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

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.

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  • 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.

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

    • 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?

    • 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.

    • 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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