405
• First Posted: Jul 4, 2008
• Last Update Posted: Feb 13, 2014
• Last Verified: Jan 1, 2014

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

Study Results

Participant Flow

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Period Title: Overall Study
STARTED	128	118
COMPLETED	79	94
NOT COMPLETED	49	24

Baseline Characteristics

Arm/Group Title	Sativex	Placebo	Total
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.	Total of all reporting groups
Overall Participants	128	118	246
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	91 71.1%	88 74.6%	179 72.8%
>=65 years	37 28.9%	30 25.4%	67 27.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.6 (14.38)	57 (14.07)	57.3 (14.21)
Sex: Female, Male (Count of Participants)
Female	85 66.4%	65 55.1%	150 61%
Male	43 33.6%	53 44.9%	96 39%
Region of Enrollment (participants) [Number]
United Kingdom	74 57.8%	72 61%	146 59.3%
Belgium	8 6.3%	7 5.9%	15 6.1%
Canada	3 2.3%	2 1.7%	5 2%
Czech Republic	35 27.3%	32 27.1%	67 27.2%
Romania	8 6.3%	5 4.2%	13 5.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Peripheral Neuropathic Pain on a 0-10 Numerical Rating Scale (NRS) Score at the End of Treatment (15 Weeks)
Description	The peripheral neuropathic pain NRS 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 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. A negative value indicates an improvement in pain score from baseline.
Time Frame	Day 7 to Day 98

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	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	77	92
Mean (Standard Deviation) [units on a scale]	-1.36 (2.02)	-0.84 (1.86)

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. Due to the low power of the test for interaction, 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	0.139
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	estimated mean treatment difference
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Neuropathic Pain Scale Score at the End of Treatment (15 Weeks)
Description	The NPS score is 0-100 sum of 10 individual pain scores (0-10 NRS, 0= no pain to 10 = most pain imaginable). A negative change from baseline indicates an improvement in pain.
Time Frame	Day 7 to Day 98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	78	93
Mean (Standard Deviation) [units on a scale]	-11.57 (16.15)	-7.19 (19.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in mean Neuropathic Pain Scale score was compared between treatment groups and centres 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	0.198
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-2.86
	Confidence Interval	(2-Sided) 95%; -7.22 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Sleep Quality 0-10 Numerical Rating Scale Scores at the End of Treatment (15 Weeks)
Description	The sleep disruption NRS 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 7 to Day 98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	81	86
Mean (Standard Deviation) [units on a scale]	-2.0 (2.70)	-1.2 (2.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline score was compared between treatment groups and centres 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	0.007
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.83
	Confidence Interval	(2-Sided) 95%; -1.43 to -0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Baseline Mean Dynamic Allodynia Test Score at the End of Treatment (15 Weeks)
Description	Dynamic allodynia was assessed by stroking the skin over the affected area five times with a standardised brush, designed specifically for sensory testing at 5 s intervals, and recording the pain severity on a 0-10 point scale (0= no pain to 10 = most pain imaginable). All strokes were of the same length, minimum 2 cm. Each dynamic allodynia score was calculated as the average of the five strokes.A negative change from baseline indicates an improvement in score.
Time Frame	Day 7 and Day 98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	112	102
Mean (Standard Deviation) [units on a scale]	-1.1 (2.16)	-1.0 (2.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change in the dynamic allodynia pain score from baseline to the end of treatment was analysed using ANCOVA with the baseline value as a covariate and country and treatment group as factors.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.795
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.52 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Baseline Mean Punctate Allodynia Test Scores at the End of Treatment (15 Weeks)
Description	Punctate allodynia was measured using an in-house built pressure algometer comprising a strain gauge connected to a metal filament with a diameter of 1 mm and blunt tip at baseline and end of study. The filament was manually directed against the skin at an angle of 90 degrees and a steadily increasing pressure applied until the patient verbally indicated that they perceived pain (punctate pressure pain threshold). Patients were asked to verbally rate the intensity of the pain elicited, choosing a number between 0 (no pain)and 10 (most intense pain imaginable).
Time Frame	Day 7 and Day 98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	112	106
Mean (Standard Deviation) [units on a scale]	0.2 (0.78)	0.3 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change in the punctate allodynia pain threshold force from baseline to the end of treatment was analysed using ANCOVA with the baseline value as a covariate and country and treatment group as factors.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.233
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Subject Global Impression of Change
Description	A 7-point Likert-type scale was used, with the question: 'Please assess the status of your pain due to peripheral neuropathy 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". At Visit 2 (Baseline) patients wrote a brief description of their pain caused by peripheral neuropathy which was used at end of treatment to aid their memory regarding their symptoms at study start. For each of above markers the number of participants were reported.
Time Frame	Day 98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	117	111
Very much improved	8 6.3%	4 3.4%
Much improved	16 12.5%	10 8.5%
Slightly improved	38 29.7%	24 20.3%
No change	44 34.4%	66 55.9%
Slightly worse	9 7%	4 3.4%
Much worse	2 1.6%	3 2.5%

