COCHRANE ROB 2 · 偏誤風險評讀
胃食道逆流症狀分數（FSSG）
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總體判斷 OVERALL－High（高風險）
Domain 與 overall 判斷由程式依 Cochrane RoB 2 官方演算法計算；AI 只負責回答下方各訊號問題。符號：＋ 低風險、？ 有些疑慮、－ 高風險（不只靠顏色）。
風險偏誤紅綠燈
- ＋Domain 1 隨機化過程：Low（低風險）
- ？Domain 2 偏離預定介入：Some concerns（有些疑慮）
- －Domain 3 缺失結局資料：High（高風險）
- ？Domain 4 結局測量：Some concerns（有些疑慮）
- ？Domain 5 選擇性報告：Some concerns（有些疑慮）
- －總體（Overall）：High（高風險）
中文摘要（給一般讀者）
這篇論文的偏誤風險與 limitation
本試驗為日本 22 家醫院之前瞻、多中心、隨機平行試驗，比較六君子湯合併標準劑量 RPZ 與加倍劑量 RPZ 對 PPI 頑固性 GERD 之 FSSG 症狀分數。隨機化以亂數表與隨機排列區組（區組 6）由獨立統計師執行、分配對臨床醫師保密，隨機過程風險低。因六君子湯難製安慰劑，本試驗為開放標籤，受試者與給藥人員均知曉分組，且主要結果 FSSG 為病人自評之主觀量表，評估可能受知情影響，惟對照為另一積極治療、兩組改善率無顯著差異，影響有限。最關鍵的問題在於分析：本試驗以療效可評估集（99/104）而非意向治療分析，含隨機後排除合格受試者（如 FSSG<8、早期胃癌史等登錄違規）與脫落／漏填者，故 2.6 判分析不適當；惟排除人數佔比小、兩組分布相近，潛在影響不大（2.7 判 PN）。整體而言主要疑慮來自開放標籤的自評結果與非 ITT 分析。
詳細評讀（給專業讀者）
Domain 1：隨機化過程 — 判斷：Low
偏誤來源：隨機分組的過程——分配序列是否隨機產生、是否隱蔽到分組為止、基線（第一期開始時）是否平衡。
1.1 Was the allocation sequence random?
分配序列是否隨機產生？
- 回答：是（Yes — 有明確證據支持）
- 原文引述：A randomization code with equal numbers of the alternative treatments was generated by an independent statistician, using random number tables which were unknown to the clinicians allocating treatment to patients. The randomization was by means of random, permuted blocks of size 6.由獨立統計師使用亂數表產生兩組等量的隨機分配碼，臨床醫師並不知曉；隨機化採用區組大小為 6 的隨機排列區組法。
- 理由：明確使用亂數表並由獨立統計師執行隨機排列區組，含隨機成分，屬適當的隨機序列產生方式。
1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?
分配是否隱蔽到分組為止？
- 回答：可能是（Probably yes — 綜合判斷後傾向「是」）
- 原文引述：A randomization code ... was generated by an independent statistician, using random number tables which were unknown to the clinicians allocating treatment to patients ... the patients were randomly divided into 2 groups using a scratch sheet for assignment in accordance with the envelope method.分配碼由獨立統計師產生，臨床分配醫師並不知曉；其後依信封法以刮刮卡進行分配。
- 理由：亂數表由獨立統計師掌控、臨床醫師不知曉，並以信封法／刮刮卡逐一分配，雖未詳述信封是否不透明密封，但中央產碼且對分配醫師保密，合理判定分配隱匿足夠（PY）。
1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?
（第一期開始時）基線差異是否暗示隨機化有問題？
- 回答：可能否（Probably no — 綜合判斷後傾向「否」）
- 原文引述：There were no marked differences in the age, gender, or BMI of the patients in the 2 groups ... However, the total FSSG score before the start of treatment in the rikkunshito group was significantly higher than that in the double-dose RPZ group (P = 0.046).兩組在年齡、性別、BMI 及內視鏡分級分布上無明顯差異；惟六君子湯組治療前 FSSG 總分顯著高於加倍 RPZ 組（P = 0.046）。
- 理由：僅單一基線變項在 0.05 臨界值附近（P = 0.046）達顯著，屬可由機遇解釋的範圍；組別人數接近 1:1（53/51），其餘主要預後因子均衡，無證據顯示隨機化過程有問題。
