″7,P″′″“αCO′ 7:`″ (薬理 と治療)vo1 46 ■o.4 2018

臨床試験のための統計解析計画書の内容に関するガイドラインで

示された「記載例」の紹介

折 笠 秀 樹 (富山大学)

「臨床試験のための統計解析計画書 (Statistical

Analysis Plan,SAP)の 内容に関するガイ ドライ

ン」は,2017年 12月 に米国医師会雑誌 (JAνA)

などで広 く公表された 1).本誌 2月 号でその紹介

をしたが 2),説明記述だけでは正 しく理解できな

い可能性 もあるだろう。そこで,原著論文の補

遺3)に

提示された「記載例」の英文を,括弧付

けとして追記 した。 さらに,1少 しわか りに くい

チェック項目については説明を加える。

番号 2は バージョンについての記載であるc_版

番号は,作成中は0.1ずつ増やし い.1,1.2,1.3な

ど), とりあえず完成 と思われた時点で 1.0増 や

して 2.0な どとする。その後 も改訂が必要 となれ

ば,そ の作業中の改訂では0.1ずつ増やし,完成

したら 1.0増やして 3.0な どとする。

番号 4cで は,中間解析時の SAP改訂について

述べた。非盲検での中間解析 を実施 した後 に

SAPを 改訂する際,SAP執筆・承認にかかわる

人は非盲検データにアクセスできないことが望ま

れる。すなわち,番号 6a/6b/6cの 項 目に名前が

ある人は中間解析実務に関与 しないよう留意され

たい。

番号 14は最終解析の時期についてである。最

終解析は最終時に 1回 と考えるのが通常だが,がん臨床試験などのように追跡が長期にわたること

がある。たとえば,平均追跡 2年時に最終解析を

行い,そ の後も再発などを評価するため 5年後に

も最終解析を行うことがある。急性心筋梗塞など

でも発症後 lヵ 月以内の短期成績に関する最終解

析があり,続いて 1年後の長期成績に関する最終

解析を行うことがあるcこ のように,最終解析を

時期によって分けて行う際の記述がこの項日にあ

たる。

番号 21は スクリーニングデータについてであ

る。スクリーニング期というのはランダム割付け

の前の患者組み入れ段階のことであり,選択バイ

アスがないことが大切である。すなわち, ランダ

ム割付けの前に除外された患者数とその理由を示

すことによって,ス クリーニング時の除外には選

択バイアスがないことを報告する。

英文記載例付 きのチェックリス トを参考にし

て,さ らなる理解を深めていただきたい。

文 献

1)Ganlblc C,Krishan A.Stockcn D.Lcwis S、 Juszczak E,Dor6

C, ct al. Guidclillcs for thc colltcnt or statlstlcal analysis

plans in clinical trials 、み1ルfi′‐12017:318(23)12337-43.

2)折笠秀樹.臨床試験のための統計解析計画書 の内容に関

するガイ ドラインの紹介 薬理 と治療 2018:46(2):293-5

3)Gamblc C,Krishan A,Stockcn D、 Lcwis S,]uszczak E、 Dolで

C. Ct al Supplclllcntary Onlinc Content of thc ``Guidclincs

for thc contcnt of stalistical analysis plans in clinical trials''

JAνA doil10 10014iama 2017 18556

6ews

641

、夕″P力′,7,,“ 0′ 動ω‐(薬埋 と治療)vo146 no.4 2018

表 SAPガ イダンス文書―臨床試験 SAPに 記載すべき項 目a

記載項目の英文事例([]で提示)に ついては,原著論文の“Supplementary OnHne COntent''3)か ら転載した。

第 1章 [管理情報]

表題と試験登録

SAPバージョン

la プロ トコルに合った記述的表題。前置あるいは副題にSAPと いう用語 を含める。もしあれば,略称 も書 く.

[StatlStiCal analySIS plan fOr the Stroke Oxygen Study(SC)2S):a lnulti― center randonllzed controlled

trial tO aSSeSS ヽヽ′hether routlne oxygen supplernentatlon in the first 72 hours after a stroke lrnproves

10ng‐ term outcome]

lb 試験登録番号。

[Trial registrationilSRCTN501 33740]

日付を伴うSAPのバージョン.

