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Edited by:  編輯：

lain Hargreaves, University of Liverpool, United Kingdom
lain Hargreaves，利物浦大學，英國

Reviewed by:  評論者：

Guillermo Lopez Lluch, Universidad Pablo de Olavide, Spain Giuseppe Vita, University of Messina, Italy
Guillermo Lopez Lluch，西班牙 Pablo de Olavide 大學 Giuseppe Vita，義大利墨西拿大學

*Correspondence:  *通訊：

Specialty section:  專長部分：

This article was submitted to Drugs Outcomes Research and
本文已提交至 Drugs Outcomes Research and
Policies,  政策、
a section of the journal Frontiers in Pharmacology
《藥理前沿》期刊的一個版塊
Received: 25 February 2022 Accepted: 31 May 2022
收到：收稿日期： 2022 年 2 月 25 日 接受日期： 2022 年 5 月 31 日收稿日期：2022 年 5 月 31 日
Published: 24 August 2022
出版日期：2022 年 8 月 24 日

Citation:  引用：

Tsai I-C, Hsu C-W, Chang C-H, Tseng P-T and Chang K-V (2022) Effectiveness of Coenzyme Q10 Supplementation for Reducing Fatigue: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Tsai I-C, Hsu C-W, Chang C-H, Tseng P-T and Chang K-V (2022) Effectiveness of Coenzyme Q10 Supplementation for Reducing Fatigue：系統回顧與隨機對照試驗的 Meta 分析。
Front. Pharmacol. 13:883251. doi: 10.3389/fphar.2022.883251
前方。Pharmacol.13:883251. DOI: 10.3389/fphar.2022.883251

Effectiveness of Coenzyme Q10 Supplementation for Reducing Fatigue: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
補充輔酵素 Q10 對減少疲勞的效果：隨機對照試驗的系統回顧與元分析

I-Chen Tsai 1 , 2 , 3 1 , 2 , 3 ^(1,2,3){ }^{1,2,3}, Chih-Wei Hsu 4 , 5 4 , 5 ^(4,5){ }^{4,5}, Chun-Hung Chang 6 , 7 , 8 6 , 7 , 8 ^(6,7,8){ }^{6,7,8}, Ping-Tao Tseng 9 , 10 , 11 9 , 10 , 11 ^(9,10,11){ }^{9,10,11} and Ke-Vin Chang 12,13,14* 12,13,14*  ^("12,13,14* "){ }^{\text {12,13,14* }} 1 1 ^(1){ }^{1} Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, 2 2 ^(2){ }^{2} Congenital Heart Disease Study Group, Asian Society of Cardiovascular Imaging, Seoul, Korea, 3 3 ^(3){ }^{3} InnovaRad Inc., Taichung, Taiwan, 4 4 ^(4){ }^{4} Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, 5 5 ^(5){ }^{5} Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan, 6 6 ^(6){ }^{6} Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, 7 7 ^(7){ }^{7} Department of Psychiatry and Brain Disease Research Center, China Medical University Hospital, Taichung, Taiwan, 8 8 ^(8){ }^{8} An Nan Hospital, China Medical University, Tainan, Taiwan, 9 9 ^(9){ }^{9} Prospect Clinic for Otorhinolaryngology and Neurology, Kaohsiung, Taiwan, 10 10 ^(10){ }^{10} Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, 11 11 ^(11){ }^{11} Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan,
1 1 ^(1){ }^{1} 國立陽明交通大學臨床醫學研究所，台北，台灣， 2 2 ^(2){ }^{2} 先天性心臟病研究小組，亞洲心血管影像學會，首爾，韓國， 3 3 ^(3){ }^{3} InnovaRad Inc、台中，台灣， 4 4 ^(4){ }^{4} 高雄長庚紀念醫院暨長庚大學醫學院精神醫學系，高雄，台灣， 5 5 ^(5){ }^{5} 國立成功大學電腦科學暨資訊工程學系，台南，台灣， 6 6 ^(6){ }^{6} 中國醫藥大學臨床醫學研究所，台中，台灣， 7 7 ^(7){ }^{7} 精神醫學系暨腦部疾病研究中心、 8 8 ^(8){ }^{8} 中國醫藥大學安南醫院，台南，台灣， 9 9 ^(9){ }^{9} 耳鼻喉神經科展望診所，高雄，台灣， 10 10 ^(10){ }^{10} 國立中山大學生物醫學研究所，高雄，台灣， 11 11 ^(11){ }^{11} 亞洲大學醫療衛生學院心理學系，台中，台灣、 12 12 ^(12){ }^{12} Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, 13 13 ^(13){ }^{13} Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan, 14 14 ^(14){ }^{14} Center for Regional Anesthesia and Pain Medicine, Wang-Fang Hospital, Taipei Medical University, Taipei, Taiwan
12 12 ^(12){ }^{12} 國立台灣大學醫院暨國立台灣大學醫學院物理醫學暨復健學系，台北，台灣， 13 13 ^(13){ }^{13} 國立台灣大學醫院北湖分院物理醫學暨復健學系，台北，台灣， 14 14 ^(14){ }^{14} 台北醫學大學王芳醫院區域麻醉暨疼痛醫學中心，台北，台灣

Coenzyme Q10 (CoQ10) is a popular nutritional supplement, an antioxidant and an essential component of the mitochondrial electron transport chain. Several clinical studies have suggested that fatigue can be reduced by antioxidant supplementation. However, the data on this topic has been sparse to date. Hence, we conducted this metaanalysis with the aim of investigating the effectiveness of fatigue reduction via CoQ10 supplementation. More specifically, we searched electronic databases for randomized controlled trials (RCTs) published from the database inception to January 2022. A random effects model was implemented to conduct the meta-analysis among 13 RCTs (with a total of 1,126 participants). As compared with the placebo groups evaluated in each RCT, the CoQ10 group showed a statistically significant reduction in fatigue scores (Hedges’ g = g = g=g= − 0.398 , 95 % − 0.398 , 95 % -0.398,95%-0.398,95 \% confidence interval = − 0.641 = − 0.641 =-0.641=-0.641 to − 0.155 , p = 0.001 − 0.155 , p = 0.001 -0.155,p=0.001-0.155, p=0.001 ). The directions of the treatment effects were consistent between the healthy and diseased participants. Compared with the placebo group, the effect of reducing fatigue was statistically significant in the subgroup using the CoQ10-only formulation but not in the subgroup using CoQ10 compounds. The results of our meta-regression demonstrate that increases in the daily dose (coefficient = − 0.0017 = − 0.0017 =-0.0017=-0.0017 per mg, p < 0.001 p < 0.001 p < 0.001p<0.001 ) and treatment duration (coefficient = − 0.0042 = − 0.0042 =-0.0042=-0.0042 per day, p = 0.007 p = 0.007 p=0.007p=0.007 ) of CoQ10 supplementation were correlated with greater fatigue reduction. There was only one adverse (gastrointestinal) event in the 602 participants who underwent the CoQ10 intervention. Based on the results of this meta-analysis, we conclude that CoQ10 is an effective and safe supplement for reducing fatigue symptoms.
輔酵素 Q10 (CoQ10) 是一種廣受歡迎的營養補充劑，是一種抗氧化劑，也是線粒體電子傳輸鏈的重要組成部分。數項臨床研究顯示，補充抗氧化劑可減少疲勞。然而，到目前為止，有關此主題的資料仍然稀少。因此，我們進行了這項彙總分析，目的是研究透過補充 CoQ10 來減少疲勞的效果。具體來說，我們在電子資料庫中搜尋了從資料庫開始到 2022 年 1 月期間所發表的隨機對照試驗 (RCT)。我們採用隨機效應模型對 13 項 RCT（共 1,126 名參與研究者）進行彙總分析。與每項 RCT 評估的安慰劑組相比，CoQ10 組顯示疲勞評分有統計上的顯著降低（Hedges' g = g = g=g= − 0.398 , 95 % − 0.398 , 95 % -0.398,95%-0.398,95 \% 置信區間 = − 0.641 = − 0.641 =-0.641=-0.641 至 − 0.155 , p = 0.001 − 0.155 , p = 0.001 -0.155,p=0.001-0.155, p=0.001 ）。健康與患病參與者的治療效果方向一致。與安慰劑組相比，在使用純 CoQ10 配方的亞組中，減少疲勞的效果在統計學上是顯著的，但在使用 CoQ10 化合物的亞組中則不顯著。我們的元回歸結果顯示，增加 CoQ10 補充劑的每日劑量 (係數 = − 0.0017 = − 0.0017 =-0.0017=-0.0017 每毫克， p < 0.001 p < 0.001 p < 0.001p<0.001 ) 和治療時間 (係數 = − 0.0042 = − 0.0042 =-0.0042=-0.0042 每日， p = 0.007 p = 0.007 p=0.007p=0.007 ) 與更大的疲勞減輕效果相關。在 602 位接受 CoQ10 干預療程的參與者中，只有一位出現不良（腸胃）事件。根據這項薈萃分析的結果，我們的結論是 CoQ10 是一種有效且安全的補充劑，可減少疲勞症狀。

Systematic Review Registration: https://inplasy.com/inplasy-2022-1-0113/, identifier INPLASY202210113
系統性文獻回顧註冊：https://inplasy.com/inplasy-2022-1-0113/，標識符 INPLASY202210113

Keywords: coenzyme Q10, fatigue, clinical trials, meta-analysis, systematic review
關鍵字：輔酵素 Q10、疲勞、臨床試驗、薈萃分析、系統回顧

1 INTRODUCTION  1 引言

Fatigue is a symptom that occurs in both healthy and diseased individuals (Finsterer and Mahjoub, 2014). This symptom is described as unusual overwhelming tiredness that cannot be explained by physiological exhaustion in the wake of physical or mental efforts and that is not sufficiently recovered by regular rest and sleep (Haß et al., 2019). In the general population, the prevalence of temporary fatigue ranges from 4 to 45 % 45 % 45%45 \%, while that of chronic fatigue (i.e., fatigue lasting for > 6 > 6 > 6>6 months) ranges from 2 to 11 % 11 % 11%11 \% (Cathébras et al., 1992; Ridsdale et al., 1993; Jason et al., 1999; Cullen et al., 2002). Fatigue is also common in patients with poliomyelitis (Peel et al., 2015) and multiple sclerosis (Sanoobar et al., 2016; Moccia et al., 2019) as well as in cancer patients undergoing chemotherapy (Iwase et al., 2016). The annual total cost of productivity loss due to chronic fatigue syndrome in the United States alone is approximately US$ 9.1 billion, which is roughly equal to US$ 20,000 per resident (Reynolds et al., 2004). Although the etiology of fatigue remains poorly understood (Filler et al., 2014), mitochondrial dysfunction (Filler et al., 2014) and pro-inflammatory status (Haß et al., 2019) may play a role. Fortunately, fatigue can be rigorously measured and is potentially treatable (Finsterer and Mahjoub, 2014).
疲勞是一種症狀，不論是健康或患病的人都會出現（Finsterer and Mahjoub, 2014）。這種症狀被描述為不尋常的壓倒性疲勞，無法用生理疲勞來解釋體力或精神上的努力，也無法透過正常的休息和睡眠來充分恢復（Haß等人，2019）。在一般人口中，暫時性疲勞的發生率介於 4 到 45 % 45 % 45%45 \% 之間，而慢性疲勞 (即持續 > 6 > 6 > 6>6 個月的疲勞) 的發生率介於 2 到 11 % 11 % 11%11 \% 之間 (Cathébras 等人，1992；Ridsdale 等人，1993；Jason 等人，1999；Cullen 等人，2002)。疲勞也常見於小兒麻痺症 (Peel 等人，2015 年) 和多發性硬化症 (Sanoobar 等人，2016 年；Moccia 等人，2019 年) 患者，以及接受化療的癌症患者 (Iwase 等人，2016 年)。單在美國，每年因慢性疲勞症候群所造成的生產力損失總成本約為 91 億美元，大約等於每位居民 20,000 美元 (Reynolds 等人，2004)。雖然疲勞的病因仍不甚明了（Filler 等人，2014 年），但線粒體功能障礙（Filler 等人，2014 年）和促發炎狀態（Haß 等人，2019 年）可能扮演一定的角色。幸運的是，疲勞可以被嚴格測量，並且有可能被治療（Finsterer and Mahjoub, 2014）。
Coenzyme Q10 (CoQ10) is a popular nutritional supplement and a lipid-soluble antioxidant that is endogenously produced by the human body. It is also an essential component of the mitochondrial electron transport chain (Aaseth et al., 2021). Case-control studies conducted by Maes et al. showed that, as compared with healthy subjects, patients with chronic fatigue syndrome have lower plasma levels of CoQ10 (Maes et al., 2009a; Maes et al., 2009b). A statistically significant inverse relationship has also been found between CoQ10 levels and fatigue severity (Maes et al., 2009a). Thus, CoQ10 supplementation has been successfully applied for reducing fatigue in patients with various conditions, including chronic fatigue syndrome (Castro-Marrero et al., 2015; Castro-Marrero et al., 2016; Fukuda et al., 2016; Castro-Marrero et al., 2021) and fibromyalgia (Cordero et al., 2013; Miyamae et al., 2013; Di Pierro et al., 2017), as well as in healthy subjects (Morikawa et al., 2019; Mizuno et al., 2020). However, inconsistencies in clinical outcomes have been identified across different trials. Therefore, in the current study, we performed a systematic review and meta-analysis to investigate the effects of CoQ10 treatment on fatigue symptoms and syndromes.
輔酵素 Q10 (CoQ10) 是一種廣受歡迎的營養補充劑，也是一種由人體內分泌的脂溶性抗氧化劑。它也是線粒體電子傳輸鏈的重要成分 (Aaseth et al., 2021)。由 Maes 等人進行的病例對照研究顯示，與健康受試者相比，慢性疲勞症候群患者的血漿 CoQ10 含量較低（Maes 等人，2009a；Maes 等人，2009b）。在統計學上也發現 CoQ10 水準與疲勞嚴重程度有顯著的反比關係 (Maes 等人，2009a)。因此，CoQ10 補充劑已成功應用於減輕慢性疲勞症候群等各種病患的疲勞（Castro-Marrero et al、2016；Fukuda 等人，2016；Castro-Marrero 等人，2021）和纖維肌痛（Cordero 等人，2013；Miyamae 等人，2013；Di Pierro 等人，2017），以及健康受試者（Morikawa 等人，2019；Mizuno 等人，2020）。然而，在不同的試驗中發現了臨床結果的不一致。因此，在目前的研究中，我們進行了系統回顧和薈萃分析，以調查 CoQ10 治療對疲勞症狀和症候群的影響。

