The SPMS trial that never was.

Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis.Brochet B, Deloire MS, Perez P, Loock T, Baschet L, Debouverie M, Pittion S, Ouallet JC, Clavelou P, de Sèze J, Collongues N, Vermersch P, Zéphir H, Castelnovo G, Labauge P, Lebrun C, Cohen M, Ruet A; PROMESS study investigators..
PLoS One. 2017 Jan 3;12(1):e0168834. doi: 10.1371/journal.pone.0168834.

BACKGROUND:Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far.
OBJECTIVE:To compare CPM to methylprednisolone (MP) in SPMS.
METHODS:Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model.
RESULTS:Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31-1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14-4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected.
CONCLUSION:Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability.
TRIAL NCT00241254.

So more not good news for SPMS, here is another trial that has failed. Cyclophophamide forms an metabolite that is active and entrers the CNS and can kill B cells as well as any other cell that is dividing including hairs in the follicles. There was a hint of activity but the trial was terminated because there were not enough volunteers.

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  • Shame they don't include screening data in the paper. It would be helpful to see numbers of people approached, reasons for exclusion, and how many people refused to participate.

  • I am not really sure which is worse SPMS or the side effect profile of cyclophosphamide including: myelosuppression, bone marrow failure, immunosuppression, serious infection, secondary malignancy, hemorrhagic cystitis, urinary bladder fibrosis, renal failure, cardiotoxicity, CHF, arrhythmias, pneumonitis, pulmonary fibrosis, pulmonary toxicity, SIADH, SJ syndrome, hepatotoxicity, pancreatitis, neurotoxicity to name but a few. I wonder if one single researcher would ever volunteer themselves or their family member to participate in this trial?

    • Good point.

      Cyclophosphamide is one of the conditioning chemicals in some HSCT regimes.
      If creates an active metabolite that may enter the CNS.
      However repeated low dose may lead to side effects

    • The point I would like to make is that if the trial does not recruit it fails.

      so if we have the best will in the world and we dont
      engage enough for people to enroll it is a dead duck

    • I'm not surprised that this trial didn't recruit. The NIH had very slow recruiting for its rituximab SPMS trial that was all-expenses travel included, most probably because it was 2:1 treated:placebo. This cyclophosphamide trial sounds less attractive.

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