Saturday, 23 April 2016

ASCEND TRIAL AT AAN

Natalizumab versus placebo in patients with secondary progressive multiple sclerosis (SPMS): results from ASCEND, a multicenter, double-blind, placebo-controlled, randomized phase 3 clinical trial

Authors: Deborah Steiner; Douglas Arnold, MD; Mark Freedman, MD, FAAN; Myla Goldman, MD; Hans-Peter Hartung, MD, FAAN; Eva Havrdova, MD; Douglas Jeffery, MD, PhD; Raj Kapoor; Aaron Miller, MD, FAAN; Finn Sellebjerg; Diogo Amarante, MD; Diego Cadavid, MD, FAAN; Bei Yu; Fiona Forrestal; Kezhen Liu

Objective: To investigate whether natalizumab slows disability progression unrelated to relapses in SPMS patients. Background: Natalizumab is highly efficacious in relapsing multiple sclerosis (RMS). However, no pharmacotherapeutics have been shown to reduce disability progression unrelated to relapses in SPMS patients. Design/Methods: ASCEND enrolled natalizumab-naive patients with SPMS for ≥2 years and disability progression unrelated to clinical relapses in the prior year. The primary endpoint (designed to capture treatment effects on key aspects of disability progression in SPMS) was a binary outcome of confirmed disability progressors or nonprogressors on a composite endpoint (Expanded Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-Hole Peg Test [9HPT]).
Results: Participants received 300-mg IV natalizumab (n=439) or placebo (n=448) every 4 weeks for 96 weeks. At baseline, most patients had advanced disability; 71% had no relapses within 2 years pre-enrollment. While 63% presented with EDSS scores of 6.0-6.5 (walking aid required), median 9HPT time was 28.6 seconds, suggesting greater lower-limb than upper-limb impairment. ASCEND did not meet the primary endpoint; a slightly smaller percent of patients treated with natalizumab were progressors (44%) compared with placebo (48%) [adjusted odds ratio [OR]: 0.86, 95% CI:0.66-1.13; P=0.29]. Natalizumab showed a statistically significant treatment effect on reducing upper-limb disability progression unrelated to relapse (measured by 9HPT, a pre-specified component of the primary endpoint; 15% natalizumab vs 23% placebo; OR: 0.56; P=0.0012). A significant treatment effect was also observed on reducing annualized relapse rate and MRI activity. Natalizumab was generally well tolerated, with adverse events consistent with its known safety profile.
Conclusions: While natalizumab did not delay progression of ambulatory disability in this SPMS population, it was associated with significant slowing of upper-extremity disability progression and reduction of relapses and MRI activity. The lack of treatment effects on ambulatory function underscores the importance of treating MS early with effective therapies like natalizumab.

CoI None

5 comments:

  1. Am I interpreting this correctly, over the 96 month period the difference between natalizumab and placebo on upper limb function was 8% less progression in disability over 96 weeks? (15% progression vs 23%)
    Yet the progressors overall were 44% on natalizumab vs 47% on placebo and so that 3% difference is deemed as insignificant?
    I hate to say it but if this is correct then this trial was a failure. Allowing for staticial inaccuracies as well as the wild varying nature of how MS progresses in different people, the above could purely be down to that.
    If I have read this wrong that I apologise, if not please comment on how this is deemed a partially successful trial? Sound like a drug company putting a spin on results to potentially gain more business.

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    Replies
    1. Yes, the ASCEND trial was overall negative on the pre-specified composite outcome measure, but positive on the 9HPT.

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    2. 9HPT produces an average time needed by a patient to perform a test. Can you please clarify what 15% and 23% refer to? A mean increase of the necessary time for each group of patients?

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    3. 15% of SPMSers on natalizumab in trial had a 20% worsening in the time it took them to complete the 9HPT; the worsening had to be confirmed at 3 months. In comparison 23% of SPMSers on placebo had confirmed worsening. The 8% difference over 2-years is highly significant and supported by the ABILHAND questionnaire. What you have to remember is that small differences over 2-years would become big difference over a long period of time.

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    4. But the 3% that was seen in overall in progression vs placebo is a failure.
      Sorry Dr G, this is a failure. You have no way of measure progression in that it can be so much quicker in some than in others. You youself have said that once people get to EDSS6/6.5 people seem to stay at that disability level for quite sometime so such a small change in progression reduction could purely be down to that.

      Doctors and numbers just don't got together. You are reaching here, and I feel your links with drug companies are for some reason clouding your normal unbiased view.

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