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ウパダシチニブについて、米国FDAより6番目の承認を取得


2022年11月10日
アッヴィ合同会社

ウパダシチニブについて、米国FDAより6番目の承認を取得
ー ウパダシチニブは、活動性のX線基準を満たさない体軸性脊椎関節炎(nr-axSpA)の成人患者さんの経口治療薬として承認された最初かつ唯一のヤヌスキナーゼ(JAK)阻害薬
ー ウパダシチニブは、活動性の強直性脊椎炎(AS)およびnr-axSpAの両疾患における治療薬として承認された最初かつ唯一のJAK阻害薬1-3
ー 臨床試験において、プラセボ群と比較して、ウパダシチニブ群の患者さんはASAS40達成に基づく迅速かつ有意な疾患コントロールを示し、14週時にnr-axSpAの徴候と症状の有意な改善も示した1,2

イリノイ州ノースシカゴ、2022年10月21日(米国時間)-アッヴィ(NYSE: ABBV)は本日、米国食品医薬品局(FDA)が、客観的な炎症の徴候が認められ、腫瘍壊死因子(TNF)阻害薬で効果不十分または不耐容であった活動性のX線基準を満たさない体軸性脊椎関節炎(nr-axSpA)の成人患者さんの経口治療薬として、ウパダシチニブ(15 mg、1日1回投与)を承認したことを発表しました。本承認は、本年4月にFDAが1剤以上のTNF阻害薬で効果不十分または不耐容であった活動性強直性脊椎炎(AS)の成人患者さんの治療薬として、ウパダシチニブの承認を取得したことに次ぐ適応追加承認取得となります。本承認により、ウパダシチニブは両疾患の治療薬として承認された最初かつ唯一のヤヌスキナーゼ(JAK)阻害薬となりました1。

双方向型マルチメディア・プレスリリースはhttps://www.multivu.com/players/English/9092951-abbvie-fda-active-non-radiographic-axial-spondyloarthritis/をご覧ください。(英語)

nr-axSpAは、関節の炎症や背部痛およびこわばりを引き起こす慢性進行性の炎症性リウマチ疾患で、X線検査では検出できません5,6。nr-axSpAおよびASは、体軸性脊椎関節炎と呼ばれる、より広い疾患概念にて構成される2つのサブタイプです。nr-axSpA患者さんの約5%は5年後に、また約19%は10年後にASへ進行するというデータもあります7。

アッヴィのsenior vice president, research and development 兼 chief scientific officerであるThomas Hudson, M.D.は、次のように述べています。「今回のFDAによる活動性nr-axSpAに対するウパダシチニブの承認は、この痛みを伴う慢性疾患における治療選択肢が限られていた患者さんにとって、1日1回投与の経口治療薬という新たな治療選択肢となります。現在、ウパダシチニブは、体軸性脊椎関節炎のスペクトラムに対する治療薬として承認されています。アッヴィは、患者さんの標準治療を進展させるべく、取り組んでいます。」

FDAによる本承認は、活動性nr-axSpAの成人患者さんを対象にウパダシチニブの有効性、安全性および忍容性を評価した第III相SELECT-AXIS 2試験の結果に基づいています。プラセボ群と比較し、ウパダシチニブ15 mg群で約半数の患者さんが、14週時に主要評価項目であるASAS40*を達成しました(ウパダシチニブ群44.9%対プラセボ群22.3%)1,2。ウパダシチニブを投与したnr-axSpAの患者さんにおいて、2週時と早期にASAS40改善が認められました。ウパダシチニブ15 mgを投与したnr-axSpAの患者さんにおける安全性プロファイルは、関節リウマチ、関節症性乾癬(乾癬性関節炎)およびASの患者さんで確認された安全性プロファイルと一致していました1。

オレゴン健康科学大学の関節炎・リウマチ性疾患科リウマチクリニック 医学部教授兼内科部長(Professor of medicine and medical director of the Rheumatology Clinics for the Division of Arthritis and Rheumatic Diseases at Oregon Health &Science University)であり、SELECT-AXIS 2(nr-axSpA)試験の治験責任医師を務めたAtul Deodhar, M.D.は次のように述べています。「現在の治療法では症状が持続し、疾患コントロールが得られていないnr-axSpA患者さんは少なくありません。SELECT-AXIS 2試験で、ウパダシチニブはnr-axSpAとASの双方に対する有効性を示し、いずれの疾患でも一貫した安全性を示しました。FDAによる本承認によって、患者さんや介助者の方に対し症状や疾患コントロールの一助となる重要かつ新たな治療選択肢が提供されました」

米国脊椎炎協会(Spondylitis Association of America)CEOのCassie Shaferは次のように述べています。「nr-axSpA患者さんは、治療選択肢が限られています。この疾患は、治療を行っていても症状が持続するため、患者さんに多くの困難をもたらすとともに、生活の質にも大きな影響を及ぼし得ると思われます。今回のウパダシチニブの承認は、当協会の対象患者さんにとって、治療目標達成の一助となり、安心を与えてくれる新たな選択肢へとつながる非常に大きな前進といえます」