2 MATERIALS AND METHODS
2 材料與方法

2.1 General Guidelines  2.1 一般指引

We followed the guidelines delineated in the latest version of the PRISMA 2020 guidelines (Supplementary Table S1) to conduct this meta-analysis (Page et al., 2021a). This study, which was registered in INPLASY with the registration number
我們遵循最新版的 PRISMA 2020 指導方針（補充表 S1）進行此項 meta 分析（Page 等人，2021a）。本研究在 INPLASY 中註冊，註冊編號為
INPLASY202210113 (Tsai and Chang, 2022), did not require ethics review board approval or participant informed consent.
INPLASY202210113 (Tsai and Chang, 2022)，不需要倫理審查委員會批准或受試者知情同意。

2.2 Database Searches and the Identification of Eligible Manuscripts
2.2 資料庫檢索與合格手稿的鑑定

Two authors (I-CT and K-VC) conducted independent electronic searches in the PubMed, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov databases using the following keywords (“Q10” OR “Q 10” OR “CoQ10” OR “Coenzyme Q10” OR “ubiquinol-10” OR “ubiquinol” OR “ubiquinone”) AND (“fatigue” OR “chronic fatigue syndrome” OR “tiredness”). The search was conducted from the inception of each database (i.e., the earliest record) to the date of the database search (16 January 2022). We note that ubiquinone is the fully oxidized form of CoQ10, and ubiquinol is the reduced form. These two forms are continually interconverted in the body and have similar bioactivities (Mantle and Dybring, 2020). The detailed search strategy for this systematic review and meta-analysis is provided in the Supplementary Material (Supplementary Table S2).
兩位作者（I-CT 和 K-VC）使用下列關鍵字（"Q10" OR "Q 10" OR "CoQ10" OR "Coenzyme Q10" OR 「泛醌醇-10」 OR 「泛醌」 OR 「泛醌酮」）和（「疲勞」 OR 「慢性疲勞症候群」 OR 「疲勞」）在 PubMed、Embase、Cochrane CENTRAL、Web of Science 和 ClinicalTrials.gov 資料庫中進行獨立的電子檢索。搜尋時間為每個資料庫開始（即最早記錄）至資料庫搜尋日期（2022 年 1 月 16 日）。我們注意到泛醌是 CoQ10 的完全氧化形式，而泛醇是還原形式。這兩種形式在人體中不斷相互轉換，具有類似的生物活性（Mantle and Dybring, 2020）。本系統性文獻回顧與薈萃分析的詳細搜尋策略請參閱補充資料（補充表 S2）。
Initially, the two authors responsible for conducting this search screened the identified titles and abstracts for eligibility through a consensus process. The PubMed and EMBASE databases were thoroughly scrutinized for any potentially eligible trials. We also checked the reference lists of an identified review article (Mehrabani et al., 2019) and performed additional manual searches. A third reviewer and study author (P-TT) was consulted for situations in which the two aforementioned authors could not reach a consensus. No language restrictions were applied to this search.
最初，負責進行這項檢索的兩位作者透過共識程序篩選出符合條件的標題和摘要。我們徹底檢查了 PubMed 和 EMBASE 資料庫中任何可能符合條件的試驗。我們還檢查了一篇已識別的評論文章（Mehrabani 等人，2019 年）的參考清單，並進行了額外的人工檢索。在上述兩位作者無法達成共識的情況下，我們徵詢了第三位審稿人兼研究作者 (P-TT) 的意見。本檢索並無語言限制。

2.3 Inclusion and Exclusion Criteria
2.3 納入與排除標準

The PICO (population, intervention, comparison, outcome) setting of the current meta-analysis was as follows: P: human participants; I: CoQ10 supplementation; C: placebo; and O: changes in fatigue symptom scores.
目前薈萃分析的 PICO（人口、干預、比較、結果）設定如下：P：人類參與者；I：CoQ10補充劑；C：安慰劑；O：疲勞症狀評分的變化。
The following inclusion criteria were used: 1) randomized controlled trials (RCTs) enrolling human participants, 2) RCTs investigating the quantitative evaluation of fatigue symptoms before and after CoQ10 supplementation, 3) placebo-controlled trials (without age or treatment duration limitations), and 4) trials with available data for pre- and post-intervention fatigue assessments or evaluations of changes in fatigue scores. Open-label studies were also included in this meta-analysis as recent studies have found that open-label placebos had similar efficacy to double-blind placebos (Lembo et al., 2021; von Wernsdorff et al., 2021).
採用下列納入標準：1）招募人類參與者的隨機對照試驗 (RCT)；2）調查 CoQ10 補充前後疲勞症狀定量評估的 RCT；3）安慰劑對照試驗（無年齡或療程限制）；4）有干預前後疲勞評估或疲勞分數變化評估資料的試驗。由於最近的研究發現開放標籤安慰劑的療效與雙盲安慰劑相似，因此開放標籤研究也被納入本彙總分析中 (Lembo et al., 2021; von Wernsdorff et al., 2021)。
The exclusion criteria for this review and meta-analysis were as follows: 1) non-RCTs, 2) studies focusing on athletic muscle exhaustion rather than generalized fatigue, 3) studies lacking a placebo-controlled group, 4) studies lacking quantitative assessments of fatigue, and 5) studies enrolling participants that overlapped with a previously published trial.
本檢討與薈萃分析的排除標準如下：1) 非 RCT 研究；2) 著重於運動肌肉疲勞而非全身性疲勞的研究；3) 缺乏安慰劑對照組的研究；4) 缺乏疲勞量化評估的研究；以及 5) 參與者與先前已發表的試驗重疊的研究。

2.4 Methodological Quality Appraisal
2.4 方法品質評估

To investigate the methodological quality of the evaluated studies, we used the Cochrane risk of bias tool for randomized trials (version 2, RoB 2, London, United Kingdom), which consists of six main items for evaluating study quality: the randomization process, intervention adherence, missing outcome data, outcome measurement, selective reporting, and the overall risk of bias (Sterne et al., 2019).
為了調查所評估研究的方法學品質，我們使用了隨機試驗的 Cochrane 偏倚風險工具 (第 2 版，RoB 2，英國倫敦)，該工具包含六個主要的研究品質評估項目：隨機化過程、干預依從性、遺失結果資料、結果測量、選擇性報告以及整體偏倚風險 (Sterne et al., 2019)。
In the intervention adherence section of the RoB 2, there are two options presented for literature assessment: intention-totreat (intervention assignment) and per-protocol (intervention adherence). In this meta-analysis, we chose the per-protocol evaluation (Sterne et al., 2019) since it fits best with the design of our included studies.
在 RoB 2 的干預依從性部分，文獻評估有兩個選項：意向治療（干預指派）和按方案（干預依從性）。在本薈萃分析中，我們選擇了按協議評估（Sterne 等人，2019），因為它最符合我們所納入研究的設計。

2.5 Primary Outcome (Fatigue Score Change)
2.5 主要結果（疲勞分數變化）

The primary outcomes evaluated in this investigation were changes in fatigue scores following CoQ10 supplementation or placebo regimens. We also examined the validity and appropriateness of the fatigue scale used in each trial (Fisk et al., 1994; Chandran et al., 2007; Fukuda et al., 2008). If there was more than one scoring system for fatigue evaluation implemented in a single trial, the index test included in the meta-analysis was decided by author consensus (I-CT and K − VC K − VC K-VC\mathrm{K}-\mathrm{VC} ).
本研究評估的主要結果是 CoQ10 補充劑或安慰劑療程後疲勞分數的變化。我們也檢視了每項試驗所使用的疲勞量表的有效性與適當性 (Fisk 等人，1994；Chandran 等人，2007；Fukuda 等人，2008)。如果在單一試驗中有超過一種疲勞評估計分系統，則納入薈萃分析的指標測試由作者共識決定 (I-CT 和 K − VC K − VC K-VC\mathrm{K}-\mathrm{VC} )。

2.6 Secondary Outcome (Treatment-Associated Adverse Event Rates)
2.6 次要結果 (治療相關不良事件率)

The secondary outcome evaluated in this investigation was the treatment-associated adverse event rate. For cells with zero events, zero was replaced by 0.5 to enable calculation (Deeks et al., 2021). The aforementioned outcomes were quantified using odds ratios.
本研究評估的次要結果為治療相關的不良事件率。對於事件率為零的細胞，以 0.5 取代零以進行計算 (Deeks et al., 2021)。上述結果使用機率比進行量化。

2.7 Data Extraction and Management
2.7 資料擷取與管理

Two independent authors (I-CT and K-VC) extracted data from the evaluated studies, including demographic data, study design parameters, details of the administered CoQ10 and placebo regimens, and the primary and secondary outcome values. To avoid misinterpretation, the evaluators paid special attention to the effect direction of the scale used in each trial. In situations where data were unavailable within the published articles, we contacted the corresponding authors to obtain the original data.
兩位獨立作者（I-CT 和 K-VC）擷取所評估研究的資料，包括人口統計資料、研究設計參數、施用 CoQ10 和安慰劑方案的細節，以及主要和次要結果數值。為避免誤解，評估人員特別注意每項試驗所用量表的效應方向。當發表的文章中沒有資料時，我們會聯絡對應的作者以取得原始資料。
Data extraction and conversion as well as merging the results from various study arms using different CoQ10 dosages were processed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and the associated medical literature (Hozo et al., 2005; Higgins et al., 2021a; Higgins et al., 2021b). If post-treatment data were available at multiple time points, we extracted the outcome reported at the end of the intervention for statistical analysis. For crossover studies, we included only the first study interval to avoid carry-over effects (Higgins et al., 2021a).
資料擷取與轉換，以及合併使用不同 CoQ10 劑量的不同研究臂的結果，都是依照 Cochrane 手冊中關於干預系統性評估及相關醫學文獻的建議處理 (Hozo 等人，2005；Higgins 等人，2021a；Higgins 等人，2021b)。如果有多個時間點的治療後資料，我們會擷取干預結束時所報告的結果進行統計分析。對於交叉研究，我們只包括第一個研究間期，以避免攜帶效應 (Higgins 等人，2021a)。

