Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis

Abstract

BackgroundTherapeutic 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.ObjectiveTo compare CPM to methylprednisolone (MP) in SPMS.MethodsRandomized, 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.ResultsDue 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.ConclusionAlthough 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 RegistrationClinicaltrials.gov NCT00241254

A potential role for cyclophosphamide in the mitigation of acute respiratory distress syndrome among patients with SARS-CoV-2

“…However, we could possibly utilize lower doses given that we are aiming at a reduction of cytotoxic T cells rather than a total elimination. As an example, when cyclophosphamide is utilized as an immunomodulator in multiple sclerosis, the applied dose is many magnitudes less [17]. So, a 10-20 mg/kg dose of cyclophosphamide could be able to demonstrate proof of concept.…”

Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences

“…Compared with new immunomodulators, conventional immunosuppressants have more side effects and worse drug targeting. However, in some countries and regions, due to economic reasons or a lack of DMDs, cyclophosphamide, tacrolimus, and other drugs are still used to treat MS and have some therapeutic effect [199][200][201] . Despite the use of DMDs, some patients still have exacerbations and develop progressive disease.…”

Failed, Interrupted, or Inconclusive Trials on Immunomodulatory Treatment Strategies in Multiple Sclerosis: Update 2015–2020

“…Patients with SPMS were randomized to receive either intravenous cyclophosphamide (750 mg/ m 2 body surface area) or methylprednisolone (1000 mg), administered every 4 weeks for the first 12 months and every 8 weeks during the second year [146]. Since the inflammatory component is more important in the early stages of SPMS, the population selected for the PROMESS trial was characterized by a recent onset of the progressive phase, with relapses present in > 30% of patients in the previous year.…”

“…Of the reviewed trial failures, six trials were completed on patient populations with progressive forms of MS [7,8,92,133,146,158]. We noted that the main reason for failed drug development in progressive MS is due to a lack of understanding of the pathophysiology of progression.…”