Centre for Biostatistics, Bioinformatics and Biomarkers, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK 2

Transcription

1 The Cannabinoid Use in Progressive Infammatory brain Disease (CUPID) tria: a randomised doube-bind pacebo-controed parae-group muticentre tria and economic evauation of cannabinoids to sow progression in mutipe scerosis Susan Ba, 1* Jane Vickery, 2 Jeremy Hobart, 2 Dave Wright, 1 Coin Green, 3 James Shearer, 3,4 Andrew Nunn, 5 Mayam Gomez Cano, 1 David MacManus, 6 David Mier, 6 Shahrukh Maik 6 and John Zajicek 2 1 Centre for Biostatistics, Bioinformatics and Biomarkers, Pymouth University Peninsua Schoos of Medicine and Dentistry, Pymouth, UK 2 Peninsua Cinica Trias Unit, Pymouth University Peninsua Schoos of Medicine and Dentistry, Pymouth, UK 3 Heath Economics Group, University of Exeter Medica Schoo, Exeter, UK 4 Centre for the Economics of Menta and Physica Heath, Institute of Psychiatry, Psychoogy and Neuroscience, King s Coege London, London, UK 5 Medica Research Counci Cinica Trias Unit, London, UK 6 University Coege London s Institute of Neuroogy, London, UK *Corresponding author Decared competing interests of authors: John Zajicek reports grants and persona fees from the Medica Research Counci, persona fees from Bayer Schering, persona fees from Institut für kinische Forschung, Berin, grants from the Mutipe Scerosis Society and grants from the Mutipe Scerosis Trust outside the submitted work. David Mier reports grants from Mutipe Scerosis Society of Great Britain and Northern Ireand, grants from University Coege London/University Coege London Hospitas Biomedica Research Centre, during the conduct of the study; grants and other from Biogen Idec, grants and other from Novartis, grants and other from GaxoSmithKine, grants from the Nationa Institute for Heath Research, grants from Genzyme, grants from the US Nationa Mutipe Scerosis Society and the Mutipe Scerosis Society of Great Britain and Northern Ireand, other from Bayer Schering, other from Mitsubishi Pharma Ltd, other from Merck, other from Chugai and persona fees from McApines Mutipe Scerosis, 4th edition, outside the submitted work. David MacManus reports grants from Biogen Idec, grants from GaxoSmithKine, grants from Apitope, grants from Novartis and grants from Richmond Pharma outside the submitted work. Pubished February 2015 DOI: /hta19120

2 Scientific summary The Cannabinoid Use in Progressive Infammatory brain Disease (CUPID) tria Heath Technoogy Assessment 2015; Vo. 19: No. 12 DOI: /hta19120 NIHR Journas Library

3 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 12 (SCIENTIFIC SUMMARY) Scientific summary Background Mutipe scerosis (MS) is the commonest cause of neuroogica disabiity in young aduts. It is generay regarded as an autoimmune disease, with eary episodes of infammation associated with axona damage, which becomes the major pathoogica process as the disease progresses. Initia cinica reapses are often repaced by secondary gradua progression after severa years. Athough therapies for the infammatory phase are avaiabe, none has been shown to sow disease progression in the absence of reapses. Cannabinoids are used to ameiorate MS-reated symptoms, particuary musce spasticity and pain. Our previous arge muticentre Cannabinoids in MS (CAMS) tria focused on testing symptomatic benefits of cannabinoids for 15 weeks in 630 participants (95% with progressive disease). A treatment effect on spasticity (assessed by the Ashworth scae) was not evident, athough more participants reported benefits from symptom aeviation in the active group than in the pacebo group. Experimenta evidence emerged to suggest that cannabinoids have neuroprotective effects and might encourage remyeination. A foow-up study, in which participants, masked to treatment, coud continue study medication for up to 12 months, reported significant effects of dronabino [Δ 9 -tetrahydrocannabino (Δ 9 -THC)] on spasticity, with some evidence of an effect on disabiity, measured by the Expanded Disabiity Status Scae (EDSS) and Rivermead Mobiity Index (RMI). This provided cinica evidence to support experimenta data suggesting that cannabinoids might have a neuroprotective effect in progressive MS and confirmed that dronabino continued to ameiorate patients symptoms for up to 12 months. The Cannabinoid Use in Progressive Infammatory brain Disease (CUPID) tria aimed to test the hypothesis that ora dronabino sows progression of primary progressive MS (PPMS) and secondary progressive MS (SPMS) over 3 years. Aims In patients with PPMS and SPMS, three primary aims were investigated over 3 years. These were to: assess the vaue of Δ 9 -THC in sowing disease progression assess the safety of Δ 9 -THC use the information gained to improve methodoogy for conducting cinica trias in progressive MS. Methods Design The CUPID tria was a randomised, doube-bind, pacebo-controed, muticentre, parae-group study in aduts with PPMS and SPMS, designed to assess the efficacy and safety of Δ 9 -THC in sowing disease progression over 3 years. Setting and participants Participants were recruited from 27 UK neuroogy or rehabiitation departments. Eigibe patients were aged years, with a diagnosis of PPMS or SPMS, evidence of disease progression in the preceding year, EDSS score and wiingness to abstain from other cannabis use during the tria. Main excusion criteria were: immunosuppressive or immunomoduatory therapy in previous 12 months corticosteroids in previous 3 months Queen s Printer and Controer of HMSO This work was produced by Ba et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. iii

