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A Study of the Safety and Effectiveness of Sativex®, for the Relief of Symptoms of Spasticity in Subjects, From Phase B, With Multiple Sclerosis (MS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GW Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier:
NCT00681538
First received: May 19, 2008
Last updated: June 13, 2013
Last verified: June 2013
  Purpose

The purpose of this study is to determine whether Sativex® versus Placebo is effective in the relief of symptoms of spasticity in subjects with multiple sclerosis, who have been identified as having a capacity to respond to Sativex.


Condition Intervention Phase
Spasticity
Multiple Sclerosis
Drug: Sativex®
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: A Two-phase, Phase 3 Study of the Safety and Efficacy of Sativex, in the Symptomatic Relief of Spasticity in Subjects With Spasticity Due to Multiple Sclerosis: Phase A - Single-blind Response Assessment; Phase B - Double-blind, Randomised, Placebo Controlled, Parallel Group Study.

Resource links provided by NLM:


Further study details as provided by GW Pharmaceuticals Ltd.:

Primary Outcome Measures:
  • The Change in Mean Spasticity Numerical Rating Scale (NRS) Score From Baseline to End of Treatment (Phase B). [ Time Frame: Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17) ] [ Designated as safety issue: No ]
    Subjects were asked "On a scale of '0 to 10' please indicate the average level of your spasticity over the last 24 hours" with the anchors: 0 = 'no spasticity' and 10 = 'worst possible spasticity'. They were asked to relate 'no spasticity' to the time prior to the onset of their spasticity.


Secondary Outcome Measures:
  • Number of Subjects Showing an Improvement of at Least 30% or 50% in Their Mean NRS Spasticity Score (Phase B) From Baseline. [ Time Frame: Baseline (Day 1) - End of treatment (last 7 days of Week 17) ] [ Designated as safety issue: No ]
    A subject was classified as a responder in the evaluable period provided they did not withdraw due to lack of efficacy and achieved at least a 30% or 50% reduction (i.e. improvement) in the mean NRS spasticity score from baseline (Day 1) to the end of treatment(last 7 days of Week 17 Phase B). All other subjects and subjects without evaluable data were considered non-responders.

  • Change in Spasm Frequency (Number of Spasms Per Day) From Baseline to End of Treatment (Phase B). [ Time Frame: Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17) ] [ Designated as safety issue: No ]
    The subjects' baseline spasm frequency was the mean of the last seven days scores (Week 4) of Phase A treatment. The variable for analysis was the change in mean spasm frequency from baseline to the end of treatment (last 7 days of Week 17 Phase B).

  • Change in Sleep Disruption (Daily 11-point NRS) From Baseline to End of Treatment (Phase B). [ Time Frame: Baseline (last 7 days of Week 4) - End of treatment (last 7 days of Week 17) ] [ Designated as safety issue: No ]
    The sleep disruption NRS score was recorded by subjects via a daily call to the interactive voice response system at bedtime. Subjects were asked "On a scale of '0 to 10' please indicate how you your spasticity disrupted your sleep last night" with the anchors: 0 = 'did not disrupt sleep' and 10 = 'completely disrupted (unable to sleep at all)'.

  • Change in Spasticity as Measured Using the Modified Ashworth Scale From Baseline to End of Treatment (Phase B). [ Time Frame: Baseline (End of Week 4) - End of treatment (End of Week 17) ] [ Designated as safety issue: No ]
    All 20 muscle groups were assessed for spasticity (using a 1-5 scale): 1= no increase in muscle tone to 5= passive movement is difficult and affected part is rigid in flexion or extension. The score for all 20 muscle groups were added to give a total score out of 100; minimum score was 20. A decrease in score indicates an improvement in condition.

  • Change in Motricity Index Score From Baseline to End of Treatment (Phase B)for Affected Limbs. [ Time Frame: Baseline (End of Week 4) - End of treatment (End of Week 17) ] [ Designated as safety issue: No ]
    Arm - 3 movements were pinch grip, elbow flexion and shoulder abduction. Leg - 3 movements were ankle dorsiflexion, knee extension and hip flexion. The total arm and leg score was the addition of the score for the 3 arm movements and 3 leg movements, respectively. One point was then added to each limb score to give a maximum score of 100; minimum was 1 point. Where both arms (or both legs) were assessed, the average of the two limbs scores was used as the assessment score; otherwise the affected limb total score was used. An increase in score indicates an improvement in condition.