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 initial model incorporated treatment and centre group as factors. The odds ratio together with its 95% CI and associated p-value are presented.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.762
	Confidence Interval	(2-Sided) 95%; 1.08 to 2.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Brief Pain Inventory (Short Form) Scores at the End of Treatment
Description	The BPI-SF 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 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 7 and Day 98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	114	105
Mean (Standard Deviation) [units on a scale]	-0.9 (1.69)	-0.6 (1.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in mean Brief Pain Inventory (short form) score was compared between treatment groups and centres 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	0.288
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.72 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Quality of Life EuroQol 5-D (Health Status Index) Score at the End of Treatment (15 Weeks)
Description	The EQ-5D questionnaire provided two outcomes:(1)A weighted health state index visual analogue scale (VAS); (2) A self-rated health status VAS. EQ-5D Health Status VAS Scale: 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition.The weighted health state index used the same VAS as above but was calculated for each assessment without imputation to account for missing values i.e., if one or more individual items was missing then the whole index was missing.
Time Frame	Day 7 and Day 98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	113	107
Mean (Standard Deviation) [units on a scale]	0.037 (0.187)	0.044 (0.214)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in mean EuroQol-5D score was compared between treatment groups and centres using ANCOVA. The model included treatment and centre groups as factors and baseline mean usage as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.617
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Quality of Life EuroQol 5-D (Health Status Visual Analogue Scale) Score at the End of Treatment (15 Weeks)
Description	The EQ-5D questionnaire provided two outcomes:(1)A weighted health state index visual analogue scale (VAS); (2) A self-rated health status VAS. EQ-5D Health Status VAS Scale: 0 = worst health state imaginable to 100 = best health state imaginable. An increase in score indicates an improvement in condition.
Time Frame	Day 7 and Day 98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	111	105
Mean (Standard Deviation) [units on a scale]	3.7 (20.6)	2.5 (21.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sativex, Placebo
	Comments	The change from baseline in mean EuroQol-5D score was compared between treatment groups and centres using ANCOVA. The model included treatment and centre groups as factors and baseline mean usage as a covariate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.75
	Confidence Interval	(2-Sided) 95%; -5.60 to 4.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.459
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in the Use of Rescue Analgesia at the End Treatment (15 Weeks)
Description	Use of break through medication was recorded daily during the study as the number of paracetamol tablets taken. The change in mean daily quantities of tablets used was calculated from baseline to the last seven days of treatment.
Time Frame	Days 0-7 and Days 92-98

Outcome Measure Data

Analysis Population Description

The primary population for the analysis of efficacy was the full analysis set, which included all randomised subjects who received at least one dose of test treatment and had on-treatment efficacy data.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	77	92
Mean (Standard Deviation) [number of tablets]	-0.99 (2.20)	-0.47 (2.08)

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 ANCOVA with baseline value as a covariate and treatment group and centre group as main 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	0.112
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Estimated mean treatment difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.85 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Incidence of Adverse Events as a Measure of Subject's Safety.
Description	The number of subjects that reported an adverse event in this study is presented.
Time Frame	19 weeks

Outcome Measure Data

Analysis Population Description

All subjects were included in this analysis.

Arm/Group Title	Sativex	Placebo
Arm/Group Description	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.	Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 24 actuations in any 24 hour period.
Measure Participants	128	118
Number [participants]	109 85.2%	83 70.3%