[Version:10 [)atel July 3,2014]

対応するプロトコルのバージョンを引用する。

[‐「 hiS dOCunnent haS been Wrltten baSed On infOrrnatlon contained in the study protocol version 15,

dated ll IDecember 201 2]

4a SAPの 改訂履歴.

4b SAP改 訂版それぞれに対する改訂根拠 .

4c 中間解析などに関連 して,SAP改訂の時期.

5 SAP貢献者の氏名・所属・役割.

6a SAPの執筆者。

6b 統計解析責任者。

6c 主任研究者/臨床指導者。

プロトコルバージョン

SAP改言T

役割と責任

署名

Protocol versionUpdated SAPverslon no

Section numberchanged

Description andreason for change

Date changed

10 20 Appendix DOrganisms added to

the appendix21/02/2014

20 20No changes

requiredSAP reviewed againstprotocolamendments 31/07/2014

第 2章 [緒論]

背景と根拠

目的

試験の背景および根拠の骨子―

臨床疑間の簡潔な記述と,本試験を実施する簡潔な理由を含める。

[‐「 O be brief,ChrOnlC fatlgue SyndrOnne lS Characterlsed by chronic disabling fatigue in the absence of

an alternatlve diagnosis, present in C)121o216%of the population The National lnstltute for Health

and ClinicaI Exce‖ ence(NICE, tJK)recolγ ュ|■lends t、 vo treatment: cognitive behaviour therapy(CBT)

and graded exercise therapy(GEE‐ T),but patient organisatlons recornrnend a third treatrlnenti adaptive

paclng therapy(APT) A definltlve randornised trial 、vas therefore needed to conlpare all three

treatnnentSヽ ″ith specialist rlnedical care(SSMC)and to corTlpare the establlshed treatnnents(CBT,

GET)against the new treatnnent(APT)]

特定の目的あるいは仮説の記述。

[Research bypothesis: The null hypOthesls ls that there ls no difference in tirne to first blood streann

infeCtiOn bet Veen the standard and irnpregnated (antibiotic and heparin connblned)grOupS ‐「he

alternatlve hypothesis is that there is a di■ erence bet、`′

een the t、″o groups

Study objectivcs: ~「 he primary objective of this trial ls tO determine the effectiveness of heparin

bOnded Or antlbiOtlC lrnpregnated CVCS(COmbined)COmpared Wlth Standard CVCS fOr preVenting

hOSpital aCquired blood strearn infection Second obiectives are:

a To deternnlne the cost effectiveness of heparln bonded or antibiotlc 11lpregnated cVcs cO1lnpared

、,vlth standard C)VCs, based on the prlmary OutcOnne and cOsts Of acute care fronn the perspective of

the NHS

b TO deternnine the effectlveness of type of CVC ln 3-、 ″ay cOrnparisons of heparin bonded versus

antibiotlc lnnpregnated versus standard c)Vcs fOr preventing hOspital acquired blood stream infection,

based on culture,quantitatlve bacterlal E)NA,and clinical 1lneasures of infectlon]

642

説明記述

″′2Pみ`′

″″αごο′777′ ′‐(薬理 と治療)vol.46 no.4 2018

表 (つづき)

第3章 [研究法]

試験デザイン

ランダム化 10

サンプルサイズ 11

枠組み 12

統計学的中間解析と中止基準 13a

試験型 (バ ラレルグルーブ,多アーム, クロスオーバー, ファクトリアルなど)お よび割付比を含む,試験デザインに関する簡潔な記述。さらに介入の簡潔な記述も含める。「

~「

he trlal ls a t、 ″o centre,randOmised,para‖ el_grOup,placeb。 _contr。 ‖ed trial Treatrlnent a‖ 。catlon isa lll ratiO PatlentS are randOnnlSed tO either gabapentin Or rnatChed placebo control」

ランタム化の詳細―

最小化法や層別化の有無について(用 いた層別因子も含む。SAPに 書かないなら,

その情報の在り処も合める)。

[I三 ach randorlizatlon is via nnininlisatlon lncorporatlng a randonn elelγ lent and incorpOrates the

fO‖OⅥ′lng faCtOrSi Centre, へ`′HC)perfOrrnance status(O or l vs 2), prior oxallplatin(yes vs no), pr10r

beVaCiZunlab(yeS Or nO), preViOuS beSt reSpOnse to therapy(PR/S[D vs F)D alone vs unknovvn)and

dOSe reduction/delay/stOp Of therapy for toxlcity durlng previous therapy(yes vs nO)

Or

The randornlsation prOcess ls described in full 、″lthin the clinical trlal protocol[)etails of the

randOrγ'ISatiOn methOd are held securely withln the statlstlcs rnaster file]

サンブルサイス算出の詳細。あるいは, ブロ トコル中のサンブルサイズ算出を引用する(SAPで 繰 り返さない).