4 SCIENTIFIC SUMMARY: THE CANNABINOID USE IN PROGRESSIVE INFLAMMATORY BRAIN DISEASE (CUPID) TRIAL significant MS reapse in previous 6 months serious iness or medica condition ikey to interfere with study assessment previous history of psychotic iness sesame seed aergy pregnancy cannabinoids (incuding nabione) taken in previous 4 weeks. Randomisation Consenting patients were randomy assigned in a 2 : 1 ratio to ora Δ 9 -THC or pacebo. Randomisation was baanced according to EDSS score, study site and disease type, by stochastic minimisation, using a computer-generated randomisation sequence. Participants and study staff were binded to treatment aocation. Interventions Ora Δ 9 -THC (maximum dose 28 mg/day, titrated against body weight and adverse effects) or matching pacebo (vegetabe oi capsues). Outcome measures Primary cinica outcomes were time to confirmed EDSS score progression (physician based) and change in Mutipe Scerosis Impact Scae-29 version 2 20-point physica subscae (MSIS-29phys) score (patient based). Secondary outcomes incuded: number and nature of adverse events (AEs); MS Waking Scae-12 version 2 (MSWS-12v2) score; MS Functiona Composite (MSFC) score; RMI score; Short Form questionnaire-36 items version 2 (SF-36v2) score; European Quaity of Life-5 Dimensions (EQ-5D) questionnaire score; MS Spasticity Scae-88 (MSSS-88) score and category rating scae. Additionay, in the magnetic resonance imaging (MRI) substudy, outcomes incuded brain atrophy [in terms of annua percentage brain voume change (PBVC)] and occurrence of new T1 hypointense and new or newy enarging T2 hyperintense esions from annua crania MRI. Expanded Disabiity Status Scae was assessed by the physician at foow-ups schedued at 3 and 6 months, then 6-monthy up to 36 months, uness EDSS score progression was seen at this time, in which case a further visit was schedued at 42 months. RMI was aso assessed at these visits. MSFC (timed 25-foot wak; 9-hoe peg test; paced auditory seria addition test) were assessed at 2 weeks (treated as baseine) and at 12, 24 and 36 or 42 months. Data on MSIS-29phys, MSWS-12v2, SF-36v2 and EQ-5D were coected from posta questionnaires at baseine, 3 and 6 months, and then 6-monthy up to 36 or 42 months. Questionnaires aso incuded MSSS-88 and category rating scaes at 12, 24 and 36 or 42 months. Sampe size and power Previous data suggested a progression rate of approximatey 70% in the pacebo group. Based on this and an expected 5% annua oss to foow-up rate, recruiting 492 patients provided 90% power to detect a one-third reduction in hazard of progression [i.e. hazard ratio (HR) 0.67], corresponding to a reative reduction in risk of progression over 3 years of 21% (from 70% to 55% progression in the Δ 9 -THC group). For the MRI substudy, aowing for a 5% annua oss to foow-up rate, it was estimated that 261 patients aocated to active treatment and pacebo in a 2 : 1 ratio gave 90% power to detect 40% sowing in atrophy rate, with scans performed pre treatment and at years 1, 2 and 3. Anaysis Anaysis of time to EDSS score progression used Cox proportiona hazards modes. Anaysis of repeated measures of MSIS-29phys score, secondary cinica outcomes and PBVC used mutieve modes, with individua differences incorporated using random coefficients. Logistic regression modes were used to anayse data on new or newy enarging T2 and T1 esions. In a modes, between-group differences were estimated, adjusted for baseine patient and disease characteristics. Anaysis, using statistica software R version (The R Foundation for Statistica Computing, Vienna, Austria), was by intention to treat. iv NIHR Journas Library

