John Zajicek

Rating scales as outcome measures for clinical trials in neurology: problems, solutions, and recommendations

Have state-of-the-art clinical trials failed to deliver treatments for neurodegenerative diseases because of shortcomings in the rating scales used? This Review assesses two methodological limitations of rating scales that might help to answer this question. First, the numbers generated by most rating scales do not satisfy the criteria for rigorous measurements. Second, we do not really know which variables most rating scales measure. We use clinical examples to highlight concerns about the limitations of rating scales, examine their underlying rationales, clarify their implications, explore potential solutions, and make some recommendations for future research. We show that improvements in the scientific rigour of rating scales can improve the chances of reaching the correct conclusions about the effectiveness of treatments.

Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up

Objective: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. Methods: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Δ9-tetrahydrocannabinol (Δ9-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to12 months in the follow up study reported here. Results: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Δ9-THC mean reduction 1·82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI −0.99 to 1.19), placebo −0.23 (n = 176, 95% CI −1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Δ9-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. Conclusions: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

Cannabis for dyskinesia in Parkinson disease A randomized double-blind crossover study

Background: The long-term treatment of Parkinson disease (PD) may be complicated by the development of levodopa-induced dyskinesia. Clinical and animal model data support the view that modulation of cannabinoid function may exert an antidyskinetic effect. The authors conducted a randomized, double-blind, placebo-controlled crossover trial to examine the hypothesis that cannabis may have a beneficial effect on dyskinesia in PD. Methods: A 4-week dose escalation study was performed to assess the safety and tolerability of cannabis in six PD patients with levodopa-induced dyskinesia. Then a randomized placebo-controlled crossover study (RCT) was performed, in which 19 PD patients were randomized to receive oral cannabis extract followed by placebo or vice versa. Each treatment phase lasted for 4 weeks with an intervening 2-week washout phase. The primary outcome measure was a change in Unified Parkinson’s Disease Rating Scale (UPDRS) (items 32 to 34) dyskinesia score. Secondary outcome measures included the Rush scale, Bain scale, tablet arm drawing task, and total UPDRS score following a levodopa challenge, as well as patient-completed measures of a dyskinesia activities of daily living (ADL) scale, the PDQ-39, on-off diaries, and a range of category rating scales. Results: Seventeen patients completed the RCT. Cannabis was well tolerated, and had no pro- or antiparkinsonian action. There was no evidence for a treatment effect on levodopa-induced dyskinesia as assessed by the UPDRS, or any of the secondary outcome measures. Conclusions: Orally administered cannabis extract resulted in no objective or subjective improvement in dyskinesias or parkinsonism.

The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS)

Objective: To test whether cannabinoids reduce urge incontinence episodes without affecting voiding in patients with multiple sclerosis. This was part of the multicentre trial of the Cannabinoids in Multiple Sclerosis (CAMS) study. Subjects and methods: The CAMS study randomised 630 patients to receive oral administration of cannabis extract, Δ9-tetrahydrocannabinol (THC) or matched placebo. For this substudy subjects completed incontinence diaries. Results: All three groups showed a significant reduction, p<0.01, in adjusted episode rate (i.e. correcting for baseline imbalance) from baseline to the end of treatment: cannabis extract, 38%; THC, 33%; and placebo, 18%. Both active treatments showed significant effects over placebo (cannabis extract, p=0.005; THC, p=0.039). Conclusion: The findings are suggestive of a clinical effect of cannabis on incontinence episodes in patients with MS. This is in contrast to the negative finding of the CAMS study, where no difference was seen in the primary outcome of spasticity.

Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort

Objective: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). Methods: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7–107.3). Results: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12–18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02–17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50–6.19) were predictive of AID expression. Conclusions: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. Classification of evidence: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.

Review: Glial lineages and myelination in the central nervous system

Oligodendrocytes, derived from stem cell precursors which arise in subventricular zones of the developing central nervous system, have as their specialist role the synthesis and maintenance of myelin. Astrocytes contribute to the cellular architecture of the central nervous system and act as a source of growth factors and cytokines; microglia are bone‐marrow derived macrophages which function as primary immunocompetent cells in the central nervous system. Myelination depends on the establishment of stable relationships between each differentiated oligodendrocyte and short segments of several neighbouring axons. There is growing evidence, especially from studies of glial cell implantation, that oligodendrocyte precursors persist in the adult nervous system and provide a limited capacity for the restoration of structure and function in myelinated pathways damaged by injury or disease.

The effect of cannabis on tremor in patients with multiple sclerosis.

Background: Disabling tremor is common in patients with multiple sclerosis (MS). Data from animal model experiments and subjective and small objective studies involving patients suggest that cannabis may be an effective treatment for tremor associated with MS. To our knowledge, there are no published double-blind randomized controlled trials of cannabis as a treatment for tremor in MS patients. Methods: The authors conducted a randomized double-blind placebo-controlled crossover trial to examine the effect of oral cannador (cannabis extract) on 14 patients with MS with upper limb tremors. There were eight women and six men, with a mean age of 45 years and mean Expanded Disability Status Scale score of 6.25. Patients were randomly assigned to receive each treatment and the doses escalated over a 2-week period before each assessment. The primary outcome was change on a tremor index, measured using a validated tremor rating scale. The study was powered to detect a functionally significant 50% improvement in the tremor index. Secondary outcomes included accelerometry, an ataxia scale, spiral drawing, finger tapping, and nine-hole pegboard test performance. Results: Analysis of the data showed no significant improvement in any of the objective measures of upper limb tremor with cannabis extract compared to placebo. Finger tapping was faster on placebo compared to cannabis extract (p < 0.02). However, there was a nonsignificant trend for patients to experience more subjective relief from their tremors while on cannabis extract compared to placebo. Conclusions: Cannabis extract does not produce a functionally significant improvement in MS-associated tremor.

MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial

Objective Multiple sclerosis (MS) is associated with chronic symptoms, including muscle stiffness, spasms, pain and insomnia. Here we report the results of the Multiple Sclerosis and Extract of Cannabis (MUSEC) study that aimed to substantiate the patient based findings of previous studies. Patients and methods Patients with stable MS at 22 UK centres were randomised to oral cannabis extract (CE) (N=144) or placebo (N=135), stratified by centre, walking ability and use of antispastic medication. This double blind, placebo controlled, phase III study had a screening period, a 2 week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily and a 10 week maintenance phase. The primary outcome measure was a category rating scale (CRS) measuring patient reported change in muscle stiffness from baseline. Further CRSs assessed body pain, spasms and sleep quality. Three validated MS specific patient reported outcome measures assessed aspects of spasticity, physical and psychological impact, and walking ability. Results The rate of relief from muscle stiffness after 12 weeks was almost twice as high with CE than with placebo (29.4% vs 15.7%; OR 2.26; 95% CI 1.24 to 4.13; p=0.004, one sided). Similar results were found after 4 weeks and 8 weeks, and also for all further CRSs. Results from the MS scales supported these findings. Conclusion The study met its primary objective to demonstrate the superiority of CE over placebo in the treatment of muscle stiffness in MS. This was supported by results for secondary efficacy variables. Adverse events in participants treated with CE were consistent with the known side effects of cannabinoids. No new safety concerns were observed. Trial registration number NCT00552604.

Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis

Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years.The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was –0.36 overall and –0.15 in those patients completing ≥1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease.We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis.

Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial

Summary Background Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ9-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis. Methods In this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18–65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0–5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668). Findings Of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68–1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol–placebo) of −0·9 points (95% CI −2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group). Interpretation Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change. Funding UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.