Clinical trial NCT00702468: Evaluate the Maintenance of Effect After Long-term Treatment With Sativex® in Subjects With Symptoms of Spasticity Due to Multiple Sclerosis
Official title: A Placebo Controlled, Parallel Group, Randomised Withdrawal Study of Subjects With Symptoms of Spasticity Due to Multiple Sclerosis Who Are Receiving Long-term Sativex®.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Spasticity
Multiple Sclerosis
Keywords: Spasticity
Multiple Sclerosis
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2008-06-20
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: The purpose of this study is to evaluate the maintenance of effect after long-term treatment with Sativex® in subjects with symptoms of spasticity due to Multiple Sclerosis (MS) who have been receiving long-term benefit from treatment with Sativex®.

Detailed description: This five week (one week baseline and four weeks randomised treatment period), multi-centre, placebo controlled, parallel group, randomized withdrawal study will evaluate the maintenance of effect after long-term treatment with Sativex® in subjects with symptoms of spasticity due to MS who have been receiving long-term benefit from treatment with Sativex®. Subjects will be selected from the Supply of Unlicensed Sativex® (SUS) or named patient supply programmes and must have been receiving Sativex® for at least 12 weeks prior to study entry. Following informed consent and screening, eligible subjects will enter the study (Visit 1, Day 1) and commence a seven day open label baseline period, before returning for a randomisation visit (Visit 2, Day 7), at which point they are randomised to receive either Sativex® or placebo (randomised withdrawal period). Subjects will return to the centre for an end of study visit at week five (Visit 3, Day 35) or earlier if they withdraw from treatment. Spasticity and sleep disruption review and dosing diaries will be completed each day from the start of the baseline period until completion or withdrawal.

Eligibility 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 MS.
* Received Sativex for the relief of spasticity for at least 12 weeks prior to screening and willing to stop dosing with their own supply for the duration of the study.
* Judged to have been receiving benefit from and shown tolerability to Sativex, in the investigators' and subjects' opinion.
* Takes a minimum dose of Sativex of two sprays per day.
* If receiving disease-modifying medications, these must have been at a stable dose for at least three months prior to screening, and willing to maintain this for the duration of the study.
* Has had a stable regimen for at least 30 days prior to study entry, for all medications and non-pharmacological therapies that may have an affect on spasticity; and willing to maintain this for the duration of the study (N.B. This should be three months prior to study entry, in the case of Interferon therapy).
* Willing to allow his or her general practitioner and consultant, if appropriate, to be notified of participation in the study.
* Willing for his or her name to be notified to the responsible authorities for participation in this study

Exclusion Criteria:

* Has any concomitant disease or disorder that has symptoms of spasticity or that may influence the subject's level of spasticity.
* Unable to rate their level of spasticity or distinguish it from other MS symptoms.
* Currently receiving a prohibited medication (Botulinum Toxin, or Acomplia (Rimonabant), and unwilling to stop or comply for the duration of the study or had received said medication/ therapy within three months prior to the screening visit.
* Unwilling to stop their own Sativex treatment for the duration of the study.
* Any known or suspected immediate family history of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition.
* Has evidence of cardiomyopathy.
* Has experienced myocardial infarction or clinically relevant cardiac dysfunction within the last 12 months or has a cardiac disorder that, in the opinion of the investigator would put the subject at risk of a clinically relevant arrhythmia or myocardial infarction.
* Has a QT interval of \> 450 ms (males) or \> 470 ms (females) at Visit 1.
* Has a secondary or tertiary atrioventricular (AV) block or sinus bradycardia (HR \<50bpm unless physiological) or sinus tachycardia (HR\>110bpm) at Visit 1.
* Has a diastolic blood pressure of \<50 mmHg or \>105 mmHg (when measured in a sitting position at rest for five minutes) prior to randomisation
* Has impaired renal function e.g. creatinine clearance is lower than 50ml/min at Visit 1 and is indicative of renal impairment.
* Has significantly impaired hepatic function, at Visit 1, in the investigator's opinion.
* 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 and for three months thereafter.
* Subjects who have received any IMP within the 12 weeks before Visit 1.
* Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, may influence the result of the study, or the subject's ability to participate in the study.
* Following a physical examination, the subject has any abnormalities that, in the opinion of the investigator, would prevent them from safely participating in the study.
* Travel outside the UK planned during the study.
* Unwilling to abstain from donation of blood during the study.
* Subjects previously randomised into this study.

Primary outcomes:
measure: Number of Subjects Who Experience Treatment Failure.
timeFrame: Week 1- Week 5
Secondary outcomes:
measure: Change in Mean Daily Spasticity Severity as Measured on a Spasticity Severity 0-10 Numerical Rating Scale (NRS).
timeFrame: Baseline (Week 1) to Week 5
measure: Change in Modified Ashworth Scale.
timeFrame: Day 7 to Day 28
measure: Change in Motricity Index
timeFrame: Week 2 and Week 5
measure: Timed 10-metre Walk.
timeFrame: Week 2 and Week 5
measure: Daily Sleep Disruption NRS
timeFrame: Week 1- Week 5
measure: Subject Global Impressions of Change.
timeFrame: Day 35
measure: Carer Global Impressions of Change for Functional Ability
timeFrame: Day 35
measure: Carer Global Impressions of Change for Ease of Transfer
timeFrame: Day 35
Other outcomes:
Locations:
city: Gorleston on Sea
country: United Kingdom
facility: James Paget University Hospital NHS Foundation Trust
state: Norfolk
Study officials:
affiliation: James Paget University Hospital NHS Foundation Trust
name: William Notcutt, MB ChB, FRCA
role: PRINCIPAL_INVESTIGATOR
References:
citation: Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex(R) (nabiximols). Mult Scler. 2012 Feb;18(2):219-28. doi: 10.1177/1352458511419700. Epub 2011 Aug 30.
citation: Di Marzo V, Centonze D. Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes. CNS Neurosci Ther. 2015 Mar;21(3):215-21. doi: 10.1111/cns.12358. Epub 2014 Dec 4.