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Clinical Trial Results:
SATIVEX® AS ADD-ON THERAPY VS. FURTHER OPTIMIZED FIRST-LINE ANTISPASTICS: THE SAVANT TRIAL

Summary
EudraCT number	2015-004451-40
Trial protocol	CZ AT
Global end of trial date	23 May 2017

Results information
Results version number	v1(current)
This version publication date	02 May 2018
First version publication date	02 May 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

H15/02

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Almirall Hermal GmbH

Sponsor organisation address

Ronda General Mitre 151, Barcelona, Spain, 08022

Public contact

Carlos Vila Silván, Almirall S.A., +34 932 913 490, carlos.vila@almirall.com

Scientific contact

Carlos Vila Silván, Almirall S.A., +34 932 913 490, carlos.vila@almirall.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 May 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 May 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to evaluate the efficacy of Sativex (tetrahydrocannabinol [THC]:cannabidiol [CBD] oromucosal spray) as add-on therapy compared to further optimized standard antispastic therapy with oral baclofen and/or tizanidine and/or dantrolene (mono- or combination therapy) in subjects with moderate to severe spasticity due to multiple sclerosis (MS) who have not gained adequate relief through 2 optimized standard antispastic drugs.

Protection of trial subjects

The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki that are consistent with International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Apr 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

Czech Republic: 190

Worldwide total number of subjects

191

EEA total number of subjects

191

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

185

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 14 centers in the Czech Republic and 1 center in Austria between 25 April 2016 (first subject first visit) and 23 May 2017 (last subject last visit).

Screening details

A total of 210 subjects were screened, 191 entered the study and 190 received treatment while 15 were screen failure, 2 withdrawn consent, 2 withdrawn due to technical reasons and 1 due to non-TEAE.

Period 1 title

Phase A

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Phase A: Sativex

Arm description

Subjects received up-titrated Sativex up to 12 sprays per day for 4 weeks as add-on to their optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

Arm type

Experimental

Investigational medicinal product name

Sativex

Investigational medicinal product code

Other name

Pharmaceutical forms

Oromucosal spray

Routes of administration

Oromucosal use

Dosage and administration details

Subjects received oromucosal spray of Sativex for 4 weeks.

Number of subjects in period 1	Phase A: Sativex
Started	191
Treated	190
Completed	134
Not completed	57
Physician decision	1
Adverse event, non-fatal	4
Noncompliance with study drug	1
Lack of efficacy	49
Protocol deviation	1
Not treated	1

Period 2 title

Washout Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Phase A: Sativex Washout

Arm description

Subjects who qualified as Sativex initial responders received their underlying optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) but not Sativex. The washout phase was to last for a minimum of 1 week and a maximum of 4 weeks, until the subject’s Phase A-improvement in MS spasticity numerical rating scale (NRS) score had been reduced by at least 80%.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Phase A: Sativex Washout
Started	134
Completed	106
Not completed	28
Consent withdrawn by subject	3
Failed to meet Inclusion criteria	22
Adverse event, non-fatal	1
Technical problems	2

Period 3 title

Phase B

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Phase B: Sativex

Arm description

Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received up-titrated Sativex to the dose identified during Phase A as being their optimal dose (up to 12 sprays per day) for 12 weeks as add-on to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

Arm type

Experimental

Investigational medicinal product name

Sativex

Investigational medicinal product code

Other name

Pharmaceutical forms

Oromucosal spray

Routes of administration

Oromucosal use

Dosage and administration details

Subjects received oromucosal spray (up to 12 sprays per day) of optimal dose of Sativex for 12 weeks.

Phase B: Placebo

Arm description

Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received matched placebo for 12 weeks as add-on to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oromucosal spray

Routes of administration

Oromucosal use

Dosage and administration details

Subjects received matched placebo for 12 weeks.

Number of subjects in period 3	Phase B: Sativex	Phase B: Placebo
Started	53	53
Completed	50	46
Not completed	3	7
Consent withdrawn by subject	3	4
Physician decision	-	1
Didn't meet inclusion criteria#14 (screen failure)	-	1
Protocol deviation	-	1

Baseline characteristics

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Reporting group title

Phase A: Sativex

Reporting group description

Reporting group values	Phase A: Sativex	Total
Number of subjects	191	191
Age categorical
Units: Subjects
Age continuous
Phase A safety set included all screened subjects who took at least 1 dose of study medication.
Units: years
arithmetic mean (standard deviation)	51.3 ( 10.2 )	-
Gender categorical
Units: Subjects
Female	134	134
Male	57	57

End points

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Reporting group title

Phase A: Sativex

Reporting group description

Reporting group title

Phase A: Sativex Washout

Reporting group description

Reporting group title

Phase B: Sativex

Reporting group description

Reporting group title

Phase B: Placebo

Reporting group description

Subject analysis set title

Phase B: Intent To Treat (ITT) population

Subject analysis set type

Intention-to-treat

Subject analysis set description

ITT set included all randomized subjects in Phase B who took at least 1 dose of study medication and had at least a baseline and 1 post-dose efficacy value (N=106).

Primary: Percentage of Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Responders After 12 Weeks of Randomized Treatment in Phase B

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End point title

Percentage of Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Responders After 12 Weeks of Randomized Treatment in Phase B

End point description

MS Spasticity was measured based on a scale of 0 to 10, 0 as “No spasticity” and 10 as “Worst possible spasticity”. A responder was defined as a subject who achieved an improvement in NRS score of greater than or equal to (>=) 30% (i.e. clinically important difference [CID]) from baseline.