2.8 Statistical Analyses
2.8 統計分析

Because of the heterogeneity of the target populations within the enrolled studies, the current meta-analysis was conducted with a random-effects model (Borenstein et al., 2009) implemented using Comprehensive Meta-Analysis software (version 3, Biostat, Englewood, NJ, United States). A two-tailed p p pp value of less than 0.05 was considered statistically significant.
由於入選研究的目標人群具有異质性，因此本 meta 分析採用 Comprehensive Meta-Analysis 軟體 (version 3, Biostat, Englewood, NJ, United States) 的隨機效果模型 (Borenstein 等人，2009 年) 進行。小於 0.05 的雙尾 p p pp 值被視為具有統計意義。
We used Hedges’ g g gg and 95 % 95 % 95%95 \% confidence intervals (CIs) to quantify the primary study outcomes (i.e., changes in fatigue scores). Hedges’ g g gg values of 0.2 , 0.5 0.2 , 0.5 0.2,0.50.2,0.5, and 0.8 were considered small, moderate, and large effect sizes, respectively (Hedges, 1981). Odds ratios (ORs) and their associated 95% CIs were evaluated to investigate secondary outcomes (i.e., treatmentassociated adverse event rates).
我們使用 Hedges 的 g g gg 和 95 % 95 % 95%95 \% 置信區間 (CI) 來量化主要研究結果（即疲勞分數的變化）。Hedges的 g g gg 值 0.2 , 0.5 0.2 , 0.5 0.2,0.50.2,0.5 ，和0.8分別被認為是小、中和大的效應量（Hedges，1981）。對於次要結果（即治療相關的不良事件率），則評估了比值比 (OR) 及其相關的 95% CI。
I 2 I 2 I^(2)I^{2} and Cochran’s Q Q QQ statistics were also examined to evaluate the degree of heterogeneity across studies. I 2 I 2 I^(2)I^{2} values of 25,50 , and 75 % 75 % 75%75 \% were considered low, moderate, and high heterogeneity,
I 2 I 2 I^(2)I^{2} 和 Cochran's Q Q QQ 統計也被檢驗以評估各研究之間的異质性程度。 I 2 I 2 I^(2)I^{2} 值為 25、50 和 75 % 75 % 75%75 \% 被視為低度、中度和高度異质性、
FIGURE 1 | PRISMA 2020 flowchart for the current meta-analysis.
圖 1 | 目前薈萃分析的 PRISMA 2020 流程圖。
Peel ( 2015 )  Peel  ( 2015 ) {:[" Peel "],[(2015)]:}\begin{aligned} & \text { Peel } \\ & (2015) \end{aligned} Australia  澳洲 Poliomyelitis  小兒麻痺症 CoQ10: 39 / 15 b , d Placebo: 32 / 17  CoQ10:  39 / 15 b , d  Placebo:  32 / 17 {:[" CoQ10: "39//15^(b,d)],[" Placebo: "32//17]:}\begin{aligned} & \text { CoQ10: } 39 / 15^{\mathrm{b}, \mathrm{~d}} \\ & \text { Placebo: } 32 / 17 \end{aligned} 69.9 ± 8.4 b 69.8 ± 8.2 69.9 ± 8.4 b 69.8 ± 8.2 {:[69.9+-8.4^(b)],[69.8+-8.2]:}\begin{aligned} & 69.9 \pm 8.4^{b} \\ & 69.8 \pm 8.2 \end{aligned} RCT, double-blind  RCT, 雙盲 Coordination center  協調中心 Matrix sequence  矩陣序列 - Cancer and Polio Research Fund (UK)
- 癌症與小兒麻痺症研究基金（英國）
Sanoobar Iran  伊朗 Multiple sclerosis  多發性硬化症 CoQ10: 20/2 c c  ^("c "){ }^{\text {c }} 33.1 ± 7.6 c 33.1 ± 7.6 c  33.1+-7.6^("c ")33.1 \pm 7.6^{\text {c }} RCT,  RCT、 Not mentioned  未提及 Not mentioned  未提及 - Tehran University of Medical Sciences
- 德黑蘭醫學大學
(2016) Placebo: 21/2  安慰劑：21/2 30.9 ± 7.7 30.9 ± 7.7 30.9+-7.730.9 \pm 7.7 double-blind  双盲
Di Pierro Italy  義大利 Fibromyalgia  纖維肌痛 CoQ10: 12/0 b,c b,c  ^("b,c "){ }^{\text {b,c }} 52.5 ± 10.4 b , c 52.5 ± 10.4 b , c 52.5+-10.4^(b,c)52.5 \pm 10.4^{\mathrm{b}, \mathrm{c}} RCT,  RCT、 Coin tossing  擲硬幣 Coin tossing  擲硬幣 N/A  不適用
(2017) Placebo: 10/0  安慰劑：10/0 53.6 ± 7.8 53.6 ± 7.8 53.6+-7.853.6 \pm 7.8 open-label  開放標籤
Morikawa  森川 Japan  日本 Healthy subjects  健康受試者 CoQ10: 16/14 b b  ^("b "){ }^{\text {b }} 40.5 ± 7.3 b 40.5 ± 7.3 b  40.5+-7.3^("b ")40.5 \pm 7.3^{\text {b }} RCT,  RCT、 Not mentioned  未提及 Stratified block  分層區塊 - Kaneka, Inc.
(2019) Placebo: 16/14  安慰劑：16/14 42.9 ± 7.3 42.9 ± 7.3 42.9+-7.342.9 \pm 7.3 double-blind  双盲
Mizuno Japan  日本 Healthy subjects with fatigue
疲勞的健康受試者		 CoQ10: 28/14 b,c b,c  ^("b,c "){ }^{\text {b,c }} 42.1 ± 10.9 b,c 42.1 ± 10.9 b,c  42.1+-10.9^("b,c ")42.1 \pm 10.9^{\text {b,c }} RCT,  RCT、 Not mentioned  未提及 Stratified  分層 - Kaneka, Inc.
(2020) Placebo: 13/7  安慰劑：13/7 41.3 ± 13.4 41.3 ± 13.4 41.3+-13.441.3 \pm 13.4 double-blind  双盲 - Japan Science and Technology Agency
- 日本科學技術廳
Mousavi  穆薩維 Iran  伊朗 Health subjects (nurses)
健康科目（護士）		 CoQ10: 47/7 ∘ ∘ ^(@){ }^{\circ} 35.1 ± 8.1 c 35.1 ± 8.1 c  35.1+-8.1^("c ")35.1 \pm 8.1^{\text {c }} RCT,  RCT、 Assignment  任務 Permuted block  永久區塊 - Isfahan University of Medical Sciences
- 伊斯法罕醫學大學
(2020) with fatigue  疲勞 Placebo: 45/6  安慰劑：45/6 35.7 ± 8.9 35.7 ± 8.9 35.7+-8.935.7 \pm 8.9 double-blind  双盲 double-blinded  雙盲
Castro-Marrero Spain  西班牙 Chronic fatigue syndrome
慢性疲勞症候群		 CoQ10+NADH: 72/0 c c  ^("c "){ }^{\text {c }} 45.38 ± 7.81 c 45.38 ± 7.81 c  45.38+-7.81^("c ")45.38 \pm 7.81^{\text {c }} RCT,  RCT、 Independent  獨立 Random number  隨機號碼 - Vitae Health Innovation
- 維他健康創新
(2021) Placebo: 72/0  安慰劑：72/0 46.79 ± 6.48 46.79 ± 6.48 46.79+-6.4846.79 \pm 6.48 double-blind  双盲 investigator  調查員 - Vall d'Hebron Hospital
- Vall d'Hebron 醫院
Research Institute  研究所
" Peel (2015)" Australia Poliomyelitis " CoQ10: 39//15^(b,d) Placebo: 32//17" "69.9+-8.4^(b) 69.8+-8.2" RCT, double-blind Coordination center Matrix sequence - Cancer and Polio Research Fund (UK) Sanoobar Iran Multiple sclerosis CoQ10: 20/2 ^("c ") 33.1+-7.6^("c ") RCT, Not mentioned Not mentioned - Tehran University of Medical Sciences (2016) Placebo: 21/2 30.9+-7.7 double-blind Di Pierro Italy Fibromyalgia CoQ10: 12/0 ^("b,c ") 52.5+-10.4^(b,c) RCT, Coin tossing Coin tossing N/A (2017) Placebo: 10/0 53.6+-7.8 open-label Morikawa Japan Healthy subjects CoQ10: 16/14 ^("b ") 40.5+-7.3^("b ") RCT, Not mentioned Stratified block - Kaneka, Inc. (2019) Placebo: 16/14 42.9+-7.3 double-blind Mizuno Japan Healthy subjects with fatigue CoQ10: 28/14 ^("b,c ") 42.1+-10.9^("b,c ") RCT, Not mentioned Stratified - Kaneka, Inc. (2020) Placebo: 13/7 41.3+-13.4 double-blind - Japan Science and Technology Agency Mousavi Iran Health subjects (nurses) CoQ10: 47/7 ^(@) 35.1+-8.1^("c ") RCT, Assignment Permuted block - Isfahan University of Medical Sciences (2020) with fatigue Placebo: 45/6 35.7+-8.9 double-blind double-blinded Castro-Marrero Spain Chronic fatigue syndrome CoQ10+NADH: 72/0 ^("c ") 45.38+-7.81^("c ") RCT, Independent Random number - Vitae Health Innovation (2021) Placebo: 72/0 46.79+-6.48 double-blind investigator - Vall d'Hebron Hospital Research Institute| $\begin{aligned} & \text { Peel } \\ & (2015) \end{aligned}$ | Australia | Poliomyelitis | $\begin{aligned} & \text { CoQ10: } 39 / 15^{\mathrm{b}, \mathrm{~d}} \\ & \text { Placebo: } 32 / 17 \end{aligned}$ | $\begin{aligned} & 69.9 \pm 8.4^{b} \\ & 69.8 \pm 8.2 \end{aligned}$ | RCT, double-blind | Coordination center | Matrix sequence | - Cancer and Polio Research Fund (UK) | | :---: | :---: | :---: | :---: | :---: | :---: | :---: | :---: | :---: | | Sanoobar | Iran | Multiple sclerosis | CoQ10: 20/2 ${ }^{\text {c }}$ | $33.1 \pm 7.6^{\text {c }}$ | RCT, | Not mentioned | Not mentioned | - Tehran University of Medical Sciences | | (2016) | | | Placebo: 21/2 | $30.9 \pm 7.7$ | double-blind | | | | | Di Pierro | Italy | Fibromyalgia | CoQ10: 12/0 ${ }^{\text {b,c }}$ | $52.5 \pm 10.4^{\mathrm{b}, \mathrm{c}}$ | RCT, | Coin tossing | Coin tossing | N/A | | (2017) | | | Placebo: 10/0 | $53.6 \pm 7.8$ | open-label | | | | | Morikawa | Japan | Healthy subjects | CoQ10: 16/14 ${ }^{\text {b }}$ | $40.5 \pm 7.3^{\text {b }}$ | RCT, | Not mentioned | Stratified block | - Kaneka, Inc. | | (2019) | | | Placebo: 16/14 | $42.9 \pm 7.3$ | double-blind | | | | | Mizuno | Japan | Healthy subjects with fatigue | CoQ10: 28/14 ${ }^{\text {b,c }}$ | $42.1 \pm 10.9^{\text {b,c }}$ | RCT, | Not mentioned | Stratified | - Kaneka, Inc. | | (2020) | | | Placebo: 13/7 | $41.3 \pm 13.4$ | double-blind | | | - Japan Science and Technology Agency | | Mousavi | Iran | Health subjects (nurses) | CoQ10: 47/7 ${ }^{\circ}$ | $35.1 \pm 8.1^{\text {c }}$ | RCT, | Assignment | Permuted block | - Isfahan University of Medical Sciences | | (2020) | | with fatigue | Placebo: 45/6 | $35.7 \pm 8.9$ | double-blind | double-blinded | | | | Castro-Marrero | Spain | Chronic fatigue syndrome | CoQ10+NADH: 72/0 ${ }^{\text {c }}$ | $45.38 \pm 7.81^{\text {c }}$ | RCT, | Independent | Random number | - Vitae Health Innovation | | (2021) | | | Placebo: 72/0 | $46.79 \pm 6.48$ | double-blind | investigator | | - Vall d'Hebron Hospital | | | | | | | | | | Research Institute |
respectively (Higgins et al., 2003). We likewise performed subgroup analyses based on disease and CoQ10 formulations. Meta-regression analyses regarding the treatment effects of daily CoQ10 doses as well as evaluations of various treatment durations were conducted to determine whether the fatigue-alleviating effects of CoQ10 correlated with the aforementioned parameters.
(Higgins 等人，2003)。同樣地，我們也根據疾病和 CoQ10 配方進行了亞組分析。我們對每日 CoQ10 劑量的治療效果進行了元回歸分析，並評估了各種治療持續時間，以確定 CoQ10 的消除疲勞效果是否與上述參數相關。
To confirm the robustness of this meta-analysis, sensitivity analyses were performed using the one-study removal method to determine whether there was a statistically significant change in the summary effect size after removing a particular trial from the analysis (Deeks et al., 2021).
為了確認這項薈萃分析的穩健性，我們使用剔除單一研究的方法進行敏感性分析，以確定從分析中剔除特定試驗後，總結效應大小是否有統計上的顯著變化 (Deeks 等人，2021)。
Potential publication bias was evaluated using guidelines set forth by the Cochrane Handbook for Systematic Reviews of Interventions (Page et al., 2021b). Funnel plots were generated and visually inspected. Egger’s regression tests were implemented when 10 or more datasets were available.
使用 Cochrane Handbook for Systematic Reviews of Interventions (Page et al., 2021b)提出的準則評估可能的出版偏差。產生漏斗圖並進行目視檢查。當有 10 個或以上的資料集時，則進行 Egger 回歸測試。

