From the Cumming School of Medicine and the Hotchkiss Brain Institute, Calgary, AB (L.M.M., G.C., J.G., M.Y., M.D.H., V.W.Y.), the University of British Columbia, Vancouver (D.K.B.L., A.L.T., A.R.), the University of Montreal, Montreal (P.D.), Western University, London, ON (M.K.), Fraser Health MS Clinic, Burnaby, BC (G.V.), the University of Ottawa and the Ottawa Hospital Research Institute, Ottawa (M.S.F.), Dalhousie University, Halifax, NS (V.B.), the University of Alberta, Edmonton (G.B.), the University of Manitoba, Winnipeg (J.J.M.), Clinique Neuro Rive-Sud, Greenfield Park, QC (F.G.), the University of Toronto, Toronto (L.L.), and CHA-Hôpital Enfant-Jésus, Quebec, QC (M.T.) - all in Canada; and Tufts University, Boston (M.E.).
N Engl J Med. 2017 Jun 1;376(22):2122-2133. doi: 10.1056/NEJMoa1608889.
On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis.
During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T-weighted MRI, cumulative number of new lesions enhanced on T-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T-weighted MRI plus new and newly enlarged lesions on T-weighted MRI]).
A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.
The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).
基于令人鼓舞的初步结果，我们进行了一项随机对照试验，以确定米诺环素是否降低了从首次脱髓鞘事件（也称为临床孤立综合征）向多发性硬化症转化的风险。
在 2009 年 1 月至 2013 年 7 月期间，我们将在过去 180 天内首次出现脱髓鞘症状的参与者随机分配接受 100mg 米诺环素，每日口服两次，或安慰剂。米诺环素或安慰剂的给药一直持续到多发性硬化症的诊断确立或随机分配后 24 个月，以先到者为准。主要结局是在随机分配后 6 个月内转化为多发性硬化症（根据 2005 年麦当劳标准诊断）。次要结局包括在随机分配后 24 个月内转化为多发性硬化症以及在 6 个月和 24 个月时的磁共振成像（MRI）变化（T 加权 MRI 上病变体积的变化、T 加权 MRI 上增强病变的累积数量[增强病变]以及累积的独特病变数量[T 加权 MRI 上的新增强病变加上 T 加权 MRI 上新和扩大的病变]）。
共有 12 家加拿大多发性硬化症诊所的 142 名符合条件的参与者进行了随机分组；72 名参与者被分配到米诺环素组，70 名参与者被分配到安慰剂组。参与者的平均年龄为 35.8 岁，68.3%为女性。在随机分配后 6 个月时，安慰剂组的多发性硬化症转化率为 61.0%，米诺环素组为 33.4%，差异为 27.6 个百分点（95%置信区间[CI]，11.4 至 43.9；P=0.001）。在调整基线时增强病变的数量后，在随机分配后 6 个月时多发性硬化症转化率的风险差异为 18.5 个百分点（95%CI，3.7 至 33.3；P=0.01）；在 24 个月的次要结局时间点，风险差异无统计学意义（P=0.06）。在 6 个月时，所有次要 MRI 结局均支持米诺环素优于安慰剂，但在 24 个月时则不然。与接受安慰剂的参与者相比，接受米诺环素的参与者更频繁地出现皮疹、头晕和牙齿变色等试验退出和不良事件。
在 6 个月内，米诺环素降低了从临床孤立综合征向多发性硬化症转化的风险，而在 24 个月内则没有。（由加拿大多发性硬化症协会资助；临床试验.gov 编号，NCT00666887）。
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