End point type

Primary

End point timeframe

Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[1]	53 ^[2]
Units: Percentage of responders
number (not applicable)
Logistic Regression Analysis (LOCF)	77.4	32.1
Generalized Linear Mixed Models (GLMM) Analysis	67.9	30.2

Notes
[1] - Phase B: ITT
[2] - Phase B: ITT

LOCF: Phase B- Sativex vs Placebo

Statistical analysis description

The adjusted statistics were computed using Logistic regression model with Phase B baseline mean value as co-variate and treatment group as factor.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Adjusted Odds ratio

Point estimate

7.03

Confidence interval

level

95%

sides

2-sided

lower limit

2.953

upper limit

16.738

GLMM Analysis: Phase B- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

6.842

Confidence interval

level

95%

sides

2-sided

lower limit

2.75

upper limit

17.023

Secondary: Percentage of Subjects Who Achieve an Improvement From Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than or Equal to (>=) 30% Clinically Important Difference (CID) After 4 and 8 Weeks of Treatment

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End point title

Percentage of Subjects Who Achieve an Improvement From Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than or Equal to (>=) 30% Clinically Important Difference (CID) After 4 and 8 Weeks of Treatment

End point description

MS Spasticity was measured based on a scale of 0 to 10, 0 as “No spasticity” and 10 as “Worst possible spasticity”.

End point type

Secondary

End point timeframe

Week 4, Week 8

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[3]	53 ^[4]
Units: Percentage of subjects
number (not applicable)
Week 4	66.0	32.1
Week 8	71.7	28.3

Notes
[3] - Phase B: ITT
[4] - Phase B: ITT

Week 4: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as covariate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0013

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

4.017

Confidence interval

level

95%

sides

2-sided

lower limit

1.747

upper limit

9.233

Week 8: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as covariate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted Odds ratio

Point estimate

6.663

Confidence interval

level

95%

sides

2-sided

lower limit

2.736

upper limit

16.225

Secondary: Percentage of Subjects Who Achieve an Improvement From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than 18% Minimum Clinically Important Difference (MCID) After 4, 8 and 12 Weeks of Treatment

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End point title

Percentage of Subjects Who Achieve an Improvement From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than 18% Minimum Clinically Important Difference (MCID) After 4, 8 and 12 Weeks of Treatment

End point description

MS Spasticity was measured based on a scale of 0 to 10, 0 as “No spasticity” and 10 as “Worst possible spasticity”.

End point type

Secondary

End point timeframe

Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[5]	53 ^[6]
Units: Percentage of subjects
number (not applicable)
Week 4	81.1	45.3
Week 8	83.0	34.0
Week 12	77.4	35.8

Notes
[5] - Phase B: ITT
[6] - Phase B: ITT

Week 4: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0007

Method

Mixed models analysis

Parameter type

Adjusted Odds ratio

Point estimate

4.911

Confidence interval

level

95%

sides

2-sided

lower limit

1.999

upper limit

12.064

Week 8: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted Odds ratio

Point estimate

10.186

Confidence interval

level

95%

sides

2-sided

lower limit

3.687

upper limit

28.139

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted Odds ratio

Point estimate

9.353

Confidence interval

level

95%

sides

2-sided

lower limit

3.381

upper limit

25.875

Notes
[7] - General Linear Mixed Model for binary repeated data with Phase B baseline mean value as covariate and treatment, week and treatment by week interaction as fixed effect factors.

Secondary: Change From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

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End point title

Change From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

End point description

MS Spasticity was measured based on a scale of 0 to 10, 0 as “No spasticity” and 10 as “Worst possible spasticity”.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[8]	53 ^[9]
Units: Score on a scale
least squares mean (confidence interval 95%)
Change at Week 4	-3.04 (-3.58 to -2.50)	-1.51 (-2.06 to -0.97)
Change at Week 8	-3.33 (-3.92 to -2.75)	-1.54 (-2.12 to -0.95)
Change at Week 12	-3.49 (-4.08 to -2.91)	-1.60 (-2.19 to -1.00)

Notes
[8] - Phase B: ITT
[9] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0001

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

-0.76

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.63

upper limit

-0.97

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.73

upper limit

-1.06

Secondary: Change From Phase B Baseline in the Frequency of Spasm After 4, 8 and 12 Weeks of Treatment

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End point title

Change From Phase B Baseline in the Frequency of Spasm After 4, 8 and 12 Weeks of Treatment

End point description

Frequency of Spasm was calculated by a daily review (at bedtime) as“number of spasms in the last 24 hours” and gave a best estimate if a large number of spasms occurred. ‘0’ was recorded if no spasms were experienced.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[10]	53 ^[11]
Units: Frequency of spasm
least squares mean (confidence interval 95%)
Change at Week 4	-18.39 (-29.40 to -7.38)	-15.34 (-26.40 to -4.27)
Change at Week 8	-19.82 (-30.91 to -8.73)	-17.80 (-29.10 to -6.50)
Change at Week 12	-20.58 (-31.80 to -9.36)	-17.75 (-29.10 to -6.41)

Notes
[10] - Phase B: ITT
[11] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7002

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-3.05

Confidence interval

level

95%

sides

2-sided

lower limit

-18.67

upper limit

12.56

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8016

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-2.02

Confidence interval

level

95%

sides

2-sided

lower limit

-17.87

upper limit

13.82

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7278

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-2.82

Confidence interval

level

95%

sides

2-sided

lower limit

-18.79

upper limit

13.14

Secondary: Change From Phase B Baseline in the Severity of Spasm After 4, 8 and 12 Weeks of Treatment

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End point title

Change From Phase B Baseline in the Severity of Spasm After 4, 8 and 12 Weeks of Treatment

End point description

Subjects made a qualitative assessment of the severity of the spasms in a 3 levels categorical scale, i.e. mild, moderate, severe. Least square means and 95% confidence interval values of severity score were reported.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[12]	53 ^[13]
Units: Severity of spasms
least squares mean (confidence interval 95%)
Change at Week 4	-0.61 (-0.75 to -0.48)	-0.34 (-0.47 to -0.21)
Change at Week 8	-0.67 (-0.82 to -0.52)	-0.36 (-0.51 to -0.21)
Change at Week 12	-0.72 (-0.87 to -0.58)	-0.38 (-0.52 to -0.24)

Notes
[12] - Phase B: ITT
[13] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0052

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

-0.08

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.004

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

-0.1

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0012

Method

Mixed Model for Repeated Measure (MMRM).