今回のFDAによるウパダシチニブ承認は、米国において4つのリウマチ性疾患を含む慢性免疫介在性疾患で6番目の適応となります1。

試験結果の詳細は以下の通りです。

14週時におけるnr-axSpAの徴候および症状の改善1,2
SELECT-AXIS 2 nr-axSpA試験では、プラセボ群と比較して、ウパダシチニブ15 mg群において、14週時にASAS複合指標の各評価項目である全般背部痛、患者さんによる疾患活動性の全般評価、朝のこわばりおよび身体機能に有意な改善が認められました。多重性を調整した評価項目は、全背部痛およびASの身体機能障害の指標(BASFI)としました。

・全般背部痛のベースラインからの平均減少量(ベースラインからの変化量-2.91)がプラセボ群(-2.00)と比較して有意に大きい2。
・BASFIのベースラインからの平均変化量で評価した身体機能(ベースラインからの変化量-2.61)がプラセボ群(-1.47)と比較して有意に改善2。

*ASAS40は、疾患活動性を評価する複合指標です2。ASAS40達成は、患者さんの疾患活動性が全般背部痛、患者さんによる疾患活動性の全般評価、身体機能、朝のこわばりの4つの評価項目のうち3項目以上で40%以上改善かつ2単位(0~10のスケール)以上改善し、残りの項目で全く悪化が見られない場合と定義2。

その他の健康関連アウトカム
プラセボ群と比較して、ウパダシチニブ15 mg群の患者さんで、14週時にASの生活の質スコアによって評価する健康関連の生活の質に大きな改善が認められました。

SELECT-AXIS 2試験のプログラムについて4
SELECT-AXIS 2試験は、マスタープロトコールに基づいて実施され、無作為化、データ収集、解析および報告を別々に実施する独立した2つの試験で構成されます。この第III相、無作為化、プラセボ対照、二重盲検試験では、生物学的疾患修飾性抗リウマチ薬で効果不十分であったAS(試験 1)およびnr-axSpA(試験 2)といった活動性体軸性脊椎関節炎(axSpA)の成人患者さんを対象として徴候および症状の軽減に対するウパダシチニブの有効性および安全性をプラセボと比較して評価しています。この試験に関する詳細はhttps://www.clinicaltrials.gov/(NCT04169373)に掲載されています。

本試験の主要評価項目は、プラセボ群と比較し、14週間のウパダシチニブ投与後にASAS40を達成した患者さんの割合としました。

ウパダシチニブについて
アッヴィの科学者が発見し、開発したウパダシチニブは、複数の免疫介在性炎症性疾患を対象に研究が進められている選択的なJAK阻害薬です。酵素および細胞アッセイにおいて、ウパダシチニブはJAK-2、JAK-3およびTYK-2と比較してJAK-1に対しより強い阻害能力を示しました1。特定のJAK酵素の阻害が、治療効果および安全性との関連性は現時点では明らかとなっていません。
関節リウマチ、アトピー性皮膚炎、関節症性乾癬(乾癬性関節炎)、体軸性脊椎関節炎、クローン病、潰瘍性大腸炎、巨細胞性動脈炎および高安動脈炎を対象とするウパダシチニブの第III相試験が進行中です4,8-14。

リウマチ領域におけるアッヴィについて
アッヴィは20年以上にわたり、リウマチ性疾患とともに生きる患者さんの治療の向上に取り組んできました。革新的な治療を発見し、提供するという当社の長年の取り組みに基づき、より多くのリウマチ性疾患の患者さんを治療目標達成に導く、有望な新たな経路や標的への理解を深める最先端科学を追求していきます。詳細についてはAbbVie in rheumatologyをご覧ください。

アッヴィについて
アッヴィのミッションは現在の深刻な健康課題を解決する革新的な医薬品の創製と提供、そして未来に向けて医療上の困難な課題に挑むことです。患者さん一人ひとりの人生を豊かなものにするため次の主要領域に取り組んでいます。免疫疾患、がん、精神・神経疾患、アイケア、ウイルス、ウイメンズヘルス、さらにアラガンエステティクスポートフォリオの製品・サービスです。アッヴィの詳細については、www.abbvie.com をご覧ください。Twitterアカウント@abbvieFacebookLinkedInInstagramでも情報を公開しています。

