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【摘錄自Chataway,DAngelisFConcPtal.Lancet Neurol. 2020 Mar; 19(3) :214-225.】
 Background: Neurodegeneration is the pathological substrate that causes major disability insecondary progressive multiple sclerosis. A synthesis of preclinical and clinical researchidentified three neuroprotective drugs acting on different axonal pathobiologies. We aimed totest the efficacy of these drugs in an efficient manner with respect to time, cost, and patientresource.
Methods: We did a phase 2b, multiarm, parallel group, double-blind, randomisedplacebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients(aged 25-65 years) with secondary progressive multiple sclerosis who were not ondisease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) scoreof 4 0-6:5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse usinga centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg,fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedureincluded minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsuleswere identical in appearance to achieve masking. Patients, investigators, and MRI readers wereunaware of treatment allocation. The primary outcome measure was volumetric MRIpercentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multipleregression, adjusting for baseline normalised brain volume and minimisation criteria. Theprimary analysis was a complete-case analysis based on the intention-to-treat population (allpatients with data at week 96). This trial is registered with Clinical Trials.gov, NCT0 1910259.Findings: Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocatedamiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primaryanalysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole(n=99), and placebo (n=99). No difference was noted between any active treatment andplacebo in PBVC (amiloride vs placebo, 0.0% [95% CI -0ㆍ4 to 0ㆍ5; p-0.99]; fluoxetine vsplacebo -0ㆍ1% [-0'5 to 0 3; p=0-86]; riluzole vs placebo -0ㆍ1% [-0ㆍ6 to 0:3; p-0.77). Noemergent safety issues were reported. The incidence of serious adverse events was low andsimilar across study groups (ten [9%] patients in the amiloride group, seven [6%] in thefluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). Themost common serious adverse events were infections and infestations. Three patients diedduring the study, from causes judged unrelated to active treatment; one patient assignedamiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemicheart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a suddendeath (primary cause) with multiple sclerosis and obesity listed as secondary causes.
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