The Cyprus Institute of Neurology and Genetics (CING) Neurology Clinic C and PALUPA Medical Ltd, Nicosia, Cyprus.
BMJ Open. 2013 Apr 17;3(4). doi: 10.1136/bmjopen-2012-002170. Print 2013.
To assess whether three novel interventions, formulated based on a systems medicine therapeutic concept, reduced disease activity in patients with relapsing-remitting multiple sclerosis (MS) who were either treated or not with disease-modifying treatment.
A 30-month randomised, double-blind, placebo-controlled, parallel design, phase II proof-of-concept clinical study.
Cyprus Institute of Neurology and Genetics.
80 participants were randomised into four groups of 20 each. A total of 41 (51%) patients completed the 30-month trial. The eligibility criteria were an age of 18-65; a diagnosis of relapsing-remitting MS according to the McDonald criteria; a score of 0.0-5.5 on the Expanded Disability Status Scale (EDSS); MRI showing lesions consistent with MS; at least one documented clinical relapse and either receiving or not a disease-modifying treatment within the 24-month period before enrolment in the study. Patients were excluded because of a recent (<30 days) relapse, prior immunosuppressant or monoclonal antibody therapy, pregnancy or nursing, other severe disease compromising organ function, progressive MS, history of recent drug or alcohol abuse, use of any additional food supplements, vitamins or any form of polyunsaturated fatty acids, and a history of severe allergic or anaphylactic reactions or known specific nutritional hypersensitivity.
The first intervention (A) was composed of Ω-3 and Ω-6 polyunsaturated fatty acids at 1:1 wt/wt. Specifically, the Ω-3 fatty acids were docosahexaenoic acid and eicosapentaenoic acid at 3:1 wt/wt, and the Ω-6 fatty acids were linoleic acid and γ-linolenic acid at 2:1 wt/wt. This intervention also included minor quantities of other specific polyunsaturated, monounsaturated and saturated fatty acids as well as vitamin A and vitamin E (α-tocopherol). The second intervention (B, PLP10) was a combination of A and γ-tocopherol. The third intervention (C) was γ-tocopherol alone. The fourth group of 20 participants received placebo. The interventions were administered per os (by mouth) once daily, 30 min before dinner for 30 months.
The primary end point was the annualised relapse rate (ARR) of the three interventions versus the placebo at 2 years. The secondary end point was the time to confirmed disability progression at 2 years.
A total of 41 (51%) patients completed the 30-month trial. Overall, for the per-protocol analysis of the 2-year primary end point, eight relapses were recorded in the PLP10 group (n=10; 0.40 ARR) versus 25 relapses in the placebo group (n=12; 1.04 ARR), representing a 64% adjusted relative rate reduction for the PLP10 group (RRR 0.36, 95% CI 0.15 to 0.87, p=0.024). In a subgroup analysis that excluded patients on monoclonal antibody (natalizumab) treatment, the observed adjusted RRR became stronger (72%) over the 2 years (RRR 0.28, 95% CI 0.10 to 0.79, p=0.016). The per-protocol analysis for the secondary outcome at 2 years, the time to disability progression, was significantly longer only for PLP10. The cumulative probability of disability progression at 2 years was 10% in the PLP10 group and 58% in the placebo group (unadjusted log-rank p=0.019). In a subgroup analysis that excluded patients on natalizumab, the cumulative probability of progression was 10% for the 10 patients in the PLP10 group and 70% for the 12 patients in the placebo group, representing a relative 86% decrease in the risk of the sustained progression of disability in the PLP10 group (unadjusted log-rank p=0.006; adjusted HR, 0.11; 95% CI 0.01 to 0.97, p=0.047). No adverse events were reported. Interventions A (10 patients) and C (9 patients) showed no significant efficacy.
In this small proof-of-concept, randomised, double-blind clinical trial; the PLP10 treatment significantly reduced the ARR and the risk of sustained disability progression without any reported serious adverse events. Larger studies are needed to further assess the safety and efficacy of PLP10.