[A sannple slze of 1 43 in eaCh group、～rill have 809′ 6 pOヽ A′ er tO deteCt a difference in n3eans of 0 50

aSSu1111ng that the COrlnl,10n Standard devlatlon is l 150 using a l、 へ′o grOup t_test、 りith a(E)05t、 ャo― sldedSignlfiCance level AI10Wlng fOr l C)% 10SS tO fO‖ OW up, やVe V′Ould need a total of(31 6 participants

(1 58 per group)‐「 he estirnate used fOr the standard devlat10n in the sannple size calculatiOn vvas

taken frOnl an audit at Alder Hey Children's NHS Foundation Trust based on children rnatching

the lnCluSiOn Criterla fOr thiS proposed study A di■ erence ln hbAlc of C)5% ls widely recognlzed

aS the threShold used by the Food and Drug Ad1lninlstratlon(FE)A)and pharrnaceutical lndustry to

deternnlne efectlveness of any ne、 へ′oral hypOglycaen lc agents Current natlonal studies lnvestigating

therapeutiC interVentiOnS in Chlldren V′ ith dlabetes 、Avere povvered using this effect size An

irlnprOVe ment of C)161%｀ A′aS deteCted in adultS in the rlneta― analySiS Of Studies included in the 2004

H~「A report suggesting that in additlon to this estirnate being the 1lninlrnunn clinica‖ y lmportant lt ls

also a realistic dlference to detect]

優越性,同 等性,あ るいは非劣性という,仮説検定の枠組み。どういった比較を示すかについても含める。[The SLEEPS trlal protocol states the secOndary Objectlve ls“ to determine whether clonldinereduces slde― effects and lrnproves clinica1 0utconnes due to its eiects on reductiOn Of syllpathetic

OutfloW, lrnprOVed organ perfusiOn and protection ln lschaellic reperfusion in」 ury'' Therefore, the

Secondary outcO1lnes are testing for super10rity rather than equlvalence like for the prirnary OutcOrne]

どういった中間解析をする計画か, およびその時点のリス トを含む,中 間解析に関する情報c

[(Dne fornnal statistlcal interin analysls ls planned on the prlmary endpoint for the lr vs irCs

COrnpariSOn ‐「 hlS interlrn analySiSヽ |′aS planned tO take plaCe Ⅵ′hen the Studyヽ へ′as at ieast 1 8 nnonths

intO reCruitiγ lent and at least half the nu nlber of patients required for the final analysis(as per the

Sarnple SiZe CalCulatiOn)ヽ Vere recruited(le (375 patlents)]

中間解析に伴う有意水準の調整法に関する計画.

早期試験中止のための指針の詳細.

[For the planned interirn analyses after One_thlrd and t、 ″o―thirds of the data co‖ ectlon, νveぃ′||l usea P of 000021 and 001189, respectively, to define early stopping crlteria 、/ve v′ ||l use a group

Sequentlal α―Spendlng funCt10n, CalCulated uSing the C)'Brien― Flenning method, 、vith two― sidedsyrniTletrlc bounds

O″

The Haybittle_PetO apprOach、 1′ :|l be ernployed for lnterl「 In analyses Ⅵ′ith 991 9%confldence lntervals

but irnpc)rtantly declsl()ns around trlal continuatlon v′ ||l not be‐ based On p_value al()ne

O″

Fornnal interirn analyses of the accun ulating data v輛 |l be perforrned at regular lntervals(at least

annua‖ y)fOr reVieⅥ ′by an independent Data lⅥ onitoring and safety cOnnnnittee(IDMSC)The lDMSCWill be asked to give advice on 、vhether the accurnulated data frOrn the trial, together 、vlth results

frOn1 0ther releVant trialS, juStifieS COntinulng reCruitrlnent Of further patientS Or further foHon′ ―up Adecislon lo dlscOntlnue recrultrnent, ln all patients or in selected subgrOups Ⅵ′ill be 1lnade only if

the result is likely to convince a broad range of clinicians lncludlng particlpants in the trial and the

general clinical corn13unity]