3 RESULTS  3 結果

3.1 Study Identification and Selection
3.1 研究的識別與選擇

The PRISMA flowchart for the literature search is shown in Figure 1. After removing duplicate articles and excluding nonrelevant articles by an examination of titles and abstracts, we ultimately included 13 RCTs in the final analysis (Berman et al., 2004; Lee et al., 2011; Cordero et al., 2013; Lesser et al., 2013; Castro-Marrero et al., 2015; Fukuda et al., 2015; Peel et al., 2015; Sanoobar et al., 2016; Di Pierro et al., 2017; Morikawa et al., 2019; Mizuno et al., 2020; Mousavi et al., 2020; Castro-Marrero et al., 2021). The articles excluded in the final stage and the reasons for exclusion are listed in Supplementary Table S3 (Singh et al., 2003; Langsjoen et al., 2005; Kumar et al., 2007; Mizuno et al., 2008; Gökbel et al., 2010; Cordero et al., 2012a; Cordero et al., 2012b; Fedacko et al., 2013; Gharahdaghi et al., 2013; Miyamae et al., 2013; Castro-Marrero et al., 2016; Fukuda et al., 2016; Iwase et al., 2016; Menon et al., 2017; Langsjoen et al., 2019; Moccia et al., 2019; Negro et al., 2019; Gomez-Centeno et al., 2020; Schweiger et al., 2020; Suzuki et al., 2021). Details of data extraction from included randomized controlled trials are summarized in Supplementary Table S4.
文獻檢索的 PRISMA 流程圖如圖 1 所示。在刪除重複文章並透過檢視標題和摘要排除不相關的文章後，我們最終在最後分析中納入了 13 篇 RCT（Berman 等人，2004；Lee 等人，2011；Cordero 等人、2013；Lesser等人，2013；Castro-Marrero等人，2015；Fukuda等人，2015；Peel等人，2015；Sanoobar等人，2016；Di Pierro等人，2017；Morikawa等人，2019；Mizuno等人，2020；Mousavi等人，2020；Castro-Marrero等人，2021）。最後階段排除的文章及排除原因列於補充表格 S3 (Singh et al., 2003; Langsjoen et al., 2005; Kumar et al., 2007; Mizuno et al., 2008; Gökbel et al., 2010; Cordero et al., 2012a; Cordero et al., 2012b; Fedacko et al、2013；Gharahdaghi等人，2013；Miyamae等人，2013；Castro-Marrero等人，2016；Fukuda等人，2016；Iwase等人，2016；Menon等人，2017；Langsjoen等人，2019；Moccia等人，2019；Negro等人，2019；Gomez-Centeno等人，2020；Schweiger等人，2020；Suzuki等人，2021）。從納入的隨機對照試驗中萃取資料的細節總結於補充表格 S4。
The 13 eligible RCTs encompassed a total of 1,126 participants with a mean age of 49.3 ± 12.6 49.3 ± 12.6 49.3+-12.649.3 \pm 12.6 (standard deviation) years, of whom 25.6 % ( n = 288 ) 25.6 % ( n = 288 ) 25.6%(n=288)25.6 \%(n=288) were male. The study duration ranged from four (Mousavi et al., 2020) to 24 weeks (Lesser et al., 2013). Subject diagnoses included chronic fatigue syndrome (CastroMarrero et al., 2015; Castro-Marrero et al., 2021), fibromyalgia (Cordero et al., 2013; Di Pierro et al., 2017), end-stage heart failure (Berman et al., 2004), obesity (Lee et al., 2011), breast cancer (with patients undergoing chemotherapy) (Lesser et al., 2013), end-stage renal disease (Fukuda et al., 2015), poliomyelitis (Peel et al., 2015), and multiple sclerosis (Sanoobar et al., 2016), and we also evaluated healthy subjects (Morikawa et al., 2019) and healthy individuals with fatigue (Mizuno et al., 2020; Mousavi et al., 2020). The details of the retrieved trials are summarized in Table 1.
13 項符合條件的 RCT 共涵蓋 1,126 名平均年齡 49.3 ± 12.6 49.3 ± 12.6 49.3+-12.649.3 \pm 12.6 （標準差）歲的參與者，其中 25.6 % ( n = 288 ) 25.6 % ( n = 288 ) 25.6%(n=288)25.6 \%(n=288) 為男性。研究時間從 4 週 (Mousavi 等人，2020) 到 24 週 (Lesser 等人，2013) 不等。受試者診斷包括慢性疲勞症候群 (CastroMarrero 等人，2015；Castro-Marrero 等人，2021)、纖維肌痛 (Cordero 等人，2013；Di Pierro 等人，2017)、末期心臟衰竭 (Berman 等人，2004)、肥胖症 (Lee 等人，2011)、乳癌 (接受化療的患者) (Lesser 等人、2013）、末期腎臟疾病（Fukuda 等人，2015）、小兒麻痺症（Peel 等人，2015）和多發性硬化症（Sanoobar 等人，2016），我們也評估了健康受試者（Morikawa 等人，2019）和疲勞的健康個體（Mizuno 等人，2020；Mousavi 等人，2020）。表 1 歸納了檢索到的試驗詳情。
Three studies evaluated compounds mixed with CoQ10. More specifically, CoQ10 with a reduced form of nicotinamide adenine
三項研究評估了與 CoQ10 混合的化合物。更明顯的是，CoQ10 與還原形式的煙醯胺腺嘌呤
dinucleotide (NADH) was evaluated in two of these trials (CastroMarrero et al., 2015; Castro-Marrero et al., 2021) and CoQ10 in a multi-vitamin nutritional drink was evaluated in the other trial (Fukuda et al., 2015). Ten studies evaluated CoQ10 only (Berman et al., 2004; Lee et al., 2011; Cordero et al., 2013; Lesser et al., 2013; Peel et al., 2015; Sanoobar et al., 2016; Di Pierro et al., 2017; Morikawa et al., 2019; Mizuno et al., 2020; Mousavi et al., 2020). The intervention details, tools for fatigue assessment, adverse events, and study withdrawals are summarized in Table 2.
二核苷酸 (NADH) 在其中兩項試驗中進行評估 (CastroMarrero 等人，2015 年；Castro-Marrero 等人，2021 年)，而在另一項試驗中則評估了多種維生素營養飲料中的 CoQ10 (Fukuda 等人，2015 年)。10 項研究僅評估 CoQ10（Berman 等人，2004；Lee 等人，2011；Cordero 等人，2013；Lesser 等人，2013；Peel 等人，2015；Sanoobar 等人，2016；Di Pierro 等人，2017；Morikawa 等人，2019；Mizuno 等人，2020；Mousavi 等人，2020）。表 2 總結了干預細節、疲勞評估工具、不良事件和研究退出情況。

3.2 Methodological Quality of the Included Studies
3.2 所納入研究的方法論品質

With respect to the overall methodological quality of the included studies, we found that 46.2 % 46.2 % 46.2%46.2 \% of the evaluated studies had a low risk of bias, 53.8 % 53.8 % 53.8%53.8 \% had some risk of bias, and 0 % 0 % 0%0 \% had a high risk of bias (Figure 2). In a detailed assessment, seven studies (Lee et al., 2011; Cordero et al., 2013; Lesser et al., 2013; Castro-Marrero et al., 2015; Sanoobar et al., 2016; Morikawa et al., 2019; Mizuno et al., 2020) were rated as having “some” risk of bias in the randomization process because they did not reveal details of the allocation concealment. One study (Lee et al., 2011) was rated as having “some” risk of bias with regard to missing outcome data, since the study excluded five subjects from the CoQ10 group due to an unchanged level of serum CoQ10 after supplementation. One study (Di Pierro et al., 2017) was rated as having “some” risk of bias in the outcome measurement because it was an open-label study and the participants were aware of the interventions they received. The details of the risk of bias assessment are summarized in Table 3.
就納入研究的整體方法學品質而言，我們發現 46.2 % 46.2 % 46.2%46.2 \% 的評估研究有低偏倚風險， 53.8 % 53.8 % 53.8%53.8 \% 有一些偏倚風險，而 0 % 0 % 0%0 \% 有高偏倚風險（圖 2）。在詳細評估中，七項研究（Lee等人，2011；Cordero等人，2013；Lesser等人，2013；Castro-Marrero等人，2015；Sanoobar等人，2016；Morikawa等人，2019；Mizuno等人，2020）因未揭露分配隱藏的細節而被評為隨機化過程有「某些」偏倚風險。一項研究（Lee et al., 2011）被評為在遺失結果資料方面有「某程度」的偏差風險，因為該研究在補充輔酶Q10後，因血清輔酶Q10水平未變而從輔酶Q10組中剔除了五名受試者。一項研究（Di Pierro 等人，2017 年）因為是開放標籤研究，且受試者知道他們所接受的干預措施，因此在結果測量方面被評為有「一些」偏倚風險。偏倚風險評估的詳細內容概述於表 3。

3.3 Primary Outcome: Effects of CoQ10 Supplementation on Fatigue
3.3 主要結果：補充 CoQ10 對疲勞的影響

In the combined 13 trials (Figure 3), CoQ10 demonstrated a statistically significant reduction with regard to fatigue symptomology (Hedges’ g = − 0.398 , 95 % CI = − 0.641 g = − 0.398 , 95 % CI = − 0.641 g=-0.398,95%CI=-0.641g=-0.398,95 \% \mathrm{CI}=-0.641 to − 0.155 , p = 0.001 , I 2 = 69.5 % ) − 0.155 , p = 0.001 , I 2 = 69.5 % {:-0.155,p=0.001,I^(2)=69.5%)\left.-0.155, p=0.001, I^{2}=69.5 \%\right). However, moderate-to-high heterogeneity was observed. A sensitivity analysis was performed using the one-study removal method. The results showed a consistently statistically significant effect of CoQ10 on fatigue reduction. The summary effect sizes did not change the statistical significance of these findings when any of the included studies were removed (Figure 4).
在合併的 13 項試驗中（圖 3），CoQ10 對疲勞症狀有顯著的統計減輕效果（Hedges' g = − 0.398 , 95 % CI = − 0.641 g = − 0.398 , 95 % CI = − 0.641 g=-0.398,95%CI=-0.641g=-0.398,95 \% \mathrm{CI}=-0.641 至 − 0.155 , p = 0.001 , I 2 = 69.5 % ) − 0.155 , p = 0.001 , I 2 = 69.5 % {:-0.155,p=0.001,I^(2)=69.5%)\left.-0.155, p=0.001, I^{2}=69.5 \%\right) ）。 不過，也觀察到中度至高度的異质性。使用剔除一項研究的方法進行了敏感性分析。結果顯示 CoQ10 對減輕疲勞有持續顯著的統計效應。剔除任何一項納入研究後，摘要效應大小並未改變這些研究結果的統計顯著性（圖 4）。
We then divided the included trials into two subgroups: healthy participants (Morikawa et al., 2019; Mizuno et al., 2020; Mousavi et al., 2020) and patients with a fatigue-associated disease (fibromyalgia (Cordero et al., 2013; Di Pierro et al., 2017), chronic fatigue syndrome (Castro-Marrero et al., 2015; CastroMarrero et al., 2021), heart failure (Berman et al., 2004), obesity (Lee et al., 2011), breast cancer (Lesser et al., 2013), end-stage renal disease (Fukuda et al., 2015), poliomyelitis (Peel et al., 2015), multiple sclerosis (Sanoobar et al., 2016)). The direction of association between the use of CoQ10 and fatigue assessment was consistent in the subgroups of healthy participants (Hedges’ g = − 0.351 , 95 % CI = g = − 0.351 , 95 % CI = g=-0.351,95%CI=g=-0.351,95 \% \mathrm{CI}= -0.756 to 0.053 , p = 0.089 0.053 , p = 0.089 0.053,p=0.0890.053, p=0.089 ) and in patients with disease (Hedges’ g = g = g=g=
接著，我們將納入的試驗分成兩個子群：健康參與者（Morikawa et al., 2019; Mizuno et al., 2020; Mousavi et al., 2020）和疲勞相關疾病患者（纖維肌痛（Cordero et al., 2013; Di Pierro et al., 2017）、慢性疲勞症候群（Castro-Marrero et al、2015；CastroMarrero 等人，2021）、心力衰竭（Berman 等人，2004）、肥胖症（Lee 等人，2011）、乳癌（Lesser 等人，2013）、末期腎病（Fukuda 等人，2015）、小兒麻痺症（Peel 等人，2015）、多發性硬化症（Sanoobar 等人，2016））。在健康參與者（Hedges「 g = − 0.351 , 95 % CI = g = − 0.351 , 95 % CI = g=-0.351,95%CI=g=-0.351,95 \% \mathrm{CI}= -0.756 至 0.053 , p = 0.089 0.053 , p = 0.089 0.053,p=0.0890.053, p=0.089 ）和疾病患者（Hedges」 g = g = g=g= ）的亞群中，使用 CoQ10 與疲勞評估的關聯方向一致。
TABLE 2 | Summary of the CoQ10 interventions administered in the study treatment arms of the retrieved trials.
表 2 | 檢索到的試驗中，研究治療臂所施用的 CoQ10 干擾摘要。
First author (year)  第一作者（年份） Population  人口 Duration  時間長度 CoQ10 product/manufacturer
CoQ10 產品/製造商		 Daily CoQ10 dose (per-protocol N)
每日 CoQ10 劑量 (每項協議 N)		 Control (per-protocol N)
對照 (每項協議 N)		 Fatigue outcome measurement (score range)
疲勞結果測量（分數範圍）		 AE associated with CoQ10 withdrawal
停用 CoQ10 相關的 AE
Berman (2004) End-stage heart failure  末期心臟衰竭 3 months  3 個月 Ultrasome capsules/ Herbamed Ltd. (Israel)
Ultrasome 膠囊/ Herbamed Ltd. (以色列)(以色列)		 60 mg / 60 mg / 60mg//60 \mathrm{mg} / day (13)   60 mg / 60 mg / 60mg//60 \mathrm{mg} / 日 (13)
  配對安慰劑 (14)
Matching
placebo (14)
Matching placebo (14)| Matching | | :--- | | placebo (14) |
 Minnesota Living with Heart Failure Questionnaire fatigue score (0-5)
明尼蘇達心臟衰竭生活問卷疲勞分數 (0-5)		 One ultrasome-induced intestinal upset withdrawal
一次超聲波引起的腸道不適退出
Lee ( 2011 )  Lee  ( 2011 ) {:[" Lee "],[(2011)]:}\begin{aligned} & \text { Lee } \\ & (2011) \end{aligned} Obesity  肥胖症 12 weeks  12 週 Ubiquinone/Daewoong Pharmacy (Korea)
Ubiquinone/Daewoong Pharmacy (韓國)		 200 mg / 200 mg / 200mg//200 \mathrm{mg} / day (17)   200 mg / 200 mg / 200mg//200 \mathrm{mg} / 日 (17) Matching placebo (19)  配對安慰劑 (19) Fatigue Severity Scale (9-63)
疲勞嚴重程度量表 (9-63)		 No  沒有
Cordero (2013)  Cordero   (2013)  {:[" Cordero "],[" (2013) "]:}\begin{aligned} & \text { Cordero } \\ & \text { (2013) } \end{aligned} Fibromyalgia  纖維肌痛 40 days  40 天 CoQ10 capsules/Pharma Nord (Denmark)
輔酶Q10膠囊/Pharma Nord (丹麥)		 300 mg / 300 mg / 300mg//300 \mathrm{mg} / day (10)   300 mg / 300 mg / 300mg//300 \mathrm{mg} / 天 (10) Matching placebo (10)  配對安慰劑 (10) Fibromyalgia Impact Questionnaire fatigue score (0-10)
纖維肌痛影響問卷疲勞分數 (0-10)		 No  沒有
Lesser (2013)  Lesser   (2013)  {:[" Lesser "],[" (2013) "]:}\begin{aligned} & \text { Lesser } \\ & \text { (2013) } \end{aligned} Breast cancer under chemotherapy
化療中的乳癌		 24 weeks  24 週 CoQ10/Soft Gel Technologies (USA)
CoQ10/Soft Gel Technologies（美國）		 300 mg / day 300 mg / day 300mg//day300 \mathrm{mg} / \mathrm{day} (78) Matching placebo (61)  配對安慰劑 (61) Profile of Mood States fatigue subscale (0-4)
情緒狀態概況疲勞分量表 (0-4)		 No. All AE-related withdrawals were due to chemotherapy based on the investigators' review.
根據研究人員的審查，所有與 AE 相關的退出都是由於化療所致。
Castro-Marrero (2015) Chronic fatigue syndrome
慢性疲勞症候群		 8 weeks  8 週 ReConnect/Vitae Natural Nutrition (Spain)
ReConnect/Vitae Natural Nutrition（西班牙）		 200 mg/day with 20 mg / 20 mg / 20mg//20 \mathrm{mg} / day NADH (39)
200 毫克/天與 20 mg / 20 mg / 20mg//20 \mathrm{mg} / 天 NADH (39)		 Matching placebo (34)  配對安慰劑 (34) Fatigue Impact Scale (0-160)
疲勞影響量表 (0-160)		 No  沒有
Fukuda (2015)  福田 (2015) End-stage renal disease  末期腎病 12 weeks  12 週 AMP01/Asahi Kasei Kuraray Medical Corporation (Japan)
AMP01/Asahi Kasei Kuraray Medical Corporation (日本)		 Nutritional drink with 30 mg / day 30 mg / day 30mg//day30 \mathrm{mg} / \mathrm{day} CoQ10 (87)
含 30 mg / day 30 mg / day 30mg//day30 \mathrm{mg} / \mathrm{day} 輔酶Q10的營養飲料 (87)		 Matching placebo (86)  配對安慰劑 (86) Fatigue Scale (0-32)  疲勞量表 (0-32) No. All AE and withdrawals were not associated with the study intervention (which was conducted by a safety monitoring board). AEassociated withdrawal: CoQ10 6/97, placebo 5/99
否。所有 AE 和退出均與研究干預（由安全監控委員會進行）無關。與 AE 相關的退出：CoQ10 6/97，安慰劑 5/99
Peel (2015) Poliomyelitis  小兒麻痺症 60 days  60 天 CoQ10 capsules/Health World Limited (Australia)
輔酶Q10膠囊/Health World Limited (澳洲)		 100 mg / 100 mg / 100mg//100 \mathrm{mg} / day ( 54 ) a ) a  )^("a "))^{\text {a }}
100 mg / 100 mg / 100mg//100 \mathrm{mg} / 天 ( 54 ) a ) a  )^("a "))^{\text {a }}
  配對安慰劑 (49)
Matching
placebo (49)
Matching placebo (49)| Matching | | :--- | | placebo (49) |
 Multidimensional Assessment of Fatigue (1-50)
疲勞的多維度評估 (1-50)		 No. All AEs were not associated with CoQ10 supplementation. AE: CoQ10 7/54, placebo 5/49. AE-associated withdrawal: CoQ10 5/54, placebo 2/49
否。所有 AE 均與 CoQ10 補充無關。AE：CoQ10 7/54，安慰劑 5/49。與 AE 相關的停藥：輔酶Q10 5/54，安慰劑 2/49。
Sanoobar (2016) Multiple sclerosis  多發性硬化症 12 weeks  12 週 CoQ10 capsules/not mentioned
輔酶Q10膠囊: 未提及		 500 mg / 500 mg / 500mg//500 \mathrm{mg} / day (22)   500 mg / 500 mg / 500mg//500 \mathrm{mg} / 日 (22)
  配對安慰劑 (23)
Matching
placebo (23)
Matching placebo (23)| Matching | | :--- | | placebo (23) |
 Fatigue Severity Scale (9-63)
疲勞嚴重程度量表 (9-63)		 No  沒有
Di Pierro (2017) Fibromyalgia  纖維肌痛 3 months  3 個月