Domain 2：偏離預定介入 — 判斷：Some concerns
偏誤來源：實際執行時偏離預定的介入——盲性如何、是否依「隨機分到的組別」分析（ITT）。
2.1 Were participants aware of their assigned intervention during the trial?
參與者是否（在每一期）知道自己的分組？
- 回答：是（Yes — 有明確證據支持）
- 原文引述：it is very difficult to produce a placebo for rikkunshito, because rikkunshito, an herbal medicine, has characteristic granules, taste, and smell on swallowing. Thus, we did not use a placebo for rikkunshito in this study.由於六君子湯為具特殊顆粒、味道與氣味的中藥，難以製作安慰劑，故本研究未對六君子湯使用安慰劑。
- 理由：本試驗為開放標籤、未使用六君子湯安慰劑，且兩組介入（合併六君子湯 vs 加倍 RPZ 劑量）明顯不同，受試者知曉自身分組。
2.2 Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?
照護／執行者是否（在每一期）知道分組？
- 回答：是（Yes — 有明確證據支持）
- 原文引述：Thus, we did not use a placebo for rikkunshito in this study. Therefore, we conducted a prospective, multicenter, randomized, parallel comparative study of 2 groups.本研究未使用六君子湯安慰劑，為開放標籤的兩組平行比較試驗。
- 理由：無安慰劑、無雙盲設計，兩組用藥方式（加用中藥顆粒 vs 加倍 PPI 劑量）外觀明顯不同，照護者與給藥人員必然知曉受試者的分組。
2.3 Were there deviations from the intended intervention that arose because of the trial context?
是否因試驗情境造成偏離？
- 回答：可能否（Probably no — 綜合判斷後傾向「否」）
- 原文引述：no adverse events/reactions requiring treatment were seen in any patients throughout the overall study period ... Treatment compliance was defined as the percentage of the test drug used. A treatment compliance of at least 66.6% was considered to be acceptable.整個研究期間未見任何需要處置的不良事件／反應；治療順從性定義為使用試驗藥物之百分比，順從率至少 66.6% 視為可接受。
- 理由：未報告因試驗情境（trial context）而導致偏離方案的非方案介入或交叉換組；雖為開放標籤，但無證據顯示存在因試驗情境而生、與方案不符的偏離，故判 PN。
2.4 Were these deviations likely to have affected the outcome?
這些偏離是否可能影響結局？
- 回答：不需評估（NA）
- 原因：條件題：依 2.3 的答案，本題依 RoB 2 官方路由不需評估（NA）。
2.5 Were these deviations from intended intervention balanced between groups?
這些偏離在兩組間是否平衡？
- 回答：不需評估（NA）
- 原因：條件題：依 2.4 的答案，本題依 RoB 2 官方路由不需評估（NA）。
2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?
是否用了適當分析（ITT）？
- 回答：可能否（Probably no — 綜合判斷後傾向「否」）
- 原文引述：One hundred and four patients were randomly assigned ... 3 patients were excluded from the efficacy assessment, because of registration violation ... 2 patients were withdrawn after registration and thus were regarded as dropout cases. Therefore, the final number of patients analyzed for efficacy was 99 ... Three patients ... were excluded from the analysis of the total FSSG score because of deletions of checking for some items of the FSSG scores.104 名受試者隨機分組後，3 名因登錄違規被排除於療效評估、2 名登錄後退出視為脫落，最終療效分析僅 99 名；另有 3 名因 FSSG 部分項目漏填而被排除於 FSSG 總分分析。
- 理由：本試驗以療效可評估集（efficacy-evaluable，99/104）進行分析，而非意向治療；其中 3 名「登錄違規」屬隨機後排除的合格受試者（FSSG<8、早期胃癌史、合併精神症狀），加上 2 名脫落與 3 名漏填者均被剔除，並非僅排除確認不合格者，亦未以 ITT 方式納入全部隨機者，故對評估指派效應而言分析方法不適當（PN）。
2.7 Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?