Parameter type

LS Mean Difference

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.54

upper limit

-0.14

Secondary: Change From Phase B Baseline in Sleep Disruption 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

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End point title

Change From Phase B Baseline in Sleep Disruption 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

End point description

Sleep disruption was measured based on a scale of 0 to 10, 0 as“did not disrupt sleep” and 10 as “completely disrupted (unable to sleep at all)”.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[14]	53 ^[15]
Units: Score on a Scale
least squares mean (confidence interval 95%)
Change at Week 4	-2.77 (-3.28 to -2.27)	-1.58 (-2.09 to -1.07)
Change at Week 8	-3.14 (-3.70 to -2.58)	-1.62 (-2.18 to -1.05)
Change at Week 12	-3.21 (-3.77 to -2.65)	-1.78 (-2.35 to -1.21)

Notes
[14] - Phase B: ITT
[15] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0014

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.19

Confidence interval

level

95%

sides

2-sided

lower limit

-1.91

upper limit

-0.47

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0002

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-2.32

upper limit

-0.73

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0006

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.43

Confidence interval

level

95%

sides

2-sided

lower limit

-2.23

upper limit

-0.63

Secondary: Change From Phase B Baseline in the Spasticity Modified Ashworth Scale After 4, 8 and 12 Weeks of Treatment (Overall Score)

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End point title

Change From Phase B Baseline in the Spasticity Modified Ashworth Scale After 4, 8 and 12 Weeks of Treatment (Overall Score)

End point description

The modified Ashworth scale had 5 categories to classify muscle spasticity by the healthcare professional as- 0) No increase in muscle tone. 1) Slight increase in muscle tone with a catch and release or minimal resistance at end of the range. 2) As 1 but minimal resistance through range following catch. 3) More marked increase in tone through range of motion (ROM). 4) Considerable increase in tone, passive movement is difficult. 5) Affected part rigid in flexion or extension.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[16]	53 ^[17]
Units: Score on a Scale
least squares mean (confidence interval 95%)
Change at Week 4	-0.26 (-0.34 to -0.17)	-0.02 (-0.11 to 0.07)
Change at Week 8	-0.30 (-0.39 to -0.21)	-0.05 (-0.15 to 0.04)
Change at Week 12	-0.30 (-0.39 to -0.21)	-0.06 (-0.16 to 0.04)

Notes
[16] - Phase B: ITT
[17] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0003

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

-0.11

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0004

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

-0.11

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0007

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

-0.1

Secondary: Change From Phase B Baseline in Expanded Disability Status Scale (EDSS) Score After 4, 8 and 12 Weeks of Treatment

Top of page

End point title

Change From Phase B Baseline in Expanded Disability Status Scale (EDSS) Score After 4, 8 and 12 Weeks of Treatment

End point description

Expanded disability status scale quantifies disability in 8 functional systems and allows neurologists to assign a Functional System Score. EDSS steps 1.0 to 4.5 refer to subjects with MS who are fully ambulatory. EDSS steps 5.0 to 9.5 are defined by the impairment to ambulation.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[18]	53 ^[19]
Units: Score on a scale
least squares mean (confidence interval 95%)
Change at Week 4	0.00 (-0.02 to 0.02)	0.00 (-0.02 to 0.02)
Change at Week 8	-0.02 (-0.04 to 0.00)	0.00 (-0.02 to 0.02)
Change at Week 12	-0.02 (-0.04 to 0.00)	-0.01 (-0.04 to 0.01)

Notes
[18] - Phase B: ITT
[19] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9878

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.03

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1706

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.01

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6259

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.03

Secondary: Change From Phase B Baseline in the Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

Top of page

End point title

Change From Phase B Baseline in the Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

End point description

The Barthel ADL index analysed the subject´s abilities to perform daily living activities quantitatively. The short form of Barthel ADL index was used in this study, which included 10 elements with a maximum total score of 20. Two elements (grooming and bathing) were on a scale of 0 to 1; 6 elements (bowels, bladder, toilet use, feeding, dressing, and stairs) were on a 0 to 2; and 2 elements (mobility and transfer) were on a scale of 0 to 3. Total possible scores range from 0 to 20, with lower scores indicating increased disability.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[20]	53 ^[21]
Units: Score on a scale
least squares mean (confidence interval 95%)
Change at Week 4	-0.08 (-0.31 to 0.15)	0.09 (-0.16 to 0.33)
Change at Week 8	-0.10 (-0.39 to 0.18)	0.13 (-0.17 to 0.43)
Change at Week 12	0.04 (-0.23 to 0.30)	0.11 (-0.17 to 0.39)

Notes
[20] - Phase B: ITT
[21] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3273

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

0.17

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2721

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.65

upper limit

0.18

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.709

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

0.31

Secondary: Percentage of Subjects who Achieve the Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

Top of page

End point title

Percentage of Subjects who Achieve the Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

End point description

The Barthel ADL index analysed the subject´s abilities to perform activities of daily living quantitatively. The short form was used in this study, which included 10 elements with a maximum total score of 20. Two elements (grooming and bathing) were on a scale of 0 to 1; 6 elements (bowels, bladder, toilet use, feeding, dressing, and stairs) were on a 0 to 2; and 2 elements (mobility and transfer) were on a scale of 0 to 3. Total possible scores range from 0 to 20, with lower scores indicating increased disability. The MCID of the Barthel ADL index is 1.85 points.