5 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 12 (SCIENTIFIC SUMMARY) Investigation of adverse and serious adverse events At each foow-up, participants were asked a question to eicit information about new or previousy reported AEs. Events which satisfied criteria for seriousness (according to standard reporting procedures for cinica trias of investigationa medicina products) were reported by system organ cass to an Independent Data Monitoring Committee for scrutiny. Serious AEs (SAEs) categorised as suspected unexpected serious adverse reactions were subject to expedited reporting to the sponsor, unbinded independenty of the trias team and reported to the Medicines and Heathcare products Reguatory Agency as required. Identification and verification of AEs was substantiated by inspection of cinica case notes during site monitoring visits. Rasch measurement theory Data from MSIS-29v2, MSWS-12v2 and MSSS-88 were examined using Rasch measurement theory (RMT) methods. RMT derives, from ordered rating scae scores, inear estimates of constructs they measure, which are more scientificay sound vaues to anayse and are associated with individua person standard errors. First, performance of the scaes as measurement instruments was examined. Second, data were examined for evidence of symptomatic changes (differences between measurements at baseine and end of dose titration period) and disease-modifying changes (differences between measurements at baseine and ast visit), at group and individua person eves. Anayses incuded patients who remained on tria medication. At the group eve, statistica and cinica significance was assessed using paired t-tests and two effect sizes (Cohen s and standardised response means), respectivey. At the individua person eve, significance of each person change score was computed, identifying them as significanty or non-significanty better, unchanged, non-significanty or significanty worse. Economic evauation In an economic evauation, the primary anaysis was based on a between-group comparison of costs and quaity-adjusted ife-years (QALYs) (cacuated using EQ-5D scores) over 3 years, from the UK NHS and Persona Services perspective. Secondary anayses considered costs from the patient perspective. Costs and QALYs were discounted after the first year at the 3.5% UK treasury rate. Missing data were imputed using mutipe imputation using chained equations. Regression methods were used to estimate between-group differences in costs and QALYs adjusting for baseine vaues and pre-specified covariates. Resuts Of the 558 patients assessed for eigibiity, 45 (8%) faied to meet the incusion criteria. Of the 513 eigibe patients, 10 (2%) decined to participate and five (1%) were excuded due to uncontroed hypertension (n = 2) and not attending screening appointment (n = 3). Of the remaining 498 patients, 332 were aocated to active treatment and 166 to pacebo, of whom 329 and 164 patients, respectivey, were anaysed. There were no important between-group differences in baseine patient and disease characteristics. Primary anaysis showed itte evidence of treatment effect on time to confirmed EDSS score progression. The HR (active : pacebo) was 0.92 [95% confidence interva (CI) 0.68 to 1.23]. Concusions from this anaysis were robust to sensitivity anayses. Pre-specified subgroup anayses of time to EDSS score progression indicated a differentia effect of treatment between participants with ower and higher baseine EDSS scores. The estimated HR (active : pacebo) for the subgroup with baseine EDSS score of was beow 1; those with an EDSS score of 6.0 and 6.5 were above 1. A mutieve mode fitted to repeated measures of MSIS-29phys score showed itte evidence of a treatment effect, i.e. the estimated between-group difference in MSIS-29phys score (dronabino pacebo) was 0.9 (95% CI 2.0 to 0.2; p = 0.11). Mutieve modes showed itte evidence of an effect of treatment on MSFC z-score [estimated between-group difference (dronabino pacebo) 0.03 (95% CI 0.19 to 0.09; p = 0.72)]; MSWS-12v2 [estimated between-group difference (dronabino pacebo) 0.19 (95% CI 0.97 to 0.60; p = 0.74)]; RMI [estimated between-group difference (dronabino pacebo) 0.04 (95% CI 0.24 to 0.32; p = 076)]; or on any other cinica outcome. Queen s Printer and Controer of HMSO This work was produced by Ba et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. v