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	Each actuation delivered 100 μl (THC 2.7 mg and CBD 2.5 mg) up to a maximum of 24 actuations in any 24 hour period.		Each 100 ul actuation delivered the excipients plus colorants, up to a maximum of 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	10/128 (7.8%)		6/118 (5.1%)
Cardiac disorders
Myocardial Infarction	1/128 (0.8%)		0/118 (0%)
Gastrointestinal disorders
Inguinal Hernia	1/128 (0.8%)		0/118 (0%)
Enterovesical Fistula	0/128 (0%)		1/118 (0.8%)
General disorders
Chest Pain	1/128 (0.8%)		0/118 (0%)
Infections and infestations
Bronchopneumonia	1/128 (0.8%)		0/118 (0%)
Infective Exacerbation of Chronic Obstructive Airway Disease	1/128 (0.8%)		0/118 (0%)
Pneumonia	1/128 (0.8%)		0/118 (0%)
Subcutaneous Abscess	1/128 (0.8%)		0/118 (0%)
Urinary Tract Infection	1/128 (0.8%)		0/118 (0%)
Injury, poisoning and procedural complications
Head Injury	0/128 (0%)		1/118 (0.8%)
Joint Dislocation	0/128 (0%)		1/118 (0.8%)
Lumbar Vertebral fracture	0/128 (0%)		1/118 (0.8%)
Road Traffic Accident	0/128 (0%)		1/118 (0.8%)
Soft Tissue Injury	0/128 (0%)		1/118 (0.8%)
Musculoskeletal and connective tissue disorders
Groin Pain	0/128 (0%)		1/118 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer Stage II	1/128 (0.8%)		0/118 (0%)
Malignant Melanoma	1/128 (0.8%)		0/118 (0%)
Neoplasm Malignant	1/128 (0.8%)		0/118 (0%)
Nervous system disorders
Transient Ischaemic Attack	1/128 (0.8%)		0/118 (0%)
Coma	0/128 (0%)		1/118 (0.8%)
Dizziness	0/128 (0%)		1/118 (0.8%)
Loss of Consciousness	0/128 (0%)		1/118 (0.8%)
Vascular disorders
Deep Vein Thrombosis	0/128 (0%)		1/118 (0.8%)
Hypotension	0/128 (0%)		1/118 (0.8%)
Other (Not Including Serious) Adverse Events
	Sativex		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	109/128 (85.2%)		83/118 (70.3%)
Ear and labyrinth disorders
Vertigo	5/128 (3.9%)		0/118 (0%)
Gastrointestinal disorders
Nausea	23/128 (18%)		14/118 (11.9%)
Vomiting	13/128 (10.2%)		7/118 (5.9%)
Diarrhoea	12/128 (9.4%)		6/118 (5.1%)
Dry Mouth	11/128 (8.6%)		4/118 (3.4%)
Abdominal Pain Upper	6/128 (4.7%)		1/118 (0.8%)
Dyspepsia	6/128 (4.7%)		4/118 (3.4%)
Constipation	4/128 (3.1%)		2/118 (1.7%)
Mouth Ulceration	4/128 (3.1%)		6/118 (5.1%)
Oral Pain	4/128 (3.1%)		3/118 (2.5%)
General disorders
Fatigue	20/128 (15.6%)		8/118 (6.8%)
Feeling Drunk	8/128 (6.3%)		3/118 (2.5%)
Application Site Pain	7/128 (5.5%)		2/118 (1.7%)
Infections and infestations
Nasopharyngitis	9/128 (7%)		8/118 (6.8%)
Gastroenteritis	4/128 (3.1%)		1/118 (0.8%)
Lower Respiratory Tract Infection	4/128 (3.1%)		3/118 (2.5%)
Metabolism and nutrition disorders
Increased Appetite	6/128 (4.7%)		1/118 (0.8%)
Anorexia	4/128 (3.1%)		1/118 (0.8%)
Nervous system disorders
Dizziness	52/128 (40.6%)		12/118 (10.2%)
Dysgeusia	14/128 (10.9%)		2/118 (1.7%)
Headache	13/128 (10.2%)		9/118 (7.6%)
Disturbance in Attention	8/128 (6.3%)		2/118 (1.7%)
Neuropathy Peripheral	6/128 (4.7%)		4/118 (3.4%)
Tremor	6/128 (4.7%)		0/118 (0%)
Somnolence	5/128 (3.9%)		2/118 (1.7%)
Balance Disorder	4/128 (3.1%)		2/118 (1.7%)
Memory Impairment	4/128 (3.1%)		2/118 (1.7%)
Sedation	4/128 (3.1%)		0/118 (0%)
Psychiatric disorders
Dissociation	9/128 (7%)		0/118 (0%)
Disorientation	8/128 (6.3%)		0/118 (0%)
Depression	6/128 (4.7%)		0/118 (0%)
Anxiety	4/128 (3.1%)		1/118 (0.8%)
Panic Attack	4/128 (3.1%)		1/118 (0.8%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal Pain	7/128 (5.5%)		5/118 (4.2%)
Dyspnoea	4/128 (3.1%)		3/118 (2.5%)
Skin and subcutaneous tissue disorders
Rash	5/128 (3.9%)		4/118 (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.