Imaging CUPID does not make it look any better

Mallik S, Ball S, Dalton C, Macmanus D, Tozer D, Miller D, Zajicek J.Cannabinoid use in progressive inflammatory brain disease (cupid) mri sub-study. J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):e2. doi: 10.1136/jnnp-2013-306573.182.

INTRODUCTION:In progressive Multiple Sclerosis (MS), there is no proven therapy for preventing accumulation of irreversible disability. The pathological substrate of irreversible disability in MS is neuroaxonal loss, and brain tissue volume loss on MRI can infer such pathology. There is experimental evidence to suggest that cannabinoids may have a neuroprotective and anti-inflammatory effect, although in a recent UK clinical trial (CUPID), oral cannabinoid did not slow the development of disability in progressive MS compared with placebo.
AIMS:Using serial MRI brain scans obtained during the CUPID trial, we compared oral Delta 9-tetrahydrocannabinol (Δ9-THC) versus placebo for the following: (i) rates of new T2 hyperintense and new T1 hypointense lesions, and (ii) rate of brain atrophy.
METHODS: A subset of progressive MS patients from the CUPID trial, who were randomised to either Δ9-THC or placebo, were followed up for 3 years with MRI scans at 4 time points: baseline, and years 1, 2 and 3. MRI sequences included axial dual echo, fast (turbo) spin echo proton density and T2 weighted scans, as well as a conventional T1 weighted spin echo scan. 46 contiguous 3 mm thick axial slices were performed for each acquisition. Scans from each time point were compared with the immediately preceding scan. New T2 lesions and new T1 lesions were marked by review of the electronic data using imaging software application JIM 6.0. If a scan had been missed, comparison was made with the last scan performed. Normalised brain volume (NBV) was estimated with SIENAX. Two-time-point percentage brain volume change (PBVC) was estimated with SIENA for three time-point pairs: baseline to year 1, year 1 to year 2, and year 2 to year 3.
RESULTS: 273 patients were entered into the sub-study. 182 (67%) received active treatment, and 91 (33%) received placebo. 45 subjects missed one or more scan. Those that only had the baseline scan were excluded from all further analyses. Losses to follow up were 27 at 1 year, 18 at 2 years, and 18 at 3 years. 32 patients did not have a baseline NBV. There was no evidence of an association between treatment group and number of new T1 lesions or T2 lesions, at any of the three time-point pairs (new T1 lesions: baseline to year 1 p=0.99, year 1 to year 2 p=0.17, year 2 to year 3 p=0.90; new T2 lesions: baseline to year 1 p=0.55, year 1 to year 2 p=0.076, year 2 to year 3 p=0.90). Mean baseline NBV was 1420ml (SD 89.02) for all subjects, with no significant difference between the arms (p=0.7). At each of the three time-point pairs, there was no evidence of a difference in mean PBVC between active and placebo arms (baseline to year 1: active -0.60%, placebo -0.59%, p=0.93; year 1 to year 2: active -0.58%, placebo -0.65%, p=0.62; year 2 to year 3: active -0.88%, placebo -0.76%, p=0.39).
CONCLUSION:Δ9-THC was not better than placebo at reducing the rates of new T1 or T2 lesions or brain atrophy in patients with progressive MS.

This is perhaps just as well as the main study demonstrated that there was no positive clinical effect and had there been positive effect on MRI what would it be telling us? However Brain volume imaging is looking to be a bit of a bust, as it failed to be of value in the lamotrigine and riluzole trials. 

In the main study there appeared to be a positive clinical effect if the study focused on people with EDSS less than 5.5. So what happened with the imaging in this group of MSers? Nothing? Something?. It may have been a good way of seeing if it was all artefact. Shame the long-term effect of treatment as reported in CAMS was not examined in CUPID. 

So cannabis as a treatment option bites the dust besides a lot of biology suggesting otherwise.

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