End point type

Secondary

End point timeframe

Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[22]	53 ^[23]
Units: Percentage of subjects
number (not applicable)
Week 4	1.9	5.7
Week 8	3.8	7.5
Week 12	5.7	5.7

Notes
[22] - Phase B: ITT
[23] - Phase B: ITT

Week 4: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2043

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

0.278

Confidence interval

level

95%

sides

2-sided

lower limit

0.038

upper limit

2.027

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3249

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

0.413

Confidence interval

level

95%

sides

2-sided

lower limit

0.07

upper limit

2.434

Week 12: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8834

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

0.879

Confidence interval

level

95%

sides

2-sided

lower limit

0.153

upper limit

5.035

Secondary: Change From Phase B Baseline in Short Form 36 (SF-36) Scores After 4, 8 and 12 Weeks of Treatment

Top of page

End point title

Change From Phase B Baseline in Short Form 36 (SF-36) Scores After 4, 8 and 12 Weeks of Treatment

End point description

The SF-36 differentiates between physical and mental health and consists of 8 different dimensions (physical functioning, vitality, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health) and is validated for bodily pain and physical function. The SF-36 scores for each dimension could range between 0 and 100. Higher score indicates better functional health and well being.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[24]	53 ^[25]
Units: Score on a scale
least squares mean (confidence interval 95%)
Change at Week 4: General health	3.14 (0.02 to 6.25)	1.69 (-1.58 to 4.96)
Change at Week 8: General health	2.73 (-0.60 to 6.07)	2.27 (-1.23 to 5.78)
Change at Week 12: General health	0.31 (-3.71 to 4.34)	1.90 (-2.34 to 6.15)
Change at Week 4: Physical role	9.05 (5.40 to 12.70)	4.26 (0.42 to 8.10)
Change at Week 8: Physical role	12.25 (8.22 to 16.27)	5.90 (1.65 to 10.14)
Change at Week 12: Physical role	7.44 (2.99 to 11.89)	4.77 (0.08 to 9.46)
Change at Week 4: Vitality	7.93 (4.08 to 11.79)	2.55 (-1.50 to 6.60)
Change at Week 8: Vitality	6.88 (2.83 to 10.92)	3.98 (-0.27 to 8.24)
Change at Week 12: Vitality	8.34 (3.89 to 12.78)	3.00 (-1.69 to 7.68)
Change at Week 4: Social functioning	8.08 (3.28 to 12.89)	3.49 (-1.56 to 8.54)
Change at Week 8: Social functioning	7.90 (2.98 to 12.82)	5.35 (0.16 to 10.54)
Change at Week 12: Social functioning	7.68 (3.12 to 12.24)	4.27 (-0.54 to 9.08)
Change at Week 4: Emotional role	5.85 (0.77 to 10.93)	7.46 (2.12 to 12.80)
Change at Week 8: Emotional role	9.38 (4.42 to 14.33)	3.84 (-1.40 to 9.07)
Change at Week 12: Emotional role	6.21 (1.32 to 11.11)	4.99 (-0.18 to 10.16)
Change at Week 4: Mental health	5.23 (2.19 to 8.26)	4.34 (1.15 to 7.53)
Change at Week 8: Mental health	6.62 (3.02 to 10.23)	3.85 (0.06 to 7.65)
Change at Week 12: Mental health	5.52 (2.09 to 8.95)	3.38 (-0.23 to 7.00)
Change at Week 4: Bodily pain	18.05 (13.81 to 22.28)	6.02 (1.57 to 10.47)
Change at Week 8: Bodily pain	19.52 (14.63 to 24.42)	9.84 (4.68 to 15.00)
Change at Week 12: Bodily pain	19.71 (14.34 to 25.09)	10.41 (4.74 to 16.08)
Change at Week 4: Physical functioning	3.90 (0.87 to 6.93)	2.63 (-0.55 to 5.82)
Change at Week 8: Physical functioning	5.31 (2.05 to 8.57)	2.68 (-0.75 to 6.12)
Change at Week 12: Physical functioning	4.08 (0.57 to 7.59)	3.65 (-0.05 to 7.35)

Notes
[24] - Phase B: ITT
[25] - Phase B: ITT

Week 4: General Health- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.526

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

1.45

Confidence interval

level

95%

sides

2-sided

lower limit

-3.07

upper limit

5.97

Week 8: General Health- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8507

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-4.38

upper limit

5.3

Week 12: General Health- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5909

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.59

Confidence interval

level

95%

sides

2-sided

lower limit

-7.44

upper limit

4.26

Week 4: Physical role- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0762

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

4.79

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

10.1

Week 8: Physical role- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.034

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

6.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

12.21

Week 12: Physical role- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4148

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

2.67

Confidence interval

level

95%

sides

2-sided

lower limit

-3.8

upper limit

9.13

Week 4: Vitality- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0592

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

5.38

Confidence interval

level

95%

sides

2-sided

lower limit

-0.21

upper limit

10.98

Week 8: Vitality- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3306

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

2.89

Confidence interval

level

95%

sides

2-sided

lower limit

-2.98

upper limit

8.77

Week 12: Vitality- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1044

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

5.34

Confidence interval

level

95%

sides

2-sided

lower limit

-1.13

upper limit

11.8

Week 4: Social functioning- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1946

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

4.59

Confidence interval

level

95%

sides

2-sided

lower limit

-2.39

upper limit

11.57

Week 8: Social functioning- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.481

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

2.55

Confidence interval

level

95%

sides

2-sided

lower limit

-4.61

upper limit

9.71

Week 12: Social functioning- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3109

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

3.41

Confidence interval

level

95%

sides

2-sided

lower limit

-3.23

upper limit

10.04

Week 4: Emotional role- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6653

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.61

Confidence interval

level

95%

sides

2-sided

lower limit

-8.99

upper limit

5.76

Week 8: Emotional role- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1304

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

5.54

Confidence interval

level

95%

sides

2-sided

lower limit

-1.67

upper limit

12.75

Week 12: Emotional role- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7336

