背景:用于治疗帕金森病的常规口服左旋多巴治疗可能与血浆浓度的变化有关。左旋多巴输注策略可能提供更一致的药物递送和更少的运动波动。我们旨在评估连续24小时/天皮下输注ND0612(左旋多巴-卡比多巴溶液)与口服速释左旋多巴-卡比多巴治疗帕金森病患者运动波动的安全性和有效性。
方法:我们进行了第三阶段,随机,双盲,双假人,主动控制,在16个国家的117个学术和社区神经病学站点进行的多中心试验,包括在欧洲,以色列,和美国。符合条件的参与者是30岁或以上的男性和女性,诊断为帕金森氏病(在开启状态下,Hoehn和Yahr阶段≤3),他们经历了至少2·5小时/天的休息时间。参与者经历了开放标签磨合期(<12周),在此期间,为口服速释左旋多巴-卡比多巴和24小时/天皮下ND0612输注(左旋多巴-卡比多巴60·0/7·5mg/mL)建立了最佳方案,如果需要,补充口服左旋多巴-卡比多巴。然后将参与者随机分配(1:1)到12周的双盲治疗,其最佳方案为皮下ND0612或口服左旋多巴-卡比多巴,根据需要给予匹配的口服或皮下安慰剂以维持盲法。随机化是通过交互式网络响应系统完成的,按地区分层,使用置换块计划。参与者,学习伙伴,对待调查员,研究现场人员,且申办方在治疗组分配中被掩盖.主要疗效终点是从基线的变化(即,随机化时间,当所有患者都接受优化的开放标签ND0612方案时),以每天的总时间完成双盲阶段,而不会出现麻烦的运动障碍,根据治疗意向进行分析。该试验已在ClinicalTrials.gov注册,NCT04006210,并完成。
结果:在2019年9月30日至2022年4月8日之间,381名参与者被注册。其中259人(68%)是随机分配的,128(49%)皮下ND0612和131(51%)口服左旋多巴-卡比多巴。243名(94%)参与者完成了研究。与口服左旋多巴-卡比多巴相比,皮下ND0612的治疗时间增加了1·72h(95%CI1·08至2·36),没有麻烦的运动障碍(从-0·48h[-0·94至-0·02]的基线变化与-2·20h[-2·65至-1·74]的口服左旋多巴·卡比01的基线变化)。在9个预设的每日休息时间分层结果中的前4个中也发现了有利于皮下ND0612的显着治疗差异(-1·40h[95%CI-1·99至-0·80]),运动障碍协会-帕金森病统一评定量表第二部分得分(-3·05[-4·28至-1·81]),患者总体变化印象(比值比[OR]5·31[2·67至10·58]),和临床总体改善印象(OR7·23[3·57至14·64])。分层测试在第四个次要终点之后结束。在开放标签ND0612优化期间,322名参与者中有287名(89%)报告了不良事件,在双盲阶段,ND0612组中128个中的103个(80%)和口服左旋多巴-卡比多巴组中131个中的97个(74%)。最常见的不良事件是输注部位反应(在开放标签ND0612期间有266名[83%]参与者,ND0612组73名[57%],而在双盲阶段口服左旋多巴-卡比多巴组56名[43%]),其中大多数是温和的。ND0612组4名参与者的严重不良事件与研究治疗相关(输注部位蜂窝织炎[n=2],输注部位脓肿和输注部位溃疡[n=1];以及感觉异常和周围感觉运动神经病[n=1])。ND0612组的一名参与者在双盲阶段死亡,但死亡与研究治疗无关(跌倒导致创伤性脑损伤)。
结论:这项3期研究的结果表明,皮下ND0612与口服速释左旋多巴-卡比多巴联合使用的时间增加,而没有麻烦的运动障碍和减少的关闭时间,具有有利的利益-风险特征。ND0612可能提供一种安全有效的皮下左旋多巴输注方法来管理帕金森病患者的运动波动。正在进行的开放标签延伸阶段将提供有关治疗长期疗效和安全性的进一步信息。
背景:神经胚层。
BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson\'s disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson\'s disease.
METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre
trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson\'s disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants,
study partners, treating investigators,
study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This
trial is registered with ClinicalTrials.gov, NCT04006210, and is complete.
RESULTS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the
study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson\'s Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury).
CONCLUSIONS: Results of this phase 3
study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson\'s disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment.
BACKGROUND: NeuroDerm.