13b

13c

643

章/項 目 説明記述

√′″P力`7′

‐′″αご0′ 動″・ (業理 と治療)vol.46 no 4 2018

表 (つづき)

最終解析の時期

アウトカム言刊面の時期

14

15

最終解析の時期―

ひとまとめ, あるいは計画 された追跡期間で層別 した時期別に,解析 しようとする

すべてのアウ トカムを含める。

[Final analysis for the lr vs lrCs co11lparlson ls planned lo take place ln t、 へ′o separate stages,

hoャvever if the PFS eVent rate and medlan fo‖ ow―up of one year for the secondary endpoint of PFS

iS reaChed at the tirne of the flrst analysls(as is antlclpated), analysis will take place in one stage:

The first innain report/publication Of the trlal ,vill be prepared fOr the lr/1rcs cO mparlson ν′hen every

patlent has reached 1 2 ャveeks follow―up and data for the prlrnary endpolnt has been received and

cleaned(antlcipated to be Novernber 201 C))Longer― terrTl endpOints for the lr vs lrCs cornparison Ⅵ′ill

be analysed vvhen the required event rate of 2 73 PFSi events across the lr vs irCs arnls,and nnedian

fo‖ o■′―up of one‐ year,has been reached(anticipated belng Novennber 201 C))]

来院時期のチャー ト(「 ウィン ドウ」)を 含め,ア ウ トカムが測定 されるすべての時点。

[~「he SChedule of study procedures ls glven ln the Table 8-l The expected visit dates and vlslt

Ⅵ′indows are defined ln Table l1 3-1 ~「 he start tirne for each calculatlon is the particlpant's date

Of birth Corrected for gestational age Then additlona‖ y. 26 weeks, 52 、″eeks, 156、～′eeks and 260

ヽヽ′eeks are added to deterrnlne the expected date for 6 11lonths, 12 1‐ nonths, 3 years and 5 years

fOHOW up VISitS]

第4章 [統計学的原則]

信頼区間とP値

遵守とプロトコル逸脱

16

17

18

統計学的有意水準

[AIl applicable statistical tests will be 2-slded and will be perforl‐ ned using a 5° 3 significance level]

多重性調整のための記述およびその根拠。 もし調整する場合,第 1種の過誤をどのようにコン トロール

するかの詳細。

報告する予定の信頼区間。

[AIl confidence lntervals presented v′ ||lbe 95%and t、へ′o― sided]

19a 介入への遵守度 と, それをどのように評価するかの定義。曝露の程度についても含める。

[COrnpllanCe iS aSSeSSed based on the percent of subiects、 A′ho have taken the scheduled nunnber Of

pills it is defined as:

°o COrnplianCe:=(nunlber Of pillS taken/nul‐ nber Of pillS Supposed to haVe been taken)'10()9()

The nullber of pills supposed to have been taken Ⅵ′||l be calculated as the duratiOn Of treatrnent(end

Of Study medication一 starl of study lTledlcation ■1)rnultiplied by 4 in this study 2 pllls are taken ln

the r130rning and 2 pllls ln the evenlng]

19b 介入への遵守度 をどのように提示するかの記述っ

[The number and° 。of participants taking more than 750。 of the prescribed treatment will be

presented ln a table for i)randonllzatlon to visit 3,and il)visit 3 to visit 4 Results Ⅵ′||l be provlded by

treat ment group

Or

Descrlptive statistics on the percent connpllance(N,lnean,SD,11ledian,1linin‐ )unl,nnaxin,urn)w‖ l be

SummarlSed by randOmlSat10n grOup]

19c 試験に対するプロ トコル逸脱の定義 c

[~「 he follov′ lng are pre―defined rnaiOr prOtOCOI V101atiOnS Ⅵ′lth a direCt bearing On the prirnary outconne:

1)~「 aking Of reSCue l‐ nedlcation(10peral■]ide)during the prlrnary outcorne assessment period l e weeks

ll-1 21 of the treatment period

2)~「 aking of antibiotics during the prirnary OutcO1lne assessnlent perlod i e 、veeks ll_12 ofthe

treatrnent perlod]