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

1.22

Confidence interval

level

95%

sides

2-sided

lower limit

-5.9

upper limit

8.35

Week 4: Mental health- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6914

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

-3.52

upper limit

5.29

Week 8: Mental health- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2964

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

2.77

Confidence interval

level

95%

sides

2-sided

lower limit

-2.47

upper limit

8.01

Week 12: Mental health- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3976

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

2.13

Confidence interval

level

95%

sides

2-sided

lower limit

-2.85

upper limit

7.12

Week 4: Bodily pain- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0002

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

12.03

Confidence interval

level

95%

sides

2-sided

lower limit

5.88

upper limit

18.18

Week 8: Bodily pain- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0082

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

9.68

Confidence interval

level

95%

sides

2-sided

lower limit

2.57

upper limit

16.8

Week 12: Bodily pain- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0201

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

9.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.49

upper limit

17.12

Week 4: Physical functioning- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5699

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

-3.13

upper limit

5.66

Week 8: Physical functioning- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2746

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

2.62

Confidence interval

level

95%

sides

2-sided

lower limit

-2.11

upper limit

7.36

Week 12: Physical functioning- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.868

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-4.67

upper limit

5.53

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Short Form 36 Quality of Life (SF-36 Qol) Scale Scores After 4, 8 and 12 Weeks of Treatment in Phase B

Top of page

End point title

Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Short Form 36 Quality of Life (SF-36 Qol) Scale Scores After 4, 8 and 12 Weeks of Treatment in Phase B

End point description

End point type

Secondary

End point timeframe

Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[26]	53 ^[27]
Units: Percentage of subjects
number (not applicable)
Week 4: Bodily pain	77.4	35.8
Week 8: Bodily pain	79.2	47.2
Week 12: Bodily pain	69.8	47.2
Week 4: Physical functioning	49.1	34.0
Week 8: Physical functioning	52.8	26.4
Week 12: Physical functioning	47.2	35.8

Notes
[26] - Phase B: ITT
[27] - Phase B: ITT

Week 4: Bodily pain- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0008

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

6.264

Confidence interval

level

95%

sides

2-sided

lower limit

2.196

upper limit

17.871

Week 8: Bodily pain- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0016

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

5.078

Confidence interval

level

95%

sides

2-sided

lower limit

1.884

upper limit

13.685

Week 12: Bodily pain- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0543

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

2.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.983

upper limit

6.669

Week 4: Physical functioning- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2454

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds Ratio

Point estimate

1.619

Confidence interval

level

95%

sides

2-sided

lower limit

0.714

upper limit

3.672

Week 8: Physical functioning- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.015

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds Ratio

Point estimate

2.948

Confidence interval

level

95%

sides

2-sided

lower limit

1.24

upper limit

7.01

Week 12: Physical functioning- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.424

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds Ratio

Point estimate

1.393

Confidence interval

level

95%

sides

2-sided

lower limit

0.614

upper limit

3.159

Secondary: Percentage of Subjects With Change From Baseline in Global Assessment Of Clinical Change (7-Item Categorical Scales) by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment

Top of page

End point title

Percentage of Subjects With Change From Baseline in Global Assessment Of Clinical Change (7-Item Categorical Scales) by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment

End point description

Subject global impression of change (SGIC) indicated the change in ability to function due to MS. The SGIC was assessed using a 7-point scale: Very much better, Much better, Minimally better, No change, Minimally worse, Much worse and Very much worse. The Physician/doctor Global assessment of clinical change (PGIC) was assessed by the physician, using the same 7-point scale used to assess the SGIC.

End point type

Secondary

End point timeframe

Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[28]	53 ^[29]
Units: Percentage of subjects
number (not applicable)
Week 4: SGIC- Very much better	1.9	0
Week 4: SGIC- Much better	11.3	1.9
Week 4: SGIC- Minimally better	41.5	15.1
Week 4: SGIC- No change	20.8	39.6
Week 4: SGIC- Minimally worse	13.2	22.6
Week 4: SGIC- Much worse	11.3	11.3
Week 4: SGIC- Very much worse	0	0
Week 8: SGIC- Very much better	3.8	0
Week 8: SGIC- Much better	13.2	9.4
Week 8: SGIC- Minimally better	32.1	13.2
Week 8: SGIC- No change	18.9	34.0
Week 8: SGIC- Minimally worse	9.4	24.5
Week 8: SGIC- Much worse	13.2	3.8
Week 8: SGIC- Very much worse	5.7	1.9
Week 12: SGIC- Very much better	0	0
Week 12: SGIC- Much better	15.1	3.8
Week 12: SGIC- Minimally better	28.3	22.6
Week 12: SGIC- No change	32.1	41.5
Week 12: SGIC- Minimally worse	5.7	17.0
Week 12: SGIC- Much worse	13.2	1.9
Week 12: SGIC- Very much worse	1.9	0
Week 4: PGIC- Very much better	0	0
Week 4: PGIC- Much better	20.8	1.9
Week 4: PGIC- Minimally better	37.7	13.2
Week 4: PGIC- No change	15.1	41.5
Week 4: PGIC- Minimally worse	17.0	24.5
Week 4: PGIC- Much worse	9.4	9.4
Week 4: PGIC- Very much worse	0	0
Week 8: PGIC- Very much better	3.8	0
Week 8: PGIC- Much better	11.3	7.5
Week 8: PGIC- Minimally better	34.0	11.3
Week 8: PGIC- No change	26.4	39.6
Week 8: PGIC- Minimally worse	9.4	26.4
Week 8: PGIC- Much worse	11.3	0
Week 8: PGIC- Very much worse	0	1.9
Week 12: PGIC- Very much better	3.8	0
Week 12: PGIC- Much better	11.3	5.7
Week 12: PGIC- Minimally better	32.1	20.8
Week 12: PGIC- No change	35.8	49.1
Week 12: PGIC- Minimally worse	5.7	9.4
Week 12: PGIC- Much worse	7.5	1.9
Week 12: PGIC- Very much worse	0	0