DDM Chinone ® ® ^(®){ }^{\circledR} 小包裝/Labomar (義大利)
DDM Chinone ® ® ^(®){ }^{\circledR} sachets/
Labomar (Italy)
DDM Chinone ^(®) sachets/ Labomar (Italy)| DDM Chinone ${ }^{\circledR}$ sachets/ | | :--- | | Labomar (Italy) |
 400 mg / 400 mg / 400mg//400 \mathrm{mg} / day (12)   400 mg / 400 mg / 400mg//400 \mathrm{mg} / 日 (12) Comparable placebo (10)  可比安慰劑 (10) Functional Assessment of Chronic Illiness Therapy (0-44)
慢性疾病治療功能評估 (0-44)		 No  沒有
Morikawa (2019)  森川 (2019) Healthy subjects  健康受試者 8 weeks  8 週 Uniquinol soft capsules/ Kaneka, Inc. (Japan)
Uniquinol 軟膠囊/ Kaneka, Inc. (日本)		 100 mg / 100 mg / 100mg//100 \mathrm{mg} / day (24)   100 mg / 100 mg / 100mg//100 \mathrm{mg} / 日 (24) Matching placebo (28)  配對安慰劑 (28) Fatigue Visual Analogue Scale (0-10)
疲勞感視覺類比量表 (0-10)

否。所有 AE 均與治療無關。AE: CoQ10 8/30，安慰劑 6/30
No. All AEs were not associated with the treatment.
AE: CoQ10 8/30, placebo 6/30
No. All AEs were not associated with the treatment. AE: CoQ10 8/30, placebo 6/30| No. All AEs were not associated with the treatment. | | :--- | | AE: CoQ10 8/30, placebo 6/30 |
Mizuno ( 2020 )  Mizuno  ( 2020 ) {:[" Mizuno "],[(2020)]:}\begin{aligned} & \text { Mizuno } \\ & (2020) \end{aligned} Healthy individuals with fatigue
有疲勞感的健康人		 12 weeks  12 週 Uniquinol soft capsules/ Kaneka, Inc. (Japan)
Uniquinol 軟膠囊/ Kaneka, Inc. (日本)

150 mg / 150 mg / 150mg//150 \mathrm{mg} / 天 (22) 100 mg / 100 mg / 100mg//100 \mathrm{mg} / 天 (20)
150 mg / 150 mg / 150mg//150 \mathrm{mg} / day (22)
100 mg / 100 mg / 100mg//100 \mathrm{mg} / day (20)
150mg// day (22) 100mg// day (20)| $150 \mathrm{mg} /$ day (22) | | :--- | | $100 \mathrm{mg} /$ day (20) |
 Matching placebo (20)  配對安慰劑 (20) Fatigue Visual Analogue Scale (0-100)
疲勞感視覺類比量表 (0-100)		 No  沒有
Mousavi (2020)  穆薩維 (2020) Nurses with fatigue  疲勞的護士 4 weeks  4 週 CoQ10 capsules/Nutri Century (Canada)
輔酶Q10膠囊/營養世紀（加拿大）		 200 mg / 200 mg / 200mg//200 \mathrm{mg} / day (54)   200 mg / 200 mg / 200mg//200 \mathrm{mg} / 日 (54) Matching placebo (51)  配對安慰劑 (51) Nurses' fatigue scale (21-105)
護士疲勞量表 (21-105)		 No  沒有
Castro-Marrero (2021) Chronic fatigue syndrome
慢性疲勞症候群		 8 weeks  8 週 ReConnect/Vitae Health Innovation (Spain)
ReConnect/Vitae Health Innovation（西班牙）		 200 mg / 200 mg / 200mg//200 \mathrm{mg} / day with 20 mg / 20 mg / 20mg//20 \mathrm{mg} / day NADH (72)
200 mg / 200 mg / 200mg//200 \mathrm{mg} / 天與 20 mg / 20 mg / 20mg//20 \mathrm{mg} / 天 NADH (72)		 Matching placebo (72)  配對安慰劑 (72) Fatigue Impact Scale (0-160)
疲勞影響量表 (0-160)