19d どういったブロ トコル逸脱 を要約するかの記述。

IPrOtOCOl deVlat10nS are ClaSSlfled priOr tO unbllnding treatnnent ~「 he nunnber(and perCentage)。 f

patlentsぃ′lth ma10r and lγ linOr prOtOCOl devlations v′ ill be surnmarised by treatrnent groupぃ ′lth details

of type of deviatlon provided ~「 he patlents that are lncluded ln the l~「 T analysis data set,vill be used

as the denonlinator to calculate the percentages No formal statlstical testingヽ ぃ′||l be undertaken]

644

章/項目 番号 説明記述

″″″力″″7`lc`,′

『′?ι″(薬フ早と,台 :1京:)vol.46 ■o 4 2018

表 (つづき)

解析集団 20 解析集団の定義―

ITT(intentiOn tO treat),Per protocol,完 遂例,安全性評価集団など。

[~「he lntention_10_treat populatlon v′ ||l include all randonnlsed patients, regardless of thelr ellgibility,

according to the treatnnent they、 へ′ere randomlsed to receive

O/

A,per― prOtOCOl pOpulat10n M′ ||l be considered lf)>59そ )of the total nurnber of patlents in this cornparisOn

are rnaiOr prOtocol violators ~「 he per_prOtOcOl analysis set cOnsists Of subjects whoゃ vere randornly

asslgned to treatrnent,have both a baseline and atleast l pOst_basellne nneasurennent on the prirnary

effiCaCy Variable, haVe a rnlnirnunl eXpOsure of 36 days to the double― bllnd treatrnent regirnen, and

have no major prOtOcOl v101ations such as viOlatlons of entry crlterla, error in treatment assignnnent

and use of excluded nnedlcations

Or‐「 he safety populat10n Ⅵ′||l cOnsist of all randonnised patients in this cornparison、 へ′ho have received at

least one dose Of study treatrlnent Patlents Ⅵ′ill be analysed according lo the treatrnent they actua‖ y

reCeiVed]

第5章 [試験対象集団]

スクリーニングデータ

適格基準

組み入れ

中止・追跡

″　　　　２３

21 試験サンブルの代表性 を記述するために, スクリーニングデータ(も しあれは)を 報告する。

11~he fO‖ 。Ⅵ′lng Sunlrnariesヽ ″ill be presented for all screened patientsI

Enroll ηenti the nunlber of days recrultlng, the nurnber of patients screened, the nunnber of patlents

recruited, the nurnber of patients recruited per day, the nurnber Of SCreened patlents nOt reCruited,

and the reason for nOn_recrultrnent ‐「his sunnrnary v√ ill be provided overall and by study centre

Or

The total nunlber Of eliglble bables vvas nOt collected durlng the conduct of this study as lt 、へ′asCOnSldered heavy on resOurces and、 へ′ould nOt be suliclently rellable l

適格基準の要旨.

[~「he nunnber Of inellgible patients randorlnised,if any,v′ ||l be repOrted,Ⅵ ′lth reasOns for lneligibllity]

CONSORTフ ローチャー トに含めるべき情報。

[The `.C(DNS()RT'' diagrarγ l cO nlprislng the nurnber of peOple screened,ellgible,consented,

randomised,receiving their a‖ Ocated treatllent,withdra、 ″ing/lost to fO‖ On′ _up

O″

were:.assessed for eligibility screenlng (elig;ble at screeningj inellgible at screening-). eligible and randomised' eligible but not randomised.. received the randomised allocation. dld not receive the randomised allocation-. lost to follow-up.' discontinued the intervention.' randomised and included in the primary analysis. randomised and excluded from the primary analysis.

*reasons will be provided.l

24a 介入時や追跡時などにおける中止の程度。

[‐「he leVel of consent、 ″ithdravval Ⅵ′ill be tabulated(classified as 'consent to continue fo‖ 。Ⅵ′_up and

data collection", ``cOnsent to continue data co‖ ection OnlyⅢ , “cOrnplete ―no further fo‖ 0■′_up data

COIleCtiOn")]

24b 中止 /脱 落データの時期。

[ThlS Will be presented in CONSORT dlagranl fOrnnat rather than as a table,wlth nunlbers andreaSOnS fOr V`lthdraVVal and/Or eXCluSiOn frOnn analySiS glVen at eaCh Stage (dellVery, 6 nlonths, 1

year,2 years)]