Notes
[28] - Phase B: ITT
[29] - Phase B: ITT

Week 4: SGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0035

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

2.852

Confidence interval

level

95%

sides

2-sided

lower limit

1.41

upper limit

5.768

Week 8: SGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1331

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

1.823

Confidence interval

level

95%

sides

2-sided

lower limit

0.833

upper limit

3.993

Week 12: SGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3515

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

1.384

Confidence interval

level

95%

sides

2-sided

lower limit

0.699

upper limit

2.741

Week 4: PGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0005

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

3.972

Confidence interval

level

95%

sides

2-sided

lower limit

1.834

upper limit

8.604

Week 8: PGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.026

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

2.418

Confidence interval

level

95%

sides

2-sided

lower limit

1.111

upper limit

5.262

Week 12: PGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for ordinal repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1615

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

1.623

Confidence interval

level

95%

sides

2-sided

lower limit

0.824

upper limit

3.198

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Global Assessment of Clinical Change by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment (Responder Analysis)

Top of page

End point title

Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Global Assessment of Clinical Change by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment (Responder Analysis)

End point description

Subject global impression of change (SGIC) indicated the change in ability to function due to MS. The SGIC was assessed using a 7-point scale: Very much better, Much better, Minimally better, No change, Minimally worse, Much worse and Very much worse. The PGIC was assessed by the physician, using the same 7-point scale used to assess the SGIC.

End point type

Secondary

End point timeframe

Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[30]	53 ^[31]
Units: Percentage of subjects
number (not applicable)
Week 4: SGIC	54.7	17.0
Week 8: SGIC	49.1	22.6
Week 12: SGIC	43.4	26.4
Week 4: PGIC	58.5	15.1
Week 8: PGIC	49.1	18.9
Week 12: PGIC	47.2	26.4

Notes
[30] - Phase B: ITT
[31] - Phase B: ITT

Week 4: SGIC- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0006 ^[32]

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

5.236

Confidence interval

level

95%

sides

2-sided

lower limit

2.077

upper limit

13.201

Notes
[32] - General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Week 8: SGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0152

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

2.96

Confidence interval

level

95%

sides

2-sided

lower limit

1.238

upper limit

7.076

Week 12: SGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1568

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

1.849

Confidence interval

level

95%

sides

2-sided

lower limit

0.786

upper limit

4.345

Week 4: PGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0001

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

7.045

Confidence interval

level

95%

sides

2-sided

lower limit

2.707

upper limit

18.334

Week 8: PGIC- Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0045

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

3.777

Confidence interval

level

95%

sides

2-sided

lower limit

1.524

upper limit

9.363

Week 12: PGIC- Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

= 0.072

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

2.183

Confidence interval

level

95%

sides

2-sided

lower limit

0.931

upper limit

5.119

Notes
[33] - General Linear Mixed Model for binary repeated data with treatment, week and treatment by week interaction as fixed effect factors.

Secondary: Change From Phase B Baseline in Pain (0-10 NRS) After 4, 8 and 12 Weeks of Treatment

Top of page

End point title

Change From Phase B Baseline in Pain (0-10 NRS) After 4, 8 and 12 Weeks of Treatment

End point description

Pain was measured based on a scale of 0 to 10, 0 as “No pain”and 10 as“Worst possible pain”.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[34]	53 ^[35]
Units: Score on a scale
least squares mean (confidence interval 95%)
Change at Week 4	-2.85 (-3.37 to -2.32)	-1.65 (-2.18 to -1.12)
Change at Week 8	-3.08 (-3.66 to -2.51)	-1.64 (-2.22 to -1.05)
Change at Week 12	-3.21 (-3.81 to -2.62)	-1.80 (-2.41 to -1.20)

Notes
[34] - Phase B: ITT
[35] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0019

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.94

upper limit

-0.45

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0007

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.44

Confidence interval

level

95%

sides

2-sided

lower limit

-2.26

upper limit

-0.62

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0014

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.41

Confidence interval

level

95%

sides

2-sided

lower limit

-2.26

upper limit

-0.56

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement in Pain (0-10 NRS) After 4, 8 And 12 Weeks of Treatment in Phase B

Top of page

End point title

Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement in Pain (0-10 NRS) After 4, 8 And 12 Weeks of Treatment in Phase B

End point description

Pain was measured based on a scale of 0 to 10, 0 as “No pain”and 10 as“Worst possible pain”.

End point type

Secondary

End point timeframe

Week 4, Week 8 And Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[36]	53 ^[37]
Units: Percentage of subjects
number (not applicable)
Week 4	77.4	62.3
Week 8	83.0	54.7
Week 12	73.6	58.5

Notes
[36] - Phase B: ITT
[37] - Phase B: ITT

Week 4: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1104

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.842

upper limit

5.236

Week 8: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0042

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

5.106

Confidence interval

level

95%

sides

2-sided

lower limit

1.693

upper limit

15.396

Week 12: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0571

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

2.688

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

7.447

Secondary: Change From Phase B Baseline in Timed 10 Minute Walk Test, After 4, 8 and 12 Weeks of Treatment

Top of page

End point title

Change From Phase B Baseline in Timed 10 Minute Walk Test, After 4, 8 and 12 Weeks of Treatment

End point description

The timed 10 minute walk test assessed walking speed in meters per second over a short distance.

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[38]	53 ^[39]
Units: Meter per second
least squares mean (confidence interval 95%)
Change at Week 4	-2.09 (-3.16 to -1.03)	-1.10 (-2.25 to 0.05)
Change at Week 8	-1.74 (-3.35 to -0.13)	-1.31 (-3.03 to 0.40)
Change at Week 12	-2.79 (-4.25 to -1.32)	-1.08 (-2.65 to 0.48)

Notes
[38] - Phase B: ITT
[39] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2111

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.99

Confidence interval

level

95%

sides

2-sided

lower limit

-2.56

upper limit

0.57

Week 8: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7158

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-2.78

upper limit

1.92

Week 12: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1174

Method

Mixed Model for Repeated Measure (MMRM)

Parameter type

LS Mean Difference

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3.84

upper limit

0.44

Secondary: Percentage of Subjects With a Clinically Important Difference (CID) Improvement in Timed 10m Walk Test, After 4, 8 and 12 Weeks of Treatment

Top of page

End point title

Percentage of Subjects With a Clinically Important Difference (CID) Improvement in Timed 10m Walk Test, After 4, 8 and 12 Weeks of Treatment

End point description

The timed 10 m walk test assessed walking speed in meters per second over a short distance.