未依隨機分組分析，是否可能對結果造成重大影響？
- 回答：可能否（Probably no — 綜合判斷後傾向「否」）
- 原文引述：Therefore, the final number of patients analyzed for efficacy was 99 (rikkunshito group: 48, double-dose RPZ group: 51) ... Three patients (rikkunshito group: 2, double-dose RPZ group: 1) were excluded from the analysis of the total FSSG score.最終療效分析人數為 99 名（六君子湯組 48、加倍 RPZ 組 51）；另 3 名（六君子湯組 2、加倍 RPZ 組 1）被排除於 FSSG 總分分析。
- 理由：排除人數佔比小（療效集排除 5/104；FSSG 總分另剔 3 人，分析數約為 45 與 50），且排除以登錄違規／漏填等與真值關聯不強的原因為主、兩組分布相近，難以對指派效應估計造成實質影響，故判 PN（潛在影響不大）。
Domain 3：缺失結局資料 — 判斷：High
偏誤來源：結局資料缺失——是否幾乎所有人都有資料、缺失是否可能與病情（結局真實值）相關。
3.1 Were data for this outcome available for all, or nearly all, participants randomized?
是否幾乎所有受試者都有此結局的資料？
- 回答：可能否（Probably no — 綜合判斷後傾向「否」）
- 原文引述：2 patients were withdrawn after registration and thus were regarded as dropout cases ... Three patients ... were excluded from the analysis of the total FSSG score because of deletions of checking for some items of the FSSG scores.2 名受試者登錄後退出視為脫落；另 3 名因 FSSG 部分項目漏填而被排除於總分分析。
- 理由：並非所有隨機者皆取得結果資料：有脫落與資料漏填造成的缺失，故 3.1 判 PN（並非幾乎所有人都有結果資料），需續答後續訊號題。
3.2 Is there evidence that the result was not biased by missing outcome data?
是否有證據顯示結果未受缺失資料偏誤？
- 回答：資訊不足（No information — 原文未提供足以判斷的資訊）
- 原文引述：原文未提供相關描述
- 理由：因 3.1 答 PN，本題（缺失是否不致造成偏誤的證據）續評；惟缺失比例小、原因多與結果真值無關，主要由 3.3 判定，本欄不需另以 NA 阻斷——依演算法 3.1 為 NPN 時應進入 3.2。
3.3 Could missingness in the outcome depend on its true value?
缺失是否可能取決於結局真實值？
- 回答：不需評估（NA）
- 原因：條件題：依 3.2 的答案，本題依 RoB 2 官方路由不需評估（NA）。
3.4 Is it likely that missingness in the outcome depended on its true value?
缺失是否很可能取決於結局真實值？
- 回答：不需評估（NA）
- 原因：條件題：依 3.3 的答案，本題依 RoB 2 官方路由不需評估（NA）。
Domain 4：結局測量 — 判斷：Some concerns
偏誤來源：結局的測量——測量工具是否恰當、評估者是否盲化、評估是否可能受分組知情影響。
4.1 Was the method of measuring the outcome inappropriate?
結局測量方法是否不適當？
- 回答：否（No — 有明確證據支持）
- 原文引述：GERD symptoms were evaluated using the FSSG questionnaire ... total scores of more than 8 were considered to indicate probable GERD, as previously validated.以 FSSG 問卷評估胃食道逆流症狀，總分 >8 視為可能之 GERD，先前已經驗證。
- 理由：FSSG 為已驗證之 GERD 症狀量表，作為本結果之測量工具合適，測量方法並無不當。
4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?
（每一序列內）結局測量是否可能因介入而異？
- 回答：否（No — 有明確證據支持）
- 原文引述：Before and after the 4-week treatment, GERD symptoms were evaluated using the FSSG questionnaire.於 4 週治療前後，皆以 FSSG 問卷評估胃食道逆流症狀。
- 理由：兩組均以相同的 FSSG 問卷於相同時間點（治療前、治療 4 週後）測量，測量方法在組間一致，不致因組別不同而異。
4.3 Were outcome assessors aware of the intervention received by study participants?
結局評估者是否知道受試者接受的介入？
- 回答：是（Yes — 有明確證據支持）
- 原文引述：Thus, we did not use a placebo for rikkunshito in this study ... GERD symptoms were evaluated using the FSSG questionnaire.本研究未使用六君子湯安慰劑；以 FSSG 問卷評估症狀。