6 SCIENTIFIC SUMMARY: THE CANNABINOID USE IN PROGRESSIVE INFLAMMATORY BRAIN DISEASE (CUPID) TRIAL There was no significant treatment effect on brain atrophy; estimated between-group difference in PBVC (dronabino pacebo) 0.01% (95% CI 0.26% to 0.24%; p = 0.94). There was an effect of time on atrophy (p < ); on average, cumuative PBVC was estimated to be 0.58%, 1.20% and 2.02% at years 1, 2 and 3, respectivey. The suggestion of a treatment effect from subgroup anaysis of time to EDSS score progression [HR (active : pacebo) 0.52, 95% CI 0.32 to 0.85; baseine EDSS score ], ed to post-hoc anaysis of progression among patients in this EDSS group, which suggested a potentiay beneficia effect of active treatment compared with pacebo (p = 0.01, og-rank test). One hundred and fourteen (35%) patients in the active group and 46 (28%) in the pacebo group experienced at east one SAE, the most common being hospita admission for MS-reated events and infections. The number and nature of SAEs was simiar across treatment groups. There were numerous non-serious AEs in both groups, consistent with effects of MS and the known safety profie of cannabinoids. The median number of events per participant was 11 (25th 75th percenties 7 17) and 10 (25th 75th percenties 6 14) in the active and pacebo group, respectivey. Loss to foow-up rate was as predicted; however, unwanted side effects contributed to a reativey high rate of discontinuation from tria medication in the active group. Among patients remaining on tria medication (n = 178 active; n = 118 pacebo), median prescribed daiy dose during the fina year of foow-up was four capsues (25th 75th percenties 2 6 capsues) and six capsues (25th 75th percenties 4 8 capsues) in the active and pacebo group, respectivey. Rasch measurement theory anaysis showed that MS-specific scaes performed we as measurement instruments. Targeting was good enough to enabe robust evauation of scae performance and individua person-eve (and group-eve) anaysis of inear estimates. A subscaes of MSIS-29v2, MSWS-12v2 and MSSS-88 had response categories that worked as intended, items that mapped out continua on which to measure peope, items that were statisticay cohesive, minima or no item bias or instabiity. However, targeting pots for some physica function scaes (e.g. MSWS-12v2) were skewed, questioning whether or not some scaes underestimate changes and differences occurring in the study. Group-eve anayses of RMT-derived inear estimates impied dronabino was not associated with symptomatic or disease-modifying benefit. There was no evidence that dronabino improved psychosocia functioning. Post-hoc disabiity-defined subgroup anayses showed no cear symptomatic or disease-modifying treatment effect. There were hints of a potentia disease-modifying effect with reduced progression measured by the MSIS-29phys and MSWS-12v2; between-group effect size differences for these two scaes/subscaes were cinicay moderate to arge. These were not supported by benefit on reated MSSS-88 subscaes. Estimated mean incrementa cost to the NHS for Δ 9 -THC over and above usua care over 3 years was 27, per treated patient, with no between-group difference in QALYs. Post-hoc subgroup anayses of patients with baseine EDSS indicated incrementa costs at 30,130 and estimated incrementa QALY gain of 0.066, with cost per QALY exceeding 400,000, we above the threshod at which the NHS woud consider an intervention cost-effective. Concusions Primary anayses faied to demonstrate evidence of an effect of dronabino in sowing progression of MS. There were no major safety concerns, athough compiance was amost certainy affected by minor side effects eading to ess treatment adherence in the active group. There was some evidence of a potentiay beneficia effect of dronabino in participants with baseine EDSS , athough this comprised ony 20% of recruited participants. Conversey, there was evidence of potentia active treatment-reated deterioration in more disabed participants. vi NIHR Journas Library

7 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 12 (SCIENTIFIC SUMMARY) As dronabino was not shown to be effective, a fu cost-effectiveness anaysis was not performed. Anaysis of costs and QALYs indicated that introduction of Δ 9 -THC, in addition to usua care, had significant additiona costs associated with treatment, with no improvement in heath outcomes and was therefore dominated by usua care (i.e. was more costy and no more effective) and not considered cost-effective. The CUPID tria was not designed to detect symptom benefit, which has been found in severa previous studies. However, there was some evidence for potentia symptom ameioration when anciary data on additiona medication and side effects were assessed. As a whoe, the popuation recruited to the CUPID tria was more disabed and progressed ess over 3 years than other simiar studies. This may have reduced the potentia for detecting a treatment effect if the opportunity to detect an effect is imited to earier disease states. Indeed, there was some evidence of a potentiay beneficia effect at these ower disabiity eves. Conversey, the antispastic symptomatic effect (demonstrated in previous studies) may have contributed to any deterioration in those ess abe to wak, as removing spasticity from weak egs may compromise strength and increase disabiity. Lack of compiance in the active group may have contributed to the inabiity to detect a treatment effect. The continuing absence of disease-modifying treatment in progressive MS demands that a opportunities to test potentia treatments rigorousy are taken. Before cannabinoids are cassed in the symptom ameioration-ony category of treatments, further studies using better-toerated treatments in ess disabed patients are warranted. Further work is aso required to identify the popuation of MS patients who are most ikey to deteriorate and in whom detection of a treatment effect is most ikey. Tria registration This tria is registered as ISRCTN Funding Funding for this study was provided by the Heath Technoogy Assessment programme of the Nationa Institute for Heath Research, the Medica Research Counci Efficacy and Mechanism Evauation programme, the Mutipe Scerosis Society and the Mutipe Scerosis Trust. Queen s Printer and Controer of HMSO This work was produced by Ba et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii

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