否。所有 AE 均與治療無關。與 AE 相關的停藥：CoQ10+NADH 8/104，安慰劑 11/103
No. All AEs were not associated with the treatment.
AE-associated withdrawal:
CoQ10+NADH 8/104, placebo 11/103
No. All AEs were not associated with the treatment. AE-associated withdrawal: CoQ10+NADH 8/104, placebo 11/103| No. All AEs were not associated with the treatment. | | :--- | | AE-associated withdrawal: | | CoQ10+NADH 8/104, placebo 11/103 |
First author (year) Population Duration CoQ10 product/manufacturer Daily CoQ10 dose (per-protocol N) Control (per-protocol N) Fatigue outcome measurement (score range) AE associated with CoQ10 withdrawal Berman (2004) End-stage heart failure 3 months Ultrasome capsules/ Herbamed Ltd. (Israel) 60mg// day (13) "Matching placebo (14)" Minnesota Living with Heart Failure Questionnaire fatigue score (0-5) One ultrasome-induced intestinal upset withdrawal " Lee (2011)" Obesity 12 weeks Ubiquinone/Daewoong Pharmacy (Korea) 200mg// day (17) Matching placebo (19) Fatigue Severity Scale (9-63) No " Cordero (2013) " Fibromyalgia 40 days CoQ10 capsules/Pharma Nord (Denmark) 300mg// day (10) Matching placebo (10) Fibromyalgia Impact Questionnaire fatigue score (0-10) No " Lesser (2013) " Breast cancer under chemotherapy 24 weeks CoQ10/Soft Gel Technologies (USA) 300mg//day (78) Matching placebo (61) Profile of Mood States fatigue subscale (0-4) No. All AE-related withdrawals were due to chemotherapy based on the investigators' review. Castro-Marrero (2015) Chronic fatigue syndrome 8 weeks ReConnect/Vitae Natural Nutrition (Spain) 200 mg/day with 20mg// day NADH (39) Matching placebo (34) Fatigue Impact Scale (0-160) No Fukuda (2015) End-stage renal disease 12 weeks AMP01/Asahi Kasei Kuraray Medical Corporation (Japan) Nutritional drink with 30mg//day CoQ10 (87) Matching placebo (86) Fatigue Scale (0-32) No. All AE and withdrawals were not associated with the study intervention (which was conducted by a safety monitoring board). AEassociated withdrawal: CoQ10 6/97, placebo 5/99 Peel (2015) Poliomyelitis 60 days CoQ10 capsules/Health World Limited (Australia) 100mg// day ( 54)^("a ") "Matching placebo (49)" Multidimensional Assessment of Fatigue (1-50) No. All AEs were not associated with CoQ10 supplementation. AE: CoQ10 7/54, placebo 5/49. AE-associated withdrawal: CoQ10 5/54, placebo 2/49 Sanoobar (2016) Multiple sclerosis 12 weeks CoQ10 capsules/not mentioned 500mg// day (22) "Matching placebo (23)" Fatigue Severity Scale (9-63) No Di Pierro (2017) Fibromyalgia 3 months "DDM Chinone ^(®) sachets/ Labomar (Italy)" 400mg// day (12) Comparable placebo (10) Functional Assessment of Chronic Illiness Therapy (0-44) No Morikawa (2019) Healthy subjects 8 weeks Uniquinol soft capsules/ Kaneka, Inc. (Japan) 100mg// day (24) Matching placebo (28) Fatigue Visual Analogue Scale (0-10) "No. All AEs were not associated with the treatment. AE: CoQ10 8/30, placebo 6/30" " Mizuno (2020)" Healthy individuals with fatigue 12 weeks Uniquinol soft capsules/ Kaneka, Inc. (Japan) "150mg// day (22) 100mg// day (20)" Matching placebo (20) Fatigue Visual Analogue Scale (0-100) No Mousavi (2020) Nurses with fatigue 4 weeks CoQ10 capsules/Nutri Century (Canada) 200mg// day (54) Matching placebo (51) Nurses' fatigue scale (21-105) No Castro-Marrero (2021) Chronic fatigue syndrome 8 weeks ReConnect/Vitae Health Innovation (Spain) 200mg// day with 20mg// day NADH (72) Matching placebo (72) Fatigue Impact Scale (0-160) "No. All AEs were not associated with the treatment. AE-associated withdrawal: CoQ10+NADH 8/104, placebo 11/103"| First author (year) | Population | Duration | CoQ10 product/manufacturer | Daily CoQ10 dose (per-protocol N) | Control (per-protocol N) | Fatigue outcome measurement (score range) | AE associated with CoQ10 withdrawal | | :---: | :---: | :---: | :---: | :---: | :---: | :---: | :---: | | Berman (2004) | End-stage heart failure | 3 months | Ultrasome capsules/ Herbamed Ltd. (Israel) | $60 \mathrm{mg} /$ day (13) | Matching <br> placebo (14) | Minnesota Living with Heart Failure Questionnaire fatigue score (0-5) | One ultrasome-induced intestinal upset withdrawal | | $\begin{aligned} & \text { Lee } \\ & (2011) \end{aligned}$ | Obesity | 12 weeks | Ubiquinone/Daewoong Pharmacy (Korea) | $200 \mathrm{mg} /$ day (17) | Matching placebo (19) | Fatigue Severity Scale (9-63) | No | | $\begin{aligned} & \text { Cordero } \\ & \text { (2013) } \end{aligned}$ | Fibromyalgia | 40 days | CoQ10 capsules/Pharma Nord (Denmark) | $300 \mathrm{mg} /$ day (10) | Matching placebo (10) | Fibromyalgia Impact Questionnaire fatigue score (0-10) | No | | $\begin{aligned} & \text { Lesser } \\ & \text { (2013) } \end{aligned}$ | Breast cancer under chemotherapy | 24 weeks | CoQ10/Soft Gel Technologies (USA) | $300 \mathrm{mg} / \mathrm{day}$ (78) | Matching placebo (61) | Profile of Mood States fatigue subscale (0-4) | No. All AE-related withdrawals were due to chemotherapy based on the investigators' review. | | Castro-Marrero (2015) | Chronic fatigue syndrome | 8 weeks | ReConnect/Vitae Natural Nutrition (Spain) | 200 mg/day with $20 \mathrm{mg} /$ day NADH (39) | Matching placebo (34) | Fatigue Impact Scale (0-160) | No | | Fukuda (2015) | End-stage renal disease | 12 weeks | AMP01/Asahi Kasei Kuraray Medical Corporation (Japan) | Nutritional drink with $30 \mathrm{mg} / \mathrm{day}$ CoQ10 (87) | Matching placebo (86) | Fatigue Scale (0-32) | No. All AE and withdrawals were not associated with the study intervention (which was conducted by a safety monitoring board). AEassociated withdrawal: CoQ10 6/97, placebo 5/99 | | Peel (2015) | Poliomyelitis | 60 days | CoQ10 capsules/Health World Limited (Australia) | $100 \mathrm{mg} /$ day ( 54$)^{\text {a }}$ | Matching <br> placebo (49) | Multidimensional Assessment of Fatigue (1-50) | No. All AEs were not associated with CoQ10 supplementation. AE: CoQ10 7/54, placebo 5/49. AE-associated withdrawal: CoQ10 5/54, placebo 2/49 | | Sanoobar (2016) | Multiple sclerosis | 12 weeks | CoQ10 capsules/not mentioned | $500 \mathrm{mg} /$ day (22) | Matching <br> placebo (23) | Fatigue Severity Scale (9-63) | No | | Di Pierro (2017) | Fibromyalgia | 3 months | DDM Chinone ${ }^{\circledR}$ sachets/ <br> Labomar (Italy) | $400 \mathrm{mg} /$ day (12) | Comparable placebo (10) | Functional Assessment of Chronic Illiness Therapy (0-44) | No | | Morikawa (2019) | Healthy subjects | 8 weeks | Uniquinol soft capsules/ Kaneka, Inc. (Japan) | $100 \mathrm{mg} /$ day (24) | Matching placebo (28) | Fatigue Visual Analogue Scale (0-10) | No. All AEs were not associated with the treatment. <br> AE: CoQ10 8/30, placebo 6/30 | | $\begin{aligned} & \text { Mizuno } \\ & (2020) \end{aligned}$ | Healthy individuals with fatigue | 12 weeks | Uniquinol soft capsules/ Kaneka, Inc. (Japan) | $150 \mathrm{mg} /$ day (22) <br> $100 \mathrm{mg} /$ day (20) | Matching placebo (20) | Fatigue Visual Analogue Scale (0-100) | No | | Mousavi (2020) | Nurses with fatigue | 4 weeks | CoQ10 capsules/Nutri Century (Canada) | $200 \mathrm{mg} /$ day (54) | Matching placebo (51) | Nurses' fatigue scale (21-105) | No | | Castro-Marrero (2021) | Chronic fatigue syndrome | 8 weeks | ReConnect/Vitae Health Innovation (Spain) | $200 \mathrm{mg} /$ day with $20 \mathrm{mg} /$ day NADH (72) | Matching placebo (72) | Fatigue Impact Scale (0-160) | No. All AEs were not associated with the treatment. <br> AE-associated withdrawal: <br> CoQ10+NADH 8/104, placebo 11/103 |
AE, adverse events; CoQ10, coenzyme Q10; NADH, reduced form of nicotinamide adenine dinucleotide; USA, United States of America
AE、不良事件；CoQ10、輔酵素 Q10；NADH、菸鹼醯胺腺嘌呤二核苷酸的還原形式；USA、美國
a a  ^("a "){ }^{\text {a }} The total number of subjects enrolled in the CoQ10 group was retrieved based on data reported in Figure 1 and Table 2, due to inconsistency in Table 1 .
a a  ^("a "){ }^{\text {a }} 由於表 1 中的數據不一致，我們根據圖 1 和表 2 中報告的數據檢索了 CoQ10 組入選受試 者的總人數 。
FIGURE 2 | Summary of quality assessment for the studies included in the current meta-analysis using version 2 of the Cochrane risk-of-bias tool for randomized trials.
使用隨機試驗的 Cochrane 風險偏倚工具第 2 版對目前薈萃分析中納入的研究進行品質評估的摘要。
First author (year)  第一作者（年份） Randomization process  隨機化過程 Intervention adherence  干預的堅持 Missing outcome data  遺漏結果資料 Outcome measurement  結果測量 Selective reporting  選擇性報告 Overall RoB  整體 RoB
Berman (2004) L L L L L L
Lee (2011) S a S a  S^("a ")S^{\text {a }} L S b S b  S^("b ")S^{\text {b }} L L S
Cordero (2013) S a S a  S^("a ")S^{\text {a }} L L L L S
Lesser (2013) S a S a  S^("a ")S^{\text {a }} L L L L S
Castro-Marrero (2015) S a S a  S^("a ")\mathrm{S}^{\text {a }} L L L L S
Fukuda (2015)  福田 (2015) L L L L L L
Peel (2015) L L L L L L
Sanoobar (2016) S a S a  S^("a ")S^{\text {a }} L L L L S
Di Pierro (2017) L L L S c S c  S^("c ")S^{\text {c }} L L
Morikawa (2019)  森川 (2019) S a S a  S^("a ")S^{\text {a }} L L L L S
Mizuno (2020) S a S a  S^("a ")S^{\text {a }} L L L L S
Mousavi (2020)  穆薩維 (2020) L L L L L L
Castro-Marrero (2021) L L L L L L
First author (year) Randomization process Intervention adherence Missing outcome data Outcome measurement Selective reporting Overall RoB Berman (2004) L L L L L L Lee (2011) S^("a ") L S^("b ") L L S Cordero (2013) S^("a ") L L L L S Lesser (2013) S^("a ") L L L L S Castro-Marrero (2015) S^("a ") L L L L S Fukuda (2015) L L L L L L Peel (2015) L L L L L L Sanoobar (2016) S^("a ") L L L L S Di Pierro (2017) L L L S^("c ") L L Morikawa (2019) S^("a ") L L L L S Mizuno (2020) S^("a ") L L L L S Mousavi (2020) L L L L L L Castro-Marrero (2021) L L L L L L| First author (year) | Randomization process | Intervention adherence | Missing outcome data | Outcome measurement | Selective reporting | Overall RoB | | :---: | :---: | :---: | :---: | :---: | :---: | :---: | | Berman (2004) | L | L | L | L | L | L | | Lee (2011) | $S^{\text {a }}$ | L | $S^{\text {b }}$ | L | L | S | | Cordero (2013) | $S^{\text {a }}$ | L | L | L | L | S | | Lesser (2013) | $S^{\text {a }}$ | L | L | L | L | S | | Castro-Marrero (2015) | $\mathrm{S}^{\text {a }}$ | L | L | L | L | S | | Fukuda (2015) | L | L | L | L | L | L | | Peel (2015) | L | L | L | L | L | L | | Sanoobar (2016) | $S^{\text {a }}$ | L | L | L | L | S | | Di Pierro (2017) | L | L | L | $S^{\text {c }}$ | L | L | | Morikawa (2019) | $S^{\text {a }}$ | L | L | L | L | S | | Mizuno (2020) | $S^{\text {a }}$ | L | L | L | L | S | | Mousavi (2020) | L | L | L | L | L | L | | Castro-Marrero (2021) | L | L | L | L | L | L |
CoQ10, coenzyme Q10; H, high risk of bias; L, low risk of bias; RoB, risk of bias; S, some risk of bias
CoQ10，輔酵素 Q10；H，偏倚風險高；L，偏倚風險低；RoB，偏倚風險；S，有一些偏倚風險
a a ^(a){ }^{a} These studies didn’t provide allocation concealment details.
a a ^(a){ }^{a} 這些研究並未提供分配隱藏的詳細資訊。
b b ^(b){ }^{b} This study excluded five subjects from the CoQ10 group because their blood levels of CoQ10 failed to increase over the study course.
b b ^(b){ }^{b} 本研究從 CoQ10 組中排除了五名受試者，因為他們血液中的 CoQ10 含量在研究過程中沒有增加。
c c  ^("c "){ }^{\text {c }} An open-label study. The participants were aware of the intervention they received.
c c  ^("c "){ }^{\text {c }} 開放標籤研究。參與者知道他們所接受的干預。
− 0.433 , 95 % CI = − 0.732 − 0.433 , 95 % CI = − 0.732 -0.433,95%CI=-0.732-0.433,95 \% \mathrm{CI}=-0.732 to − 0.133 , p = 0.005 − 0.133 , p = 0.005 -0.133,p=0.005-0.133, p=0.005 ), with overlapping 95% CIs (Figure 5).
− 0.433 , 95 % CI = − 0.732 − 0.433 , 95 % CI = − 0.732 -0.433,95%CI=-0.732-0.433,95 \% \mathrm{CI}=-0.732 到 − 0.133 , p = 0.005 − 0.133 , p = 0.005 -0.133,p=0.005-0.133, p=0.005 ），95% CIs 有重疊（圖 5）。
Another subgroup analysis was performed according to differences in the evaluated CoQ10 regimens. The group that used only CoQ10 showed a statistically significant fatigue reduction after supplementation (Hedges’ g = − 0.552 , 95 % CI = − 0.863 g = − 0.552 , 95 % CI = − 0.863 g=-0.552,95%CI=-0.863g=-0.552,95 \% \mathrm{CI}=-0.863 to -0.241 , and p = 0.001 p = 0.001 p=0.001p=0.001 ). However, the effect of fatigue reduction in the group using CoQ10 compounds (Figure 6) was trivial and statistically insignificant as compared with the placebo group (Hedges’ g = − 0.028 , 95 % g = − 0.028 , 95 % g=-0.028,95%g=-0.028,95 \% CI = − 0.225 CI = − 0.225 CI=-0.225\mathrm{CI}=-0.225 to 0.170 , p = 0.781 0.170 , p = 0.781 0.170,p=0.7810.170, p=0.781 ).
根據 CoQ10 評估方案的差異進行了另一項亞組分析。只使用 CoQ10 的組別在補充後顯示出統計上顯著的疲勞減輕效果 (Hedges' g = − 0.552 , 95 % CI = − 0.863 g = − 0.552 , 95 % CI = − 0.863 g=-0.552,95%CI=-0.863g=-0.552,95 \% \mathrm{CI}=-0.863 to -0.241 , and p = 0.001 p = 0.001 p=0.001p=0.001 )。然而，與安慰劑組相比，使用 CoQ10 化合物的組別（圖 6）減少疲勞的效果微不足道，在統計學上也不顯著（Hedges' g = − 0.028 , 95 % g = − 0.028 , 95 % g=-0.028,95%g=-0.028,95 \% CI = − 0.225 CI = − 0.225 CI=-0.225\mathrm{CI}=-0.225 至 0.170 , p = 0.781 0.170 , p = 0.781 0.170,p=0.7810.170, p=0.781 ）。
Meta-regression was performed to examine whether daily CoQ10 dose and treatment duration could modify effects on fatigue reduction. Both daily doses (coefficient = − 0.0017 = − 0.0017 =-0.0017=-0.0017 per mg , p < mg , p < mg,p <\mathrm{mg}, p< 0.001 ) and treatment duration (coefficient = − 0.0042 = − 0.0042 =-0.0042=-0.0042 per day, p = p = p=p= 0.007 ) correlated with increased fatigue reduction (Figures 7, 8). The
進行元回歸來檢驗每日 CoQ10 劑量和治療時間是否能改變對疲勞減輕的效果。每日劑量 (係數 = − 0.0017 = − 0.0017 =-0.0017=-0.0017 每 mg , p < mg , p < mg,p <\mathrm{mg}, p< 0.001) 和療程時間 (係數 = − 0.0042 = − 0.0042 =-0.0042=-0.0042 每天， p = p = p=p= 0.007) 都與疲勞減少程度的增加相關 (圖 7、8)。圖 9
funnel plot of the 13 included trials showed some asymmetry in effect size distributions (Supplementary Figure S1). Egger’s regression test showed a p p pp-value of 0.008 , indicating potential publication bias.
13 項納入試驗的漏斗圖顯示效果大小分佈有些不對稱 (補充圖 S1)。Egger's 回歸測試顯示 p p pp -值為 0.008，顯示可能有發表偏差。

3.4 Secondary Outcome: Treatment-Associated Adverse Event Rates
3.4 次要結果：治療相關不良事件率

Among the 602 participants treated with CoQ10, only one subject presented with an adverse event (i.e., gastrointestinal upset) and was thus withdrawn from the study conducted by Berman et al. (Berman et al., 2004). The meta-analysis of treatment-associated adverse event rates (Supplementary Figure S2) showed no between-group differences (odds ratio [OR] = 1.05 , 95 % CI = = 1.05 , 95 % CI = =1.05,95%CI==1.05,95 \% \mathrm{CI}= 0.36 to 3.08 , p = 0.933 , I 2 < 0.01 % 3.08 , p = 0.933 , I 2 < 0.01 % 3.08,p=0.933,I^(2) < 0.01%3.08, p=0.933, I^{2}<0.01 \% ).
在 602 位接受 CoQ10 治療的受試者中，只有一位受試者出現不良事件 (即腸胃不適)，因此退出 Berman 等人進行的研究 (Berman et al., 2004)。治療相關的不良事件發生率的薈萃分析（補充圖 S2）顯示組別間並無差異（機率比 [OR] = 1.05 , 95 % CI = = 1.05 , 95 % CI = =1.05,95%CI==1.05,95 \% \mathrm{CI}= 0.36 至 3.08 , p = 0.933 , I 2 < 0.01 % 3.08 , p = 0.933 , I 2 < 0.01 % 3.08,p=0.933,I^(2) < 0.01%3.08, p=0.933, I^{2}<0.01 \% ）。