End point type

Secondary

End point timeframe

Week 4, Week 8 and Week 12

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[40]	53 ^[41]
Units: Percentage of subjects
number (not applicable)
Week 4	15.1	11.3
Week 8	17.0	13.2
Week 12	18.9	7.5

Notes
[40] - Phase B: ITT
[41] - Phase B: ITT

Week 4: Sativex vs Placebo

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other ^[42]

P-value

= 0.7698

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

1.194

Confidence interval

level

95%

sides

2-sided

lower limit

0.358

upper limit

3.983

Notes
[42] - General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Week 8: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7819

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

1.173

Confidence interval

level

95%

sides

2-sided

lower limit

0.373

upper limit

3.69

Week 12: Sativex vs Placebo

Statistical analysis description

General Linear Mixed Model for binary repeated data with Phase B baseline mean value as co-variate and treatment, week and treatment by week interaction as fixed effect factors.

Comparison groups

Phase B: Sativex v Phase B: Placebo

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1537

Method

Generalized Linear Mixed model

Parameter type

Adjusted Odds ratio

Point estimate

2.596

Confidence interval

level

95%

sides

2-sided

lower limit

0.695

upper limit

9.701

Secondary: Percentage of Subjects With Changes in Concomitant/Underlying Antispastic Standard Therapy Between Visit 4 and Visit 7

Top of page

End point title

Percentage of Subjects With Changes in Concomitant/Underlying Antispastic Standard Therapy Between Visit 4 and Visit 7

End point description

Any changes in concomitant medication - particularly any changes in antispastic medication – during the study period was recorded in the eCRF.

End point type

Secondary

End point timeframe

Phase B: Start of study drug administration up to 12 weeks

End point values	Phase B: Sativex	Phase B: Placebo
Number of subjects analysed	53 ^[43]	53 ^[44]
Units: Percentage of subjects
number (not applicable)
Baclofen	3.8	7.5
Tizanidine	0	0
Dantrolene	0	0
Benzodiazepine derivatives	1.9	0

Notes
[43] - Phase B: ITT
[44] - Phase B: ITT

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From start of study drug administration until 20 weeks

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Phase A: Sativex

Reporting group description

Reporting group title

Phase B: Sativex

Reporting group description

Reporting group title

Phase B: Placebo

Reporting group description

Subjects who were initial responders and whose Phase A-improvement in MS spasticity NRS score had been reduced by at least 80% during the washout phase received matched placebo for 12 weeks as addon to their optimized standard antispastic medication until they achieved optimized symptom relief and maintained this optimal dose. At least a 15-minute gap was maintained between sprays.

Reporting group title

Phase A: Sativex Washout

Reporting group description

Subjects who qualified as Sativex initial responders received their underlying optimized standard antispastic medication (oral baclofen and/or tizanidine and/or dantrolene) but not Sativex up to 4 weeks, until the subject’s Phase A-gain in MS spasticity NRS score had been reduced by at least 80%.

Serious adverse events	Phase A: Sativex	Phase B: Sativex	Phase B: Placebo	Phase A: Sativex Washout
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 191 (1.05%)	1 / 53 (1.89%)	1 / 53 (1.89%)	0 / 134 (0.00%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Renal and urinary disorders
Tubulointerstitial nephritis
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 134 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Erysipelas
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase A: Sativex	Phase B: Sativex	Phase B: Placebo	Phase A: Sativex Washout
Total subjects affected by non serious adverse events
subjects affected / exposed	46 / 191 (24.08%)	19 / 53 (35.85%)	8 / 53 (15.09%)	12 / 134 (8.96%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Paraesthesia
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	3 / 191 (1.57%)	0 / 53 (0.00%)	0 / 53 (0.00%)	2 / 134 (1.49%)
occurrences all number	3	0	0	2
General disorders and administration site conditions
Fatigue
subjects affected / exposed	3 / 191 (1.57%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	3	0	0	1
Asthenia
subjects affected / exposed	2 / 191 (1.05%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	2	0	0	0
Administration site pain
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Gait disturbance
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Hunger
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	1	0	0	1
Peripheral swelling
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	1	0	0	1
Reproductive system and breast disorders
Prostatic neoplasms and hypertrophy
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Benign prostatic hyperplasia
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Dry throat
subjects affected / exposed	2 / 191 (1.05%)	0 / 53 (0.00%)	0 / 53 (0.00%)	2 / 134 (1.49%)
occurrences all number	2	0	0	2
Throat tightness
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Epistaxis
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Upper respiratory tract inflammation
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Psychiatric disorders
Psychotic disorder
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	0	0	0	1
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 191 (2.09%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	4	0	0	1
Somnolence
subjects affected / exposed	3 / 191 (1.57%)	2 / 53 (3.77%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	6	2	0	0
Dysaesthesia
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Hypoaesthesia
subjects affected / exposed	1 / 191 (0.52%)	1 / 53 (1.89%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	1	1	0	1
Multiple sclerosis relapse
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	2	0	0	1
Disturbance in attention
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Headache
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Hypotonia
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Muscle spasticity
subjects affected / exposed	1 / 191 (0.52%)	1 / 53 (1.89%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	1	1	0	1
Dysgeusia
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 134 (0.00%)
occurrences all number	1	0	1	0
Tremor
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Hypogeusia
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Psychomotor skills impaired
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	14 / 191 (7.33%)	1 / 53 (1.89%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	15	1	0	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	4 / 191 (2.09%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	4	0	0	0
Diarrhoea
subjects affected / exposed	4 / 191 (2.09%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	4	0	0	1
Dry mouth
subjects affected / exposed	3 / 191 (1.57%)	1 / 53 (1.89%)	0 / 53 (0.00%)	2 / 134 (1.49%)
occurrences all number	3	1	0	2
Abdominal pain upper
subjects affected / exposed	2 / 191 (1.05%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	2	0	0	0
Oral pain
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Hepatobiliary disorders
Hepatic cyst
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Renal and urinary disorders
Tubulointerstitial nephritis
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 134 (0.00%)
occurrences all number	0	0	1	0
Hydronephrosis
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Obstructive nephropathy
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Haematuria
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	2 / 191 (1.05%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	2	0	0	0
Muscle spasms
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	1	0	0	1
Bursitis
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Infections and infestations
Cystitis
subjects affected / exposed	2 / 191 (1.05%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	2	1	0	0
Erysipelas
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	1	0	0	0
Influenza
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	1	0	0	1
Tonsillitis
subjects affected / exposed	1 / 191 (0.52%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 134 (0.00%)
occurrences all number	1	0	1	0
Urinary tract infection
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	0	0	0	2
Nasopharyngitis
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 134 (0.75%)
occurrences all number	0	0	0	1
Herpes zoster
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 134 (0.00%)
occurrences all number	0	0	1	0
Oral herpes
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0
Viral infection
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 134 (0.00%)
occurrences all number	0	0	2	0
Gastroenteritis
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 134 (0.00%)
occurrences all number	0	0	1	0
Pulpitis dental
subjects affected / exposed	0 / 191 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 134 (0.00%)
occurrences all number	0	0	1	0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 191 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

