單胺氧化酶B型抑制劑作為左旋多巴的輔助療法治療巴金森氏症的系統性回顧、統合分析與臨床試驗計畫書

Abstract

背景 巴金森氏症（Parkinson’s disease, PD）是老化社會中第二常見的神經退化性疾病，60歲以上的人口中盛行率大於1%以上。此疾病的特徵為神經元內 α-突觸核蛋白（α-synuclein）聚集，導致路易氏體形成，並造成中腦黑質緻密部（substantia nigra pars compacta, SNc）內多巴胺神經元的持續性退化，導致多巴胺不足，進而產生僵硬、動作遲緩、靜止性顫抖及姿勢不穩等臨床症狀。 左旋多巴（Levodopa）仍是治療運動症狀的黃金標準，然而長期使用合併疾病病程演進，病患會出現藥物波動(motor fluctuation) 的現象，其特徵為藥效變短，或是出現藥效減退時動作功能不良的所謂關電現象（off time）與運動功能改善的開電現象（on time）交替出現。MAO-B (monoamine oxidase type B) 為神經突觸中降解多巴胺的酵素酶，MAO-B抑制劑透過抑制此酵素來降低多巴胺的降解，進而增加其在神經突觸間的濃度，進而增加藥物的作用時間。目前臨床上有三種MAO-B 抑制劑：Safinamide、Rasagiline 和Selegiline，其結構與藥理特性各異。目前少有head-to-head 的臨床試驗比較此三種藥物。本研究旨在評估與比較這三種MAO-B 抑制劑在治療巴金森氏症方面的相對療效、效益與限制。

方法 我們系統性地搜尋了四個資料庫，檢索時間從搜尋之資料庫建庫1974年起至2025年3月。檢索策略根據「病患－介入－對照組－結果」（Patient–Intervention–Comparator–Outcome, PICO）架構設計。納入研究需符合所有預先設定的納入標準。品質評估採用 Cochrane 偏差風險評估工具 2.0（Risk of Bias 2.0 tool）進行。 統合分析採用隨機效應模型進行。網絡統合分析在頻率主義架構下進行，亦使用隨機效應模型。主要評估結果包含針對巴金森症動作症狀改善程度 (以The unified Parkinson's disease rating scale，也被稱為UPDRS評分量表)的 Part III 動作功能分數變化、關電off time、無異動症之開電on time以及藥物不良事件（adverse events, AEs）發生率等這幾個面向來比較。

結果 我們納入了17件雙盲隨機對照試驗（double-blinded placebo-controlled randomized controlled trials, RCTs），共計4940位巴金森氏症患者。Safinamide 相較於安慰劑，顯著減少每日平均 off time 1.15小時 (95% CI, 0.87~1.43)。在三種藥物彼此間接比較中，Safinamide 也顯著優於 Rasagiline可以減少關電off time（p = 0.0084）。此外，Safinamide 在增加“無異動症的 on time”上也優於 Rasagiline，雖然該差異未達統計顯著性（p = 0.4167）。 以 UPDRS 第三部分運動嚴重度分數為依據的運動功能評估結果則顯示Selegiline 相較於安慰劑可改善 UPDRS part III 分數達 -4.93 (95% CI, -8.63~-1.24)， Safinamide 相較安慰劑改善-3.12 (95% CI, -4.78~-1.47) Rasagiline 相較安慰劑改善-2.50 (95% CI, -4.48~-0.52)，這三組藥物互相比較之間未觀察到顯著差異（p = 0.5218）。我們的統合分析安全性評估顯示，Safinamide 與安慰劑相比，整體耐受性良好，與其他兩種藥物比較亦無顯著差異 (p = 0.2779)。

結論 我們的研究結果顯示Safinamide 可能是目前臨床可用的 MAO-B 抑制劑中減少藥物波動現象中關電off time最具潛力的選擇。然而，現有比較 MAO-B 抑制劑的證據大多為間接資料。未來仍需進一步進行直接比較的臨床試驗，以全面評估這些藥物在其他面向，例如增加開電時間或是減少動作或是非動作症狀的治療效益。

Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder in aging societies, affecting more than 1% of the population over 60 years of age. The disease is characterized by neuronal α-synuclein accumulation, resulting in Lewy bodies formation and progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) of the midbrain, leading to the clinical manifestations of rigidity, bradykinesia, resting tremor, and postural instability. Levodopa remains the gold standard treatment for motor symptoms; however, long-term use is associated with motor fluctuations, characterized by alternating periods of poor or absent motor function (“off time”) and periods of improved motor function (“on time”). Monoamine oxidase type B (MAO-B) is one of the enzymes that degrade dopamine in the synaptic junction. MAO-B inhibitors increase synaptic dopamine concentration by inhibiting its degradation, thereby extending its half-life in the downstream striatum. Three MAO-B inhibitors, Selegiline, Rasagiline, and Safinamide, have been approved for clinical use. They differ in key aspects. Selegiline is an irreversible MAO-B inhibitor derived from amphetamine, which may cause central nervous system stimulation and is typically used in early-stage PD. Rasagiline is also an irreversible inhibitor but has a non-amphetamine structure, making it better tolerated. Safinamide is a reversible MAO-B inhibitor combining with additional actions, including glutamate inhibition and sodium channel modulation. It is mainly used in mid-to-late stages, particularly in patients with motor fluctuations. However, rare studies compared the efficacy of these three MAO-B inhibitors in symptoms of PD. This study aimed to compare the efficacy and limitations of currently available MAO-B inhibitors in the treatment of PD in the following aspects, reducing motor dysfunction (measured by the unified Parkinson's disease rating scale part III motor scores), reducing off time, and increasing on time without troublesome dyskinesia. Methods We systematically searched four databases from 1974 to March 2025. The search strategy was developed based on PICO framework. Studies were included if they met all predefined eligibility criteria. Quality assessment was conducted using risk-of-bias tool 2. Meta-analysis was performed using a random effects model. Network meta-analysis was conducted under a frequentist framework, also employing a random effects model. Outcomes included incidence of adverse events (AEs), changes in daily “off-time”, “on time without dyskinesia”, and UPDRS part III motor severity scores. Results A total of 17 double-blinded placebo controlled randomized controlled trials (RCTs) comprising 4950 patients with PD were included. Safinamide significantly reduced mean daily “off time” by 1.15 hours compared to placebo (95% CI, 0.87~1.43). In indirect comparisons, Safinamide was also significantly more effective than Rasagiline (p = 0.0084). Additionally, Safinamide appeared to be more effective than Rasagiline in increasing “on time without dyskinesia”, although the difference was not statistically significant (p = 0.4167). Selegiline improved UPDRS part III motor severity score by -4.93 compared to placebo (95% CI, -8.63~-1.24), Safinamide improved the scores by -3.12 (95% CI, -4.78~-1.47) and Rasagiline was -2.50 (95% CI, -4.48~-0.52), albeit there was no significant difference between groups (p = 0.5218). The safety assessment in our meta-analysis showed that Safinamide was generally well tolerated compared to placebo, and there was no significant difference between groups (p = 0.2779). Conclusion Our findings demonstrated that Safinamide appears to be the most potentially effective MAO-B inhibitor in reducing off time compared to other groups. Future head-to-head clinical trials are needed to directly compare the efficacy of these three groups of MAO-B inhibitors in regards of reducing both motor and non-motor symptoms and increasing on time without troublesome dyskinesia.