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. 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 , , and is complete. 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 –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 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). 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. NeuroDerm.

中文翻译：

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连续皮下注射左旋多巴-卡比多巴 (ND0612) 治疗伴有运动波动的帕金森病 (BouNDless) 的安全性和有效性：一项 3 期、随机、双盲、双模拟、多中心试验

治疗帕金森病的常规口服左旋多巴疗法可能与血浆浓度的变化有关。左旋多巴输注策略可能会提供更一致的药物输送和更少的运动波动。我们的目的是评估每天 24 小时皮下连续输注 ND0612（左旋多巴-卡比多巴溶液）与口服速释左旋多巴-卡比多巴相比，治疗帕金森病患者运动波动的安全性和有效性。我们在欧洲、以色列和美国等 16 个国家的 117 个学术和社区神经病学中心进行了一项随机、双盲、双模拟、主动对照、多中心的 3 期试验。符合资格的参与者是年龄在 30 岁或以上、被诊断患有帕金森病（Hoehn 和 Yahr 阶段≤3 级）且每天至少休息 2·5 小时的男性和女性。参与者经历了开放标签磨合阶段（<12周），在此期间，建立了口服速释左旋多巴-卡比多巴和24小时/天皮下注射ND0612（左旋多巴-卡比多巴60·0/7）的最佳方案。 ·5 mg/mL)，如果需要，补充口服左旋多巴-卡比多巴。然后，参与者被随机分配 (1:1) 接受 12 周的双盲治疗，采用皮下注射 ND0612 或口服左旋多巴-卡比多巴的优化方案，并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，按区域分层，使用排列的区块时间表。参与者、研究合作伙伴、治疗研究者、研究中心工作人员和申办者对治疗组的分配情况不知情。主要疗效终点是从基线（即随机化时间，即所有患者均接受优化的开放标签 ND0612 方案时）到双盲阶段结束时每天总准时时间的变化，无麻烦的运动障碍，通过意向分析对待。该试用已在 、 、 注册，并已完成。 2019年9月30日至2022年4月8日期间，共有381名参与者入组，其中259名（68%）被随机分配，其中128名（49%）接受皮下注射ND0612，131名（51%）接受口服左旋多巴-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，皮下注射 ND0612 治疗可将准时时间延长 1·72 小时（95% CI 1·08 至 2·36），且不会出现麻烦的运动障碍（相对于基线的变化为 –0·48 小时 [–0·94至 –0·02] 皮下注射 ND0612 –2·20 小时 [–2·65 至 –1·74] 口服左旋多巴-卡比多巴；p<0·0001）。在每日休息时间（–1·40 小时 [95% CI –1·99 至 –0·80]）、运动障碍协会-联合帕金森氏病的九个预先指定的分级结果中的前四个中也发现了有利于皮下注射 ND0612 的显着治疗差异疾病评定量表第二部分评分（–3·05 [–4·28 至 –1·81]），患者总体印象变化（比值比 [OR] 5·31 [2·67 至 10·58]），和临床总体改善印象（OR 7·23 [3·57 至 14·64]）。分层测试在第四个次要终点后结束。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，ND0612 组 128 名参与者中有 103 名（80%）报告了不良事件，口服左旋多巴-卡比多巴组 131 名参与者中有 97 名（74%）报告了不良事件。双盲阶段。最常见的不良事件是输注部位反应（开放标签 ND0612 期间有 266 名参与者 [83%]，双盲期间 ND0612 组有 73 名参与者 [57%]，口服左旋多巴-卡比多巴组有 56 名参与者 [43%]阶段），其中大多数是轻微的。 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变 [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）。这项 3 期研究的结果表明，皮下注射 ND0612 与口服速释左旋多巴-卡比多巴联合使用，可以增加给药时间，且不会出现麻烦的运动障碍，并减少停药时间，具有良好的效益-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控制帕金森病患者的运动波动。正在进行的开放标签扩展阶段将提供有关治疗的长期疗效和安全性的进一步信息。神经真皮。正在进行的开放标签扩展阶段将提供有关治疗的长期疗效和安全性的进一步信息。神经真皮。正在进行的开放标签扩展阶段将提供有关治疗的长期疗效和安全性的进一步信息。神经真皮。