24c 中止/脱落を提示する方法の詳細,お よびその理由。

[‐「 he nunlberS(ヽ ″lth reasons)Of 10SeS tO folloⅥ′―up(drOp-OutS andぃ ′ithdra、 vals)OVer the course of the

trlal will be summarised by treatment arnl]

“A CONSORT f10W diagran(appendix A)w‖ l be used to sumnnarlse the number of patlents whO

645

章/項目 番号| 説明記述

力″P力α7‐′″“

0′ 動′″(薬埋 と治療)vol.46 no 4 2018

表 (つづき)

ベースラインでの患者背景 25a 要約 しようとするベースラインでの患者背景の リス ト.

IPatients w‖ l be described wlth respect to age,gender,tlme since diagnosis,cancer type,perforrnance status, the nunnber Of previOus chennotheraples and presence of brain rnetastases at

baseline,both overall and separately fOr the tゃ 、′o randolT、 ised group]

25b ベースラインでの患者背景 を, どのように して記述的に要約するかの詳細.

[Categorlcal dala v′ ||l be surlnnnarlsed by nunlbers and percentages cOntinuOus data ν′||l be

sumrlnarised by nlean, SE)and range if data are norrnal and lnedian, IQR and range if data are

ske、′′ed Mlnirlnunn and r‐ naxinlurn values ぃ′||l be also be presented for continuous data Tests

of statlstical slgnlflcance v′ ill nOt be undertaken for basellne characteristlcsi rather the cllnical

i「npOrtanCe Of any lrnbalanCeい′ill be nOted]

第6章 [解析]

アウトカムの定義

解析手法

26a

26b

26c

主要および副次的アウ トカムのそれぞれについて,羅列 して記述する。それには次の詳細 を含める。

アウ トカムと時期の列挙.も しあれば,主要エン ドポイン トあるいは主な副次的エン ドポイン トの優先

順位 を含める (検定の順番など)。

測定項 目と単位 を定める (血糖コン トロールでは,hbAlc hmol/molあ るいは%])。

アウ トカムを導出するのに用いる計算式, あるいは変換 (初期値からの変化量,QOLス コア, イベン ト

までの時間,対数など).

[For the sleep OutcOrnes calculated uslng sleep diarles and actlgraphy, a nlinirnum Of 5 nights of

data fronn the 7 days before the randOrγ lisatiOn vlsil date and a rninirnurl1 0f 5 nlghts of data fro1ln day

77 1o day 84 frol・ the randonnisatlon visil date are requlred

Tlotal night‐ tillle slccp calculated using slccp diaries

The total arnount of sleep for l nightヽ vlll be calculated ln nninutes using the arnount of tlrne bet、 ′ヽeen

the tirne that the child、 へ′ent to sleep and the tirne that the child、へ′oke up the fOI10v′ ing n10rning rnlnus

any nlght― tirne a、vakenlngs that the chlld has had The basellne lnneasurernent Ⅵ′||l be calculated

uSlng the aVerage total arnount of sleep in the 7 days before randonっ lsation and the pOst‐ treatrnent

nneaSurement Will be the aVerage total arnount of sleep fronn day 77 1o day 184 pOst randolnlsatlon

(lhis corresponds to the fina1 7 days of treatrnent as patlents recelved enough drug supply only fOr

84 days)A minlrnunn of 5,nights of sleep frorln each tlnne period is requlred for the data to contribute

tO the prirnary OutCOnle lf a child has く〔5 out of 7 nighis conlpleted the data Ⅵ′||l be regarded as

miSSing and the renlaining data wlll nOi be inclじ ded ln the prlnlary analysis]

27a どういった解析手法 を用いて,治療効果 をどのように提示するか。

[The number and percentage of deaths by 90 days after randOmlsatiOn wlll be repOrted for each

treatrnent group The prlrnary‐ e■ ect estlnnate v′ ill be the relative risk of 9C)‐ day innOrtality, repOrted

、、′lth a 95% CI The abSOlute risk reduction and 95% Cl v′ ill also be reported IDeaths by 90 days

after randOnllSatiOn ν′||l be COnlpared betWeen the treatrnent groups, unadjusted, uslng the Fisher

eXaCt test]

27b 共変量の調整。

[ adiuSted fOr baSeline Varlables, M′ ||l also be cOnducted, using innultlleve1 logistic regresslon

Baseline variables adiuSted fOr ln the rnultilevel logistic regressiOn n10del 、″||l be the colnpOnents

of the Mi三[)S score(age, |‐netastatic cancer, nursing horne residence, altered l1lental status, septlc

ShOCk, resplratory di「 iculty, loぃ ′ platelet cOunt and loν ′ neutrophil count)and a site‐ level randorn

elect]

27c 統計手法で確認すべき仮定の検証方法.