References:
1.RINVOQ(R)(upadacitinib) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
2.Deodhar A, Van den Bosch F, Poddubnyy D, et al. U Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2022;400:369–79. doi:10.1016/S0140-6736(22)01212-0.
3.van der Heijde D, Baraliakos X, Sieper J, et al. Efficacy and safety of upadacitinib for active ankylosing spondylitis refractory to biological therapy: a double-blind, randomized, placebo-controlled phase 3 trial. Ann Rheum Dis. 2022;0:1–9. doi:10.1136/annrheumdis-2022-222608.
4.A Study to Evaluate Efficacy and Safety of Upadacitinib in Adult Participants With Axial Spondyloarthritis (SELECT AXIS 2). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT04169373.  Accessed October 21, 2022.
5.Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet 2017;390: 73–84.
6.Deodhar AA, Understanding Axial Spondyloarthritis: A Primer for Managed Care. Am J Manag Care. 2019;25:S319-S330.
7.Wang R, Ward MM. Epidemiology of axial spondyloarthritis: an update. Curr Opin Rheumatol. 2018 Mar;30(2):137-143. doi: 10.1097/BOR.0000000000000475. PMID: 29227352;PMCID: PMC5811203.
8.A study comparing upadacitinib (ABT-494) to placebo and to adalimumab in adults with rheumatoid arthritis who are on a stable dose of methotrexate and who have an inadequate response to methotrexate (SELECT-COMPARE). ClinicalTrials.gov identifier: NCT02629159.
Accessed October 21, 2022. https://www.clinicaltrials.gov/ct2/show/NCT02629159 
9.A Study to Evaluate the Safety and Efficacy of ABT-494 for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis. ClinicalTrials.gov.
Available at: https://clinicaltrials.gov/ct2/show/NCT02819635. Accessed on October 21, 2022.
10.A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of ABT-494 for the Induction of Symptomatic and Endoscopic Remission in Subjects With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Immunomodulators or Anti-TNF Therapy. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02365649. Accessed on October 21, 2022.
 11.A Study to Evaluate the Safety and Efficacy of Upadacitinib in Participants With Giant Cell Arteritis (SELECT-GCA). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03725202. Accessed: October 21, 2022.
 12.A Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Participants With Psoriatic Arthritis Who Have an Inadequate Response to at Least One Non-Biologic Disease Modifying Anti-Rheumatic Drug (SELECT - PsA 1). ClinicalTrials.gov.
Available at: https://clinicaltrials.gov/ct2/show/NCT03104400. Accessed on October 21, 2022.
 13.A Study to Compare Safety and Efficacy of Upadacitinib to Dupilumab in Adult Participants With Moderate to Severe Atopic Dermatitis (Heads Up). ClinicalTrials.gov.
Available at: https://clinicaltrials.gov/ct2/show/NCT03738397. Accessed: October 21, 2022.
 14.A Study to Evaluate the Efficacy and Safety of Upadacitinib in Subjects With Takayasu Arteritis (SELECT-TAK). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/record/NCT04161898. Accessed: October 21, 2022.

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      Function: callBlock

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
      Line: 184
      Function: callBlock

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
      Line: 186
      Function: process

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
      Line: 156
      Function: process

      File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/fbdaa42e51518f8881faeabdc1199f6dd175d1ce_0.file.base_index_layout.tpl.php
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      Function: instanceBlock

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      Function: content_66f26b3cb92fa0_94546305

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
      Line: 114
      Function: getRenderedTemplateCode

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
      Line: 217
      Function: render

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
      Line: 386
      Function: render

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
      Line: 116
      Function: _subTemplateRender

      File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/597cefa22c7600eaa32b117569a9685c70819274_0.file.show.tpl.php
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      Function: endChild

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
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      Function: content_675a781dcbf339_49719938

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
      Line: 114
      Function: getRenderedTemplateCode

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
      Line: 217
      Function: render

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_templatebase.php
      Line: 238
      Function: render

      File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_templatebase.php
      Line: 116
      Function: _execute

      File: /www/wwwroot/homev2.kingsoft.jp/application/libraries/SmartyLibrary.php
      Line: 45
      Function: fetch

      File: /www/wwwroot/homev2.kingsoft.jp/application/controllers/ArticleController.php
      Line: 32
      Function: view

      File: /www/wwwroot/homev2.kingsoft.jp/public/index.php
      Line: 292
      Function: require_once

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    Line Number: 29

    Backtrace:

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/49292b3df7e5bd60f7381ff16c5ca4532cf9476f_0.file.card.tpl.php
    Line: 29
    Function: _error_handler

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3d136f97_11902452

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 384
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/08d1cc69876d91563afb9c1f4d21cc8b7b96caa4_0.file.tips.tpl.php
    Line: 41
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3d14aa11_83151422

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/d064ec4523cd2f49c67136b7b84705846d19c90b_0.file.side.tpl.php
    Line: 43
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b47775ef5_14228348

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/597cefa22c7600eaa32b117569a9685c70819274_0.file.show.tpl.php
    Line: 416
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 248
    Function: callBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 184
    Function: callBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 186
    Function: process

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 156
    Function: process

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/fbdaa42e51518f8881faeabdc1199f6dd175d