21 Oct 2016

- The investigational medicinal product (IMP) was not to be weighed - Subjects were to be withdrawn from the study if they had a relapse of MS. - Systemic corticosteroids were not to be prohibited. - Addition of a secondary efficacy variable: CID improvement in timed 10 minute walk test after 4, 8 and 12 weeks

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: SATIVEX® AS ADD-ON THERAPY VS. FURTHER OPTIMIZED FIRST-LINE ANTISPASTICS: THE SAVANT TRIAL

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Responders After 12 Weeks of Randomized Treatment in Phase B

Primary: Percentage of Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Responders After 12 Weeks of Randomized Treatment in Phase B

Secondary: Percentage of Subjects Who Achieve an Improvement From Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than or Equal to (>=) 30% Clinically Important Difference (CID) After 4 and 8 Weeks of Treatment

Secondary: Percentage of Subjects Who Achieve an Improvement From Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than or Equal to (>=) 30% Clinically Important Difference (CID) After 4 and 8 Weeks of Treatment

Secondary: Percentage of Subjects Who Achieve an Improvement From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than 18% Minimum Clinically Important Difference (MCID) After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects Who Achieve an Improvement From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) Score of Greater Than 18% Minimum Clinically Important Difference (MCID) After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Multiple Sclerosis (MS) Spasticity 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in the Frequency of Spasm After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in the Frequency of Spasm After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in the Severity of Spasm After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in the Severity of Spasm After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Sleep Disruption 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Sleep Disruption 0-10 Numerical Rating Scale (NRS) After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in the Spasticity Modified Ashworth Scale After 4, 8 and 12 Weeks of Treatment (Overall Score)

Secondary: Change From Phase B Baseline in the Spasticity Modified Ashworth Scale After 4, 8 and 12 Weeks of Treatment (Overall Score)

Secondary: Change From Phase B Baseline in Expanded Disability Status Scale (EDSS) Score After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Expanded Disability Status Scale (EDSS) Score After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in the Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in the Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects who Achieve the Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects who Achieve the Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Barthel Activities of Daily Living (ADL) Index After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Short Form 36 (SF-36) Scores After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Short Form 36 (SF-36) Scores After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Short Form 36 Quality of Life (SF-36 Qol) Scale Scores After 4, 8 and 12 Weeks of Treatment in Phase B

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Short Form 36 Quality of Life (SF-36 Qol) Scale Scores After 4, 8 and 12 Weeks of Treatment in Phase B

Secondary: Percentage of Subjects With Change From Baseline in Global Assessment Of Clinical Change (7-Item Categorical Scales) by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects With Change From Baseline in Global Assessment Of Clinical Change (7-Item Categorical Scales) by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Global Assessment of Clinical Change by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment (Responder Analysis)

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement From Phase B Baseline in Global Assessment of Clinical Change by the Subject (SGIC) and the Doctor (PGIC) After 4, 8 and 12 Weeks of Treatment (Responder Analysis)

Secondary: Change From Phase B Baseline in Pain (0-10 NRS) After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Pain (0-10 NRS) After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement in Pain (0-10 NRS) After 4, 8 And 12 Weeks of Treatment in Phase B

Secondary: Percentage of Subjects With an Minimum Clinically Important Difference (MCID) Improvement in Pain (0-10 NRS) After 4, 8 And 12 Weeks of Treatment in Phase B

Secondary: Change From Phase B Baseline in Timed 10 Minute Walk Test, After 4, 8 and 12 Weeks of Treatment

Secondary: Change From Phase B Baseline in Timed 10 Minute Walk Test, After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects With a Clinically Important Difference (CID) Improvement in Timed 10m Walk Test, After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects With a Clinically Important Difference (CID) Improvement in Timed 10m Walk Test, After 4, 8 and 12 Weeks of Treatment

Secondary: Percentage of Subjects With Changes in Concomitant/Underlying Antispastic Standard Therapy Between Visit 4 and Visit 7

Secondary: Percentage of Subjects With Changes in Concomitant/Underlying Antispastic Standard Therapy Between Visit 4 and Visit 7

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
SATIVEX® AS ADD-ON THERAPY VS. FURTHER OPTIMIZED FIRST-LINE ANTISPASTICS: THE SAVANT TRIAL