[~「he PH assunlption Ⅵ′||l be checked by addlng tl「 ne― dependent covarlates and graphing scaled

SChOenfeld reSidualS against tirne(Therneau〈 & Granlbsch, 2000)lf PH is found not to fit the data

adequately, an AF~「 alternatlve will be fltted and the adequacy of its fit assessed using Q― Q plots

(Bradburn et a1 2003)]

27d 分布上の仮定 (正規性や比例ハザー ド性など)が成立 しないときに用いる,別の手法の詳細じ

[lf P卜 1 1S fOund nOt to fit the data adequately,an AFT alternatlve Ⅵ′||l be fltted and the adequacy Of

itS fit aSSeSSed uslng Q― Q plols(Bradburn et a1 2()()3)lf thls too does not fit,a residual life analysis

(Royston&Parrnar 201 1)Ⅵ√||l be used as the basis for surnrnarising the trealrlnent e■ ect]

27e もしあれば, アウ トカムごとに実施する感度解析の計画。

[A sensitivity analysis ,′ ||l be perforrned to lnclude the patients thatャ vere not included ln the prlrnary

analysis because they did not fu‖ y cOrnplete the 10ading dose and t、へ′o hour rTlaintenance perlod

They Ⅵ′||l be assunned to be not adequately sedated le AS‐ C)‐「he per― protocol analysis and

Sensitivlty analyses、″||l test the rObustness Of the prlrnary cornplete― case analysls]

646

章 /項 目 説明記述

″″P力

“′7″αCO′ 7乃′″(薬理 と治療)vo146 no.4 2018

表 (つづき)

欠測データ

追加的解析

害

統計ソフ ト

27f アウ トカムごとに実施するサフグループ解析の計画。サブグループの定義 も含める。

[The fO‖ OWing pre―speclfled subgroup analyses wlll be performed on the primary outcomes stratlied

by:

・ Vヽhether randorγ llsed ln the l st or 2nd 124 hours after birth

・geStal10nal age at birth as per llinir)■ sation:23、へ′,24、Ⅳ,25ヽ A′ ,26/27、″,23/29/30、、′

・rlnale versus fenlale

・colonised versus not colonised at 2 vveeks

・gestatlonal ageく 28■′versus≧ 28、″

Resultsぃ ′||l be presented on forest plots Ⅵ′ith the lnteraction results alongslde]

28 欠測データを処理するための仮定および統計手法 (多重補完法など),お よびその報告方法.

[ヽ4ultlple irnputation(MI)、 ″||l be used to account for partlcipants vvho have an observed outcon3e

at 6 n10nthS, but are nnlsSing the outco1lne at 1 21 1´ nonths, as ャvell as participants vvho colllpleted

SO1lne,but nOt a‖ ,of the questlons on the C)PG disability score at 1 2 1nnonths 20 irnputations will be

perfOrrned,and results vvill be col´ nblned using Rubin's Rules (Dnly participants who will be lncluded

in the analysis Ⅵ′||l be included in the irnputatiOn il10del lrnputation v′ ill be perforrned separately

ぃ′lthin each treatrnent ariΥ I The lrllputation l‐nodel wlll lnclude the three quest10ns vvhich fOrrTl the