4 DISCUSSION  4 討論

In this meta-analysis, CoQ10 was shown to statistically significantly reduce fatigue, and statistical significance was maintained within sensitivity analyses. The background condition of the participants did not have a statistically significant impact on the direction of the association between the use of CoQ10 and fatigue reduction. We found that CoQ10only formulations were effective in relieving fatigue, in contrast to
在這項薈萃分析中，CoQ10 在統計學上可顯著減少疲勞，在敏感性分析中也維持統計學上的顯著性。參與者的背景條件對使用 CoQ10 與減少疲勞的關聯方向並無統計上的顯著影響。我們發現只含輔酶Q10的配方能有效舒緩疲勞，而不含輔酶Q10的配方則不能。
CoQ10 compounds. Moreover, an increase in the daily dose and treatment duration of CoQ10 correlated with a better reduction in fatigue. To our knowledge, our study is the first systematic review or meta-analysis to demonstrate that CoQ10 has a mild-to-moderate effect (Hedges, 1981).
CoQ10 化合物。此外，增加 CoQ10 的每日劑量和療程時間與疲勞的減輕有較好的相關性。據我們所知，我們的研究是第一個系統性回顧或薈萃分析證實 CoQ10 有輕度至中度效果的研究 (Hedges，1981)。
Previous meta-analyses have suggested that CoQ10 supplementation can reduce oxidative stress (Sangsefidi et al., 2020) and inflammatory markers (Fan et al., 2017). And in heart failure patients, it is related to lower mortality and higher exercise
先前的 meta 分析顯示，補充 CoQ10 可降低氧化壓力 (Sangsefidi 等人，2020) 和發炎指標 (Fan 等人，2017)。而在心臟衰竭患者中，它與較低的死亡率和較高的運動
Group by  組別 Study name  研究名稱 Statistics for each study
每項研究的統計資料		 Hedges's g and 95% CI
Hedges's g 和 95% CI
Disease  疾病 Hedges's g Lower limit  下限 Upper limit  上限 p-Value  p 值 Relative weight  相對重量
0. Healthy  0.健康 Morikawa 2019  森川 2019 -0.034 -0.571 0.503 0.901 - 31.15
0. Healthy  0.健康 Mizuno 2020  美津濃 2020 -0.227 -0.755 0.300 0.398 31.55
0. Healthy  0.健康 Mousavi 2020  穆薩維 2020 -0.685 -1.076 -0.294 0.001 37.30
0. Healthy  0.健康 -0.338 -0.844 0.168 0.191
1. Disease  1.疾病 Berman 2004 -2.173 -3.107 -1.240 0.000 5.96
1. Disease  1.疾病 Lee 2011 -0.375 -1.020 0.271 0.255 - 8.81
1. Disease  1.疾病 Cordero 2013 -1.405 -2.351 -0.459 0.004 5.86
1. Disease  1.疾病 Lesser 2013 -0.237 -0.572 0.097 0.164 - 12.97
1. Disease  1.疾病 Castro-Marrero 2015 -0.169 -0.625 0.286 0.466 11.29
1. Disease  1.疾病 Fukuda 2015  福田 2015 0.046 -0.251 0.343 0.761 13.47
1. Disease  1.疾病 Peel 2015 -0.133 -0.517 0.251 0.497 12.29
1. Disease  1.疾病 Sanoobar 2016 -1.018 -1.630 -0.407 0.001 9.22
1. Disease  1.疾病 Di Pierro 2017 -0.291 -1.103 0.521 0.482 7.02
1. Disease  1.疾病 Castro-Marrero 2021 -0.045 -0.370 0.280 0.787 13.10
1. Disease  1.疾病 -0.425 -0.714 -0.136 0.004
-3.00 -1.50 0.00 1.50 3.00
CoQ10  輔酶Q10 lacebo  睫毛膏
Group by Study name Statistics for each study Hedges's g and 95% CI Disease Hedges's g Lower limit Upper limit p-Value Relative weight 0. Healthy Morikawa 2019 -0.034 -0.571 0.503 0.901 - 31.15 0. Healthy Mizuno 2020 -0.227 -0.755 0.300 0.398 31.55 0. Healthy Mousavi 2020 -0.685 -1.076 -0.294 0.001 37.30 0. Healthy -0.338 -0.844 0.168 0.191 1. Disease Berman 2004 -2.173 -3.107 -1.240 0.000 5.96 1. Disease Lee 2011 -0.375 -1.020 0.271 0.255 - 8.81 1. Disease Cordero 2013 -1.405 -2.351 -0.459 0.004 5.86 1. Disease Lesser 2013 -0.237 -0.572 0.097 0.164 - 12.97 1. Disease Castro-Marrero 2015 -0.169 -0.625 0.286 0.466 11.29 1. Disease Fukuda 2015 0.046 -0.251 0.343 0.761 13.47 1. Disease Peel 2015 -0.133 -0.517 0.251 0.497 12.29 1. Disease Sanoobar 2016 -1.018 -1.630 -0.407 0.001 9.22 1. Disease Di Pierro 2017 -0.291 -1.103 0.521 0.482 7.02 1. Disease Castro-Marrero 2021 -0.045 -0.370 0.280 0.787 13.10 1. Disease -0.425 -0.714 -0.136 0.004 -3.00 -1.50 0.00 1.50 3.00 CoQ10 lacebo | Group by | Study name | Statistics for each study | | | | Hedges's g and 95% CI | | | | | :---: | :---: | :---: | :---: | :---: | :---: | :---: | :---: | :---: | :---: | | Disease | | Hedges's g | Lower limit | Upper limit | p-Value | | | | Relative weight | | 0. Healthy | Morikawa 2019 | -0.034 | -0.571 | 0.503 | 0.901 | | - | | 31.15 | | 0. Healthy | Mizuno 2020 | -0.227 | -0.755 | 0.300 | 0.398 | | | | 31.55 | | 0. Healthy | Mousavi 2020 | -0.685 | -1.076 | -0.294 | 0.001 | | | | 37.30 | | 0. Healthy | | -0.338 | -0.844 | 0.168 | 0.191 | | | | | | 1. Disease | Berman 2004 | -2.173 | -3.107 | -1.240 | 0.000 | | | | 5.96 | | 1. Disease | Lee 2011 | -0.375 | -1.020 | 0.271 | 0.255 | | - | | 8.81 | | 1. Disease | Cordero 2013 | -1.405 | -2.351 | -0.459 | 0.004 | | | | 5.86 | | 1. Disease | Lesser 2013 | -0.237 | -0.572 | 0.097 | 0.164 | | - | | 12.97 | | 1. Disease | Castro-Marrero 2015 | -0.169 | -0.625 | 0.286 | 0.466 | | | | 11.29 | | 1. Disease | Fukuda 2015 | 0.046 | -0.251 | 0.343 | 0.761 | | | | 13.47 | | 1. Disease | Peel 2015 | -0.133 | -0.517 | 0.251 | 0.497 | | | | 12.29 | | 1. Disease | Sanoobar 2016 | -1.018 | -1.630 | -0.407 | 0.001 | | | | 9.22 | | 1. Disease | Di Pierro 2017 | -0.291 | -1.103 | 0.521 | 0.482 | | | | 7.02 | | 1. Disease | Castro-Marrero 2021 | -0.045 | -0.370 | 0.280 | 0.787 | | | | 13.10 | | 1. Disease | | -0.425 | -0.714 | -0.136 | 0.004 | | | | | | | | | | | | -3.00 | -1.50 0.00 | 1.50 | 3.00 | | | | | | | | | CoQ10 | lacebo | |
FIGURE 5| The forest plot of subgroup analysis using the participants’ condition as the moderator, including healthy participants and patients with disease. The directions of association between the use of coenzyme Q10 (CoQ10) and fatigue assessment were consistent in the subgroups, with overlapping 95 % 95 % 95%95 \% confidence intervals (Cls).
圖5|以參與者的狀況為中介，包括健康參與者和疾病患者的亞組分析森林繪圖。使用輔酶Q10（CoQ10）和疲勞評估之間的關聯方向在亞組中是一致的，有重疊的 95 % 95 % 95%95 \% 置信區間（Cls）。