  • Change in Timed 10-metre Walk From Baseline to End of Treatment (Phase B). [ Time Frame: Baseline (End of Week 4) - End of treatment (End of Week 17) ] [ Designated as safety issue: No ]
    Only those subjects for whom it was appropriate (i.e. ambulatory subjects) were timed how long it took to walk 10 metres. Walk time was only assessed for subjects who successfully completed the Timed 10 Metre Walk. A negative difference from baseline indicates an improvement walk time.

  • Subject Global Impressions of Change at End of Treatment (Phase B). [ Time Frame: End of Treatment (WeeK 17) ] [ Designated as safety issue: No ]
  • Carer Global Impressions of Change at of Treatment (Phase B). [ Time Frame: End of treatment (Week 17) ] [ Designated as safety issue: No ]
  • Carer Ease of Transfer Global Impressions of Change at End of Treatment (Phase B). [ Time Frame: End of treatment (week 17) ] [ Designated as safety issue: No ]
  • Physician Global Impressions of Change at End of Treatment (Phase B). [ Time Frame: End of treatment (week 17) ] [ Designated as safety issue: No ]
  • Change EuroQoL Quality of Life Questionnaire (EQ-5D)From Baseline to End of Treatment (Phase B) [ Time Frame: [Baseline (End of Week 4) - End of treatment (End of Week 17) ] [ Designated as safety issue: No ]

    The EQ-5D questionnaire provided two outcomes:

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

    The weighted health state index used the same VAS as above but was calculated for each assessment without imputation to account for missing values i.e., if one or more individual items was missing then the whole index was missing.


  • Mood Assessment: Change in Beck Depression Inventory - II (BDI-II)From Baseline to End of Treatment (Phase B) [ Time Frame: Baseline (End of week 4) - end of treatment (end of week 17) ] [ Designated as safety issue: No ]
    This was a 21-question multiple choice self-report inventory. Subjects' responses to the 21 questions were assigned a score ranging from zero to three, indicating the severity of the symptom. The sum of all BDI-II question scores indicated the severity of depression; score range 0-63. An decrease in score indicates an improvement in condition.


Enrollment: 572
Study Start Date: January 2008
Study Completion Date: January 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sativex

Contains Δ9 tetrahydrocannabinol (THC), 27 mg/ml: cannabidiol (CBD), 25 mg/ml, as extracts of Cannabis sativa L.

Subjects received study medication delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations (THC 32.4 mg:CBD 30 mg) in 24 hours

Drug: Sativex®
containing THC (27 mg/ml):CBD (25 mg/ml), in ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring. Maximum dose within any 24-hour interval is 12 sprays (THC 32.4 mg: CBD 30 mg)
Other Name: GW-1000-02
Placebo Comparator: Placebo
Contains no active drug but colourants and excipients. Subjects received placebo delivered in 100 microlitre actuations by a pump action oromucosal spray. Maximum permitted dose was 12 actuations in 24 hours.
Drug: Placebo
containing ethanol:propylene glycol (50:50) excipients, with peppermint oil (0.05%) flavouring and colouring FD&C Yellow No.5 (E102 tartrazine) (0.0260%), FD&C Yellow No.6 (E110 sunset yellow) (0.0038%), FD&C Red No. 40 (E129 Allura red AC) (0.00330%) and FD&C Blue No.1 (E133 Brilliant blue FCF) (0.00058%).
Other Name: GA0034

Detailed Description:

This 19 week, multicentre study was conducted in two phases. Phase A was a preliminary, single-blind four week treatment period to identify subjects with a capacity to respond to Sativex; eligible, consenting subjects entered a seven day screening period prior to returning to the study centre to begin a four week single-blind course of Sativex treatment. At the end of this phase, subjects' response to Sativex was assessed; those with the capacity to respond (i.e. at least a 20% reduction in mean 0-10 point numerical rating scale (NRS) spasticity score between screening and the end of the four week Phase A treatment) were eligible for entry into Phase B while those who did not respond took no further part in the study other than a follow up visit 14 days later.