C)PG dlsabillty score at baseline, 6 rnonths, and 12 ,1lonths, as ャvell as slte of recruitrnent, age,

gender, the 卜IAE)S depresslon score at baseline, and ernployrnent status (ennployed or ln full tirlne

eduCat10n VS nOt ennp10yed or ln full tirne education)(1 4 variables in total)ln the lntervention arnl,

multllevel irnputation vvill be perforrned,v′ lth .cOurse' included in the lrnputatlon nlodel as a randorn

efect Misslng data in any of the covarlates lo be adiusted for in the analysis(site Of recrultrrlent,

age, gender, HA[)S depression score, CPG disabillty and baseline)、 ″||l be accounted for using the

sarne nlultlple irnputatlon lllodel as above /ヽve will perfOrnn three sensitivlty analyses for the prirnary

outcorne to assess the robustness Of the results tO Other methods of account for rnlsslng data The

first sensitivity analysis involves specifying a di■ erent irllputation nlodel than that used in the prirlnary

analysis, and the last t、 A′o sensltlvlty ana:yses inv。 lve re― analyse the pril■ lary outconne using tゃ 、′。

apprOachesヽ ″hich are nol based on MI]

29 追加的な統計解析の詳細―

道守者平均に関する因果推論解析10'な

どc

I~「he dellvery of a cornplex lnterventiOn rnay irnprOve v√ ith tirne as those delivering the lntervent10n

galn experience and fanllllarity ‐「yplca‖ y,such irnprove1lnents Ⅵ′ill be llore rapld at first and then tall

Off OVer tirne tO reaCh a steady state:terrned a “learning curve'' Modelllng the learning curve enables

eStirnat10n Of the treatrnent eiect for an experience teainn A site― level learning curve for patlents

randOrllly a‖ OCated tO early, goal― directed, protocollsed resuscitalion(1三 G〔DPR)、″||l be l^node‖ ed by

repeating the rnultilevel loglstic regresslon On the prlrnary Outcorne and including a pOvver curve(aX― b)

fOr the Sequential observatlon nu ηber(X)for each EICiDF)Rl patient within each site

Or

Cor,nplier Average Causal EIect(CACE)analysls: lnstrurlnental variable regresslon Ⅵ′ill be used to

investlgate the e■ ect of colγlpliance to treatnnent dOse, assunllng llnear dose― response retatiOnship

The estlmate of lncreased Or decreased treatnnent e「 ect、vith every l% lncrease Of c01lpliance v′ |||

be preSented]

30 安全性データの要約に関する十分詳細な事項―

重症度・予測性・因果に関する情報など。有害事象は

どのようにコー ド化あるいは分類するか, どのように有害事象データを解析するか (グ レー ド3/4の み,

発生ケース解析,介入実施時に基つ く解析など)の詳細。

[~「he nunnber Of treatrnent related serious adverse events(SAE), includlng treatrrlent related deaths,

are reported dlvlded by their relat10nship as `definitely', `probably' and 'posslbly' related tO

treatrlnent l｀ he prOpOrt10nS of patlents Ⅵ′ith grade(3/4 1oxicity or SAEE will be compared descrlptlvely

across treatrnents and diferences assessed fOr clinical signlficance

The nurnber(and perCentage)of patients experlencing each AE/SAE vvlll be presented for each

treatrnent arl■ l categorlsed by severlty For each patient, only the maxlmun severity experienced of

each type of AEl ν′||l be displayed The number(and percentage)Of Occurrences Of each AE/SAE

い′||l alSO be presented for each treatnnent arrT, No forrnal statlstical testing Ⅵ′||l be undertaken]

31 解析に用いる統計ソフ トの詳細.

[~「he analySIS Ⅵ′||l be carried out using Stata version 12 C)ther packages such as R, SAS, or

REALCOM rnay be used if necessary]

647

章 /項 目 番号 説明記述

″72P力α′77,“ 0′ 乃″‐(薬理 と治療)vo1 46 no.4 2018

表 (つづき)

引用文献 32a 標準的ではない統計手法に対する引用文献.

32b データマネージメン ト計画書の引用。

32c 試験マスターファイルと統計マスターファイルの引用.

32d 他のSOP(標準業務手順書)あ るいは遵守すべき文書の引用。

a原著者から許可 を得て複写すること.

1°

' Dunn G,ヽ4aracy Iヾ1,Tomenson B Estimating treatment eiects fro11l randonnized clinlcal trlals、 vlth nonconlpllance and loss to fo‖ o、v_upi the role

Of inStrulγlental Variable rrlethods Stat卜′ethods lⅥ ed Res 2005:14(4):369-95

略言吾iC(DNSORT(Consolidated Standards Of Reportlng Trials),hbAlc(herTloglobin A l c),QOL(quality of life),SAP(statlstlcal analysis plan)

648

章/項目 説明記述