capacity as compared with placebo-treated group (Lei and Liu, 2017). In 2019, Mehrabani et al. published a systematic review (Mehrabani et al., 2019) reported that CoQ10 was effective against fatigue in patients with myopathy associated with statin use (Fedacko et al., 2013) as well as in patients with fibromyalgia (Cordero et al., 2012a; Cordero et al., 2013; Miyamae et al., 2013; Di Pierro et al., 2017). However, the aforementioned review did not quantify the fatigue-reducing
能力與安慰劑治療組相比（Lei and Liu，2017）。2019 年，Mehrabani 等人發表的系統回顧（Mehrabani et al., 2019）報告指出，CoQ10 對他汀類藥物使用相關的肌病患者（Fedacko et al., 2013）以及纖維肌痛患者（Cordero et al., 2012a；Cordero et al., 2013；Miyamae et al., 2013；Di Pierro et al., 2017）的疲勞狀況有效。然而，前述回顧並未量化減輕疲勞的
effect of CoQ10. Thus, our meta-analysis was highly novel in addressing a gap in the current literature.
CoQ10 的影響。因此，我們的薈萃分析在解決目前文獻中的空白方面具有高度的新穎性。
The causes of fatigue are multifactorial (Manjaly et al., 2019), including inflammatory oxidative injury in neurons (Haß et al., 2019; Manjaly et al., 2019) and mitochondrial dysfunction (Filler et al., 2014) and CoQ10 is likewise known to be involved in pathogenic pathways. First, CoQ10 plays a crucial role in inhibiting oxidation of lipid-containing structures, such as
引起疲勞的原因是多因素的（Manjaly等人，2019），包括神經元的炎症氧化損傷（Haß等人，2019；Manjaly等人，2019）和線粒體功能障礙（Filler等人，2014），而CoQ10同樣也是已知的致病途徑。首先，CoQ10 在抑制含脂結構氧化方面扮演重要角色，例如
FIGURE 7 | Meta-regression of Hedges’ g g gg on daily dose (mg/day). The coefficient was -0.0017 with a p p pp value < 0.001 < 0.001 < 0.001<0.001.
圖 7 | Hedges 的 g g gg 對每日劑量 (mg/day) 的元回歸。系數為 -0.0017， p p pp 值為 < 0.001 < 0.001 < 0.001<0.001 。
cellular membranes and lipoproteins (Aaseth et al., 2021). For example, in a rat model, CoQ10 was found to protect both the peripheral and central nervous systems after passing through the blood-brain barrier (Belousova et al., 2016). CoQ10 may provide widespread protection to neurons through neural pathways connecting the brain to the muscles (Aaseth et al., 2021). Second, CoQ10 regulates the mitochondrial respiratory chain and is an intensively studied enzyme associated with mitochondrial dysfunction (Filler et al., 2014). To this end, Maes et al. compared patients with depression (Maes et al., 2009b) and chronic fatigue syndrome (Maes et al., 2009a) with healthy volunteers and found that CoQ10 deficiency was positively associated with fatigue, whereas serum CoQ10 levels were inversely correlated with fatigue severity (Maes et al., 2009a; Maes et al., 2009b). The above pathways and clinical observations could explain the fatigue-reducing effect of CoQ10 concluded by our meta-analysis.
細胞膜和脂蛋白 (Aaseth et al., 2021)。例如，在大鼠模型中，發現 CoQ10 在通過血腦屏障後可保護外周和中樞神經系統（Belousova 等人，2016 年）。CoQ10 可能會透過連接大腦與肌肉的神經通路，為神經元提供廣泛的保護（Aaseth 等人，2021）。其次，CoQ10 可調節線粒體呼吸鏈，是與線粒體功能障礙相關的深入研究的酶 (Filler 等人，2014)。為此，Maes 等人比較了憂鬱症 (Maes 等人，2009b) 和慢性疲勞症候群 (Maes 等人，2009a) 患者與健康志願者，發現 CoQ10 缺乏與疲勞呈正相關，而血清 CoQ10 水準則與疲勞嚴重程度成反比 (Maes 等人，2009a；Maes 等人，2009b)。上述途徑和臨床觀察可以解釋我們的薈萃分析所得出的 CoQ10 有減輕疲勞的效果。
In the subgroup analysis evaluating healthy participants separately from patients with disease, the directions of the CoQ10-associated effect sizes in both subgroups were consistent. We found that the subgroup of patients demonstrated statistical significance ( p = 0.004 p = 0.004 p=0.004p=0.004 ) in terms of the summary effect size, while the healthy subgroup did not show statistical significance ( p = p = p=p= 0.191 ); however, this subgroup showed a strong tendency towards positive effects of CoQ10, with demonstrated marginal significance and the upper limit of the 95 % 95 % 95%95 \% CI just crossing zero (Hedges’ g = g = g=g= − 0.338 , 95 % CI = − 0.844 − 0.338 , 95 % CI = − 0.844 -0.338,95%CI=-0.844-0.338,95 \% \mathrm{CI}=-0.844 to 0.168 ). This could be related to betweengroup differences in CoQ10 depletion, which might be more severe in patients with diseases than in healthy participants, thus indicating that CoQ10 was more effective in reducing fatigue in the former population within the evaluated studies. Additionally, the number of studies included in the patient subgroup was greater than in the healthy subgroup, which subsequently increased the statistical power and narrowed the pooled 95 % 95 % 95%95 \% CI to facilitate a statistically significant result.
在將健康參與者與疾病患者分開評估的亞組分析中，兩個亞組的 CoQ10 相關效應大小方向一致。我們發現，就總體效應大小而言，患者亞組顯示出統計上的顯著性 ( p = 0.004 p = 0.004 p=0.004p=0.004 )，而健康亞組則未顯示出統計上的顯著性 ( p = p = p=p= 0.191 )；然而，該亞組顯示出 CoQ10 強烈的正面效應傾向，顯示出邊際顯著性，且 95 % 95 % 95%95 \% CI 的上限剛好跨越零 (Hedges' g = g = g=g= − 0.338 , 95 % CI = − 0.844 − 0.338 , 95 % CI = − 0.844 -0.338,95%CI=-0.844-0.338,95 \% \mathrm{CI}=-0.844 至 0.168 )。這可能與CoQ10耗竭的組別差異有關，疾病患者的CoQ10耗竭可能比健康參與者更嚴重，因此顯示在評估的研究中，CoQ10對於前者更能有效減少疲勞。此外，患者亞組所納入的研究數目多於健康亞組，因此增加了統計效力，並縮窄了匯集的 95 % 95 % 95%95 \% CI，有助於獲得統計上顯著的結果。
The fatigue-reducing effects of CoQ10 were not statistically significant in the subgroup treated with CoQ10-compounds. We speculated that this might be associated with the lower CoQ10
在使用 CoQ10 化合物治療的亞組中，CoQ10 的疲勞減輕效果在統計學上並不顯著。我們推測，這可能與CoQ10-複合物的劑量較低有關。
FIGURE 8 8 8\mathbf{8} | Meta-regression of Hedges’ g g gg on treatment duration (day). The coefficient was -0.0042 with a p p pp value of 0.007 .
圖 8 8 8\mathbf{8} | Hedges的 g g gg 對治療時間（天）的元回歸。系數為 -0.0042， p p pp 值為 0.007 。
dose in the evaluated CoQ10 compound regimens (i.e., 30 mg / 30 mg / 30mg//30 \mathrm{mg} / day (Fukuda et al., 2015) to 200 mg / 200 mg / 200mg//200 \mathrm{mg} / day (Castro-Marrero et al., 2015; Castro-Marrero et al., 2021)). In contrast, in the subgroup using CoQ10 only (Berman et al., 2004; Lee et al., 2011; Cordero et al., 2013; Lesser et al., 2013; Peel et al., 2015; Sanoobar et al., 2016; Di Pierro et al., 2017; Morikawa et al., 2019; Mizuno et al., 2020; Mousavi et al., 2020), the daily dose ranged from 60 to 500 mg / 500 mg / 500mg//500 \mathrm{mg} / day with four studies utilizing 300-500 mg/day (Cordero et al., 2013; Lesser et al., 2013; Sanoobar et al., 2016; Di Pierro et al., 2017). Meta-regression also confirmed that the daily dose of CoQ10 was associated with fatigue reduction (Kirkland, 2022; NOW, 2022).
在評估的 CoQ10 複合療法中，劑量由 30 mg / 30 mg / 30mg//30 \mathrm{mg} / 天 (Fukuda 等人，2015) 改為 200 mg / 200 mg / 200mg//200 \mathrm{mg} / 天 (Castro-Marrero 等人，2015；Castro-Marrero 等人，2021)。相反，在僅使用 CoQ10 的亞組中（Berman 等人，2004；Lee 等人，2011；Cordero 等人，2013；Lesser 等人，2013；Peel 等人，2015；Sanoobar 等人，2016；Di Pierro 等人，2017；Morikawa 等人、2019；Mizuno等人，2020；Mousavi等人，2020），每日劑量從60到 500 mg / 500 mg / 500mg//500 \mathrm{mg} / 天不等，其中四項研究利用300-500 mg/天（Cordero等人，2013；Lesser等人，2013；Sanoobar等人，2016；Di Pierro等人，2017）。Meta-regression 也證實 CoQ10 的每日劑量與疲勞減少有關（Kirkland，2022；NOW，2022）。
Moreover, we identified a positive relationship between treatment duration and fatigue reduction. In our included studies, the longest period of CoQ10 supplementation was 6 months. As fatigue is a complicated disorder involving both psychological and physiological pathways, a sufficient period of intervention is needed to restore CoQ10 from chronic depletion status. Our speculation was evident in the results of a prior study (Hershey et al., 2007), which indicated that it takes approximately 3 months for CoQ10 supplementation to take effect in patients with chronic illness and CoQ10 deficiency. In the future, a prospective trial may be necessary to examine when ceiling effects are expected within CoQ10 interventions.
此外，我們還發現治療時間長短與疲勞減輕之間存在正向關係。在我們納入的研究中，補充 CoQ10 的最長時間為 6 個月。由於疲勞是一種複雜的失調，同時涉及心理和生理的途徑，因此需要足夠的干預時間來恢復 CoQ10 的慢性消耗狀態。我們的推測在先前的研究結果（Hershey 等人，2007）中顯示，對於慢性疾病且缺乏 CoQ10 的病患，CoQ10 補充約需 3 個月才能見效。未來，可能需要進行前瞻性試驗，以檢視輔酶Q10干預的天花板效應預期會在何時出現。
We also tried to explore if the fatigue-reducing effect of CoQ10 is related to the formulation, bioavailability or the patient’s disease. However, no specific pattern can be found. For example, in the three studies (Berman et al., 2004; Cordero et al., 2013; Sanoobar et al., 2016) with the Hedges’ g < − 1.0 g < − 1.0 g < -1.0g<-1.0, the formulations and manufacturers of CoQ10 were all different. Furthermore, Cordero et al. (Cordero et al., 2013) studied patients with fibromyalgia and the Hedges’ g g gg was -1.405 . Nonetheless, Di Pierro et al. (Di Pierro et al., 2017) studied the same fibromyalgia condition just got an Hedges’ g g gg of -0.291 . The effects of the formulation, bioavailability and disease might need more studies to conclude.
我們也嘗試探究 CoQ10 的消除疲勞效果是否與配方、生物利用度或病患的疾病有關。然而，並沒有找到特定的模式。例如，在Hedges的三項研究中（Berman等人，2004；Cordero等人，2013；Sanoobar等人，2016） g < − 1.0 g < − 1.0 g < -1.0g<-1.0 ，CoQ10的配方和製造商都不相同。此外，Cordero 等人（Cordero et al., 2013）研究纖維肌痛患者，Hedges' g g gg 為 -1.405 。然而，Di Pierro 等人（Di Pierro et al., 2017）對同樣的纖維肌痛狀況進行研究，得到的 Hedges' g g gg 為 -0.291 。配方、生物利用度和疾病的影響可能需要更多的研究才能得出結論。
Coenzyme Q10 is a well-studied substance with a welldocumented safety level of 1 , 200 mg / 1 , 200 mg / 1,200mg//1,200 \mathrm{mg} / day per person (Hidaka
輔酵素 Q10 是一種經過充分研究的物質，其安全標準為每人每天 1 , 200 mg / 1 , 200 mg / 1,200mg//1,200 \mathrm{mg} / (Hidaka)
et al., 2008). Moreover, evidence from pharmacokinetic studies suggests that exogenous CoQ10 does not influence the biosynthesis of endogenous CoQ10 and is less likely to accumulate in plasma or tissues after the cessation of supplementation (Bhagavan and Chopra, 2007; Miles, 2007). The high safety profile in the latter research was also compatible with our findings that, even at relatively high daily doses of 300 − 500 mg / 300 − 500 mg / 300-500mg//300-500 \mathrm{mg} / day, the adverse event rate in the CoQ10 group was never higher than in the placebo group.
等人，2008）。此外，藥物動力學研究的證據顯示，外源性 CoQ10 不會影響內源性 CoQ10 的生物合成，而且在停止補充之後也較不容易累積在血漿或組織中（Bhagavan and Chopra, 2007; Miles, 2007）。後者研究的高安全性也與我們的發現相符，即使每日劑量相對較高，達到 300 − 500 mg / 300 − 500 mg / 300-500mg//300-500 \mathrm{mg} / 天，CoQ10 組的不良事件發生率也從未高於安慰劑組。
This study has several limitations. First, the fatigue scales used in different trials differed, which may have contributed to heterogeneity. Thus, in this study, we standardized measurements using Hedges’ g g gg, employed a random-effects model to pool the studies, and conducted a subgroup analysis in accordance with the standard practice for addressing heterogeneity suggested by the Cochrane Handbook (Higgins et al., 2021a; Higgins et al., 2021b; Page et al., 2021b; Deeks et al., 2021; Tsai et al., 2021). Second, the daily dose and intervention duration were different in each trial, which may have contributed to variations in the estimated effects. Therefore, meta-regressions were performed to examine whether a linear relationship exists between the aforementioned factors and fatigue reduction. Third, these studies did not follow the participants after the cessation of CoQ10 supplementation to investigate how long the fatigue-reducing effect lasted, which serves as an intriguing topic to explore in future trials.
本研究有幾項限制。首先，不同試驗使用的疲勞量表不同，可能造成異质性。因此，在本研究中，我們使用 Hedges's g g gg 標準化測量，使用隨機效果模型匯集研究，並根據 Cochrane 手冊建議的處理異质性的標準做法進行子群分析 (Higgins 等人，2021a；Higgins 等人，2021b；Page 等人，2021b；Deeks 等人，2021；Tsai 等人，2021)。其次，每項試驗的每日劑量和干預時間都不同，這可能會造成估計效果的差異。因此，我們進行了元回歸，以檢視上述因素與疲勞減少之間是否存在線性關係。第三，這些研究並沒有在停止補充 CoQ10 後追蹤參與者，以調查減少疲勞的效果能維持多久，這也是未來試驗中值得探討的課題。
In conclusion, CoQ10 demonstrated a statistically significant fatigue-alleviating effect as compared with the evaluated placebos. The effect was statistically significantly correlated with daily dose and treatment duration. Future studies are needed to investigate the lasting effects of CoQ10 on fatigue reduction after the discontinuation of supplementation.
總之，與評估的安慰劑相比，CoQ10 在統計學上有顯著的緩解疲勞效果。在統計學上，此效果與每日劑量及治療時間長短有顯著關係。未來的研究需要探討停止補充 CoQ10 後，CoQ10 對於減輕疲勞的持久效果。

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DATA AVAILABILITY STATEMENT
資料可用性聲明

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.
研究中提出的原始貢獻包含在文章/補充材料中，進一步的諮詢可以直接聯絡對應作者。

AUTHOR CONTRIBUTIONS  作者貢獻

Data curation, I-CT and K-VC; formal analysis I-CT and K-VC; investigation, C-WH, C-HC, P-TT, K-VC; methodology, C-WH, P-TT, K-VC; software, I-CT, P-TT; supervision, P-TT, K-VC; validation, C − WH , C − HC , P − TT , K − VC C − WH , C − HC , P − TT , K − VC C-WH,C-HC,P-TT,K-VC\mathrm{C}-\mathrm{WH}, \mathrm{C}-\mathrm{HC}, \mathrm{P}-\mathrm{TT}, \mathrm{K}-\mathrm{VC}; writing the original draft, I-CT; writing review and editing, C-WH, C-HC, P-TT, K-VC. All authors have read and agreed to the published version of the manuscript.
資料整理，I-CT 和 K-VC；形式分析，I-CT 和 K-VC；調查，C-WH、C-HC、P-TT、K-VC；方法，C-WH、P-TT、K-VC；軟體，I-CT、P-TT；監督，P-TT、K-VC；驗證， C − WH , C − HC , P − TT , K − VC C − WH , C − HC , P − TT , K − VC C-WH,C-HC,P-TT,K-VC\mathrm{C}-\mathrm{WH}, \mathrm{C}-\mathrm{HC}, \mathrm{P}-\mathrm{TT}, \mathrm{K}-\mathrm{VC} ；撰寫原稿，I-CT；撰寫審查和編輯，C-WH、C-HC、P-TT、K-VC。所有作者均已閱讀並同意稿件的出版版本。

FUNDING  資金

This study was funded by the National Taiwan University Hospital, Bei-Hu Branch; Ministry of Science and Technology, Taiwan (MOST 106-2314-B-002-180-MY3 and MOST 109-2314-B-002-114-MY3); and the Taiwan Society of Ultrasound in Medicine. APC was funded by the Ministry of Science and Technology of Taiwan and Taiwan Society of Ultrasound in Medicine.
本研究由台灣大學醫院北湖分院、台灣科技部 (MOST 106-2314-B-002-180-MY3 及 MOST 109-2314-B-002-114-MY3)、台灣超音波醫學會資助。APC 由台灣科學技術部和台灣超音波醫學會資助。

SUPPLEMENTARY MATERIAL  補充材料

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2022.883251/ full#supplementary-material
本文的補充資料可於下列網址找到： https://www.frontiersin.org/articles/10.3389/fphar.2022.883251/ full#supplementary-material
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Conflict of Interest: I-CT is the founder of the company InnovaRad Inc.
利益衝突：I-CT 是 InnovaRad 公司的創辦人。
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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  1. CoQ10, coenzyme Q10; NADH, reduced form of nicotinamide adenine dinucleotide; RCT, randomized controlled trial; UK, United Kingdom; USA, United States of America.
    CoQ10，輔酵素 Q10；NADH，菸鹼醯胺腺嘌呤二核苷酸的還原形式；RCT，隨機對照試驗；UK，英國；USA，美國。
    a a ^(a){ }^{a} Age is presented as means ± ± +-\pm standard deviations or as medians (ranges).
    a a ^(a){ }^{a} 年齡以平均值 ± ± +-\pm 標準差或中間值（範圍）表示。
    b b ^(b){ }^{b} Allocated participants.
    b b ^(b){ }^{b} 分配的參與者。
    CP Per-protocol participants. CP Per-protocol participants.  ^("CP Per-protocol participants. "){ }^{\text {CP Per-protocol participants. }}
    d d ^("d"){ }^{\text {d}} The total sample size of the CoQ10 group was retrieved from data presented in Figure 1 and Table 2 due to inconsistency in Table 1 .
    d d ^("d"){ }^{\text {d}} 由於表1中的數據不一致，CoQ10組的總樣本數取自圖1和表2中的數據。