International Standard Randomised Controlled Trial, number ISRCTN87818535.
评估三种新的干预措施是否能降低复发缓解型多发性硬化症（MS）患者的疾病活动度，这些患者要么接受了疾病修正治疗，要么未接受疾病修正治疗。
一项 30 个月的随机、双盲、安慰剂对照、平行设计、二期概念验证临床研究。
塞浦路斯神经病学与遗传学研究所。
80 名参与者被随机分为 4 组，每组 20 名。共有 41 名（51%）患者完成了 30 个月的试验。入选标准为年龄 18-65 岁；根据 McDonald 标准诊断为复发缓解型 MS；扩展残疾状况量表（EDSS）得分为 0.0-5.5；MRI 显示符合 MS 的病变；在研究入组前 24 个月内至少有一次记录的临床复发，并且要么正在接受疾病修正治疗，要么未接受疾病修正治疗。患者因近期（<30 天）复发、先前的免疫抑制剂或单克隆抗体治疗、妊娠或哺乳期、其他严重疾病导致器官功能受损、进行性 MS、近期药物或酒精滥用史、使用任何其他补充食品补充剂、维生素或任何形式的多不饱和脂肪酸、以及严重过敏或过敏反应史或已知的特定营养过敏而被排除在外。
第一种干预措施（A）由 ω-3 和 ω-6 多不饱和脂肪酸以 1:1 的重量/重量比组成。具体来说，ω-3 脂肪酸是二十二碳六烯酸和二十碳五烯酸，重量比为 3:1，ω-6 脂肪酸是亚油酸和 γ-亚麻酸，重量比为 2:1。这种干预措施还包括其他特定的多不饱和、单不饱和和饱和脂肪酸以及维生素 A 和维生素 E（α-生育酚）的少量成分。第二种干预措施（B，PLP10）是 A 和 γ-生育酚的组合。第三种干预措施（C）是单独的 γ-生育酚。第四组 20 名参与者接受安慰剂。干预措施通过口服（经口）每日一次，在晚餐前 30 分钟给药，持续 30 个月。
主要终点是 2 年时三种干预措施与安慰剂的年复发率（ARR）。次要终点是 2 年时确认的残疾进展时间。
共有 41 名（51%）患者完成了 30 个月的试验。总体而言，对于 2 年主要终点的方案分析，PLP10 组有 8 例复发（n=10；0.40ARR），安慰剂组有 25 例复发（n=12；1.04ARR），PLP10 组的调整相对风险降低了 64%（RRR 0.36，95%CI 0.15-0.87，p=0.024）。在排除了接受单克隆抗体（那他珠单抗）治疗的患者的亚组分析中，观察到的调整后的 RRR 在 2 年内更强（72%）（RRR 0.28，95%CI 0.10-0.79，p=0.016）。2 年时的次要终点，残疾进展时间的方案分析显示，仅 PLP10 组的时间显著延长。2 年时残疾进展的累积概率在 PLP10 组为 10%，在安慰剂组为 58%（未调整的对数秩检验 p=0.019）。在排除了那他珠单抗患者的亚组分析中，PLP10 组的 10 名患者中，有 10%的患者出现残疾进展，安慰剂组的 12 名患者中，有 70%的患者出现残疾进展，这表明 PLP10 组残疾持续进展的风险降低了 86%（未调整的对数秩检验 p=0.006；调整后的 HR，0.11；95%CI 0.01-0.97，p=0.047）。没有报告不良事件。干预措施 A（10 名患者）和 C（9 名患者）没有显示出显著的疗效。
在这项小规模的概念验证、随机、双盲临床试验中，PLP10 治疗显著降低了 ARR 和持续残疾进展的风险，没有报告任何严重不良事件。需要更大的研究来进一步评估 PLP10 的安全性和疗效。
国际标准随机对照试验，编号 ISRCTN87818535。
