Thursday, 22 March 2018

If we #Thinkhand we would have another treatment for Progressive MS.

Another DMT for progressive MS bites the dust! Yet another poorly designed progressive trial. If only it had been designed better it would have transformed the management of SPMS. Have we learnt from our mistakes?

Kapoor R, Ho PR, Campbell N, Chang I, Deykin A, Forrestal F, Lucas N, Yu B, Arnold DL, Freedman MS, Goldman MD, Hartung HP, Havrdov√° EK, Jeffery D, Miller A, Sellebjerg F, Cadavid D, Mikol D, Steiner D; ASCEND investigators. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis(ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 2018 Mar 12. pii: S1474-4422(18)30069-3.

BACKGROUND:Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.
METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with, number NCT01416181.
FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.
INTERPRETATION:Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.

In a week where we have had the suggestion of guest authors on trials, I scan through the authors to see some familiar faces, but I am surprsied to see that this paper does not have ProfG as one of the lead authors. 

Why...he has been saying that if we use the EDSS as the primary outcome, we are throwing treatments for progressive MS away. He also argued that the original ACSEND trial was not long enough to see an effect on progression. 

We are so focussed on the legs as an outcome with the EDSS However, we should be focussing on upper limb and head function as it will have more reserve in the system to save by treatment.

As can be seen by this study, if you focussed on hand function you would have had a positive trial, as the Nine hole peg test showed a signficant treatment effect. The  effect on the lower limbs did not.

The regulators and neuros need to wake up and get rid of their EDSS-tinted tunnel vision.


  1. Why today's article about Siponimod has just disappeared?

    1. It's under embargo until later tonight (23:30). It went live by mistake.

    2. Okay! Thank you, prof G.

  2. My mistake. I was not aware of embargo.

  3. Natalizumab is not an effective treatments in progressive MS. I do not consider < 25% decrease in rate of progression above placebo (by siponimod, ocrezulimab and natalizumab) a great success, but more of a statistical manipulation even taking into account the theoretical therapeutic lag and length-dependent axonopathy, which could make the % slightly higher but then again worsen with aging.

    A successful treatment should actually noticeably improve the quality of the life of a progressive MS patient by the actual patient, not by MRI (ie. see Gilenya) or by manipulated statistics. It should improve their EDSS, 9 hole peg test, 25 foot walk test, 6 minute treadmill test, bladder and bowel function, cognitive and depression scores.

    Their quote is: "it did reduce progression on its upper-limb component". So we are going to worsen just a little slower to the same endpoint. Fantastic, we are really shooting for the stars.

    Where are the effective neurodegeneration, remyelination and neurorestorative treatments that will actually noticeably improve progressive MS patients? This madness of neurology researchers focusing mainly on neuroinflammatory treatments must end in progressive MS. I would even go as far as saying that the Pharma driven cash cow neuroinflammatory treatments have obstructed meaningful other treatments in progressive MS.


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