Phase B was a 12 week double-blind, randomised, placebo controlled, parallel group study with visits at 28 day intervals and a final follow up visit 14 days after completion or withdrawal.

The level of spasticity, spasm frequency and sleep disruption were collected each day during the entire study via an interactive voice response system (IVRS). In addition, study medication dosing data were recorded via IVRS throughout Phases A and B. Assessments of other secondary and functional measures of spasticity, safety and tolerability, QOL (quality of life) and mood were also gathered throughout the study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Willing and able to give written informed consent for participation in the study.
  • Male or female, aged 18 years or above.
  • Subject is able (in the investigator's opinion) and willing to comply with all study requirements.
  • Diagnosed with any disease sub-type of MS of at least six months duration.
  • Spasticity due to MS of at least three months duration, which is not wholly relieved with current anti-spasticity therapy, and which is expected to remain stable for the duration of the study.
  • Subject fulfils at least one of the two criteria below. Subject must be either: Currently established on a regular dose of anti-spasticity therapy or Previously tried and failed, or could not tolerate suitable anti-spasticity therapy.
  • Subject is currently receiving a stable regimen (for at least 30 days prior to study entry) of all medications that may have an effect on spasticity; and willing to maintain this for the duration of the study. If the subject is currently taking disease-modifying medication, this must be at a stable dose for at least three months prior to the screening visit; the dose must also remain stable for the duration of the study.
  • Willing for his or her name to be notified to his or her primary care physician, and consultant and the responsible authorities for participation in this study, as applicable.

Exclusion Criteria:

  • Any concomitant disease or disorder that has spasticity-like symptoms or that may influence the subject's level of spasticity.
  • Subject's medical history suggests that relapse/remission is likely to occur during the study (over the next 19 weeks) which, in the opinion of the investigator, is expected to influence the subject's spasticity.
  • Currently receiving a prohibited medication and unwilling to stop for the stated period prior to the screening visit and for the duration of the study.
  • Any known or suspected history of: schizophrenia or other psychotic illness;diagnosed dependence disorder;poorly controlled epilepsy or recurrent seizures;hypersensitivity to cannabinoids.
  • Significant cardiac, renal or hepatic disease.
  • Female subjects of child bearing potential and male subjects whose partner is of child bearing potential, unless willing to ensure that they or their partner use effective contraception during the study and for three months thereafter.
  • Female subject who is pregnant, lactating or planning pregnancy during the course of the study or for three months thereafter.
  • Subjects who have received an IMP within the 12 weeks before Visit 1.
  • Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or may influence the result of the study, or the subject's ability to participate in the study.
  • Following a physical examination, the subject has any abnormalities that, in the opinion of the investigator, would prevent them from safely participating in the study.
  • Unwilling to abstain from donation of blood during the study.
  • Travel outside the country of residence planned during the study.
  • Subjects previously randomised into this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00681538

Locations
United Kingdom
Department of Neurology, Northampton General Hospital
Cliftonville, Northampton, United Kingdom, NN1 5BD
Sponsors and Collaborators
GW Pharmaceuticals Ltd.
Investigators
Principal Investigator: Paul Davies, MRCP, FRCP Department of Neurology
  More Information

Publications:
Responsible Party: GW Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT00681538     History of Changes
Other Study ID Numbers: GWSP0604
Study First Received: May 19, 2008
Results First Received: March 23, 2011
Last Updated: June 13, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
Czech Republic: State Institute for Drug Control
Spain: Spanish Agency of Medicines
Italy: Ethics Committee
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by GW Pharmaceuticals Ltd.:
Spasticity
Multiple Sclerosis

Additional relevant MeSH terms:
Muscle Spasticity
Multiple Sclerosis
Sclerosis
Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Demyelinating Autoimmune Diseases, CNS
Demyelinating Diseases
Immune System Diseases
Muscle Hypertonia
Muscular Diseases
Musculoskeletal Diseases
Nervous System Diseases
Neurologic Manifestations
Neuromuscular Manifestations
Pathologic Processes
Signs and Symptoms

ClinicalTrials.gov processed this record on October 20, 2014