- 理由：FSSG 為受試者自填之病人報告結果，結果評估者即受試者本人；因試驗為開放標籤，受試者知曉自身分組，故結果評估者知曉所接受之介入。
4.4 Could assessment of the outcome have been influenced by knowledge of intervention received?
結局評估是否可能受介入知情影響？
- 回答：是（Yes — 有明確證據支持）
- 原文引述：the scores are calculated according to the frequency of the symptoms ... The total score is given by the sum of the RS and ARD scores.分數依症狀出現頻率計算，總分為逆流症狀（RS）與酸相關運動障礙症狀（ARD）兩域之和。
- 理由：FSSG 為主觀的病人自評症狀量表，受試者對自身症狀的評分可能受其知曉所接受介入（中藥 vs 加倍 PPI）的影響。
4.5 Is it likely that assessment of the outcome was influenced by knowledge of intervention received?
結局評估是否很可能受介入知情影響？
- 回答：可能否（Probably no — 綜合判斷後傾向「否」）
- 原文引述：in a previous report on non-ulcer dyspepsia patients, a standard dose of rikkunshito showed significant potent therapeutic efficacy compared with a very low dose of rikkunshito (mimicking a placebo) ... Thus, it appears that the present effect of rikkunshito indicated pharmacological efficacy and not a placebo effect.先前在非潰瘍性消化不良的研究中，標準劑量六君子湯相較於極低劑量（模擬安慰劑）顯示顯著療效；故本研究的效果應屬藥理療效而非安慰劑效應。
- 理由：雖為開放標籤、自評結果可能受影響（4.4 為 Y），但對照組為另一積極治療（加倍 PPI）而非無治療，受試者未必預設某組較佳，且兩組改善率無顯著差異；無強烈理由相信評估確實被知情所左右，故判 PN（屬「有疑慮」而非「高風險」）。
Domain 5：選擇性報告 — 判斷：Some concerns
偏誤來源：選擇性報告結果——是否依事前訂定的分析計畫分析、有無從多個結果中挑選有利者報告（交叉另含：是否因偵測到殘留而只報第一期）。
5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?
是否依事前訂定（取得未盲化資料前定版）的分析計畫分析？
- 回答：資訊不足（No information — 原文未提供足以判斷的資訊）
- 原文引述：This study (UMIN000003716) was a prospective, multicenter, randomized, parallel comparative study ... The primary endpoint was the improvement rate, which was calculated based on the FSSG scores before and after treatment.本研究（UMIN000003716）為前瞻、多中心、隨機平行比較試驗；主要終點為依治療前後 FSSG 分數計算之改善率。
- 理由：雖有試驗註冊號（UMIN000003716），但報告未提供可供查核的事前分析計畫（含定稿日期早於解盲資料取得之佐證），無從確認分析是否依事前計畫執行，故判 NI。
5.2 Is the numerical result being assessed likely to have been selected, on the basis of the results, from multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?
此數值結果是否可能依結果，從多個量表／定義／時間點中選出？
- 回答：可能否（Probably no — 綜合判斷後傾向「否」）
- 原文引述：The primary endpoint was the improvement rate, which was calculated based on the FSSG scores before and after treatment ... To compare the effects between the two groups, the mean improvement rate was used.主要終點為以治療前後 FSSG 分數計算之改善率，並以兩組平均改善率比較組間效果。
- 理由：FSSG 總分為事前指定之主要測量，報告完整呈現治療前後分數、改善率及各亞組，無證據顯示是從多個結果測量中依結果擇優呈報，故判 PN。
5.3 Is the numerical result being assessed likely to have been selected, on the basis of the results, from multiple eligible analyses of the data?
此數值結果是否可能依結果，從多種分析中選出？
- 回答：可能否（Probably no — 綜合判斷後傾向「否」）
- 原文引述：the improvement rate in each subject was calculated from these scores, and the mean values were compared between the two groups using Wilcoxon's rank sum test ... Significance was regarded as P < 0.05.依各受試者分數計算改善率，並以 Wilcoxon 等級和檢定比較兩組平均值，顯著性以 P < 0.05 判定。
- 理由：事前指定之統計方法明確（Wilcoxon 檢定、改善率定義公式固定），主要結果按既定方法分析並完整呈報，無證據顯示自多種分析中依結果擇優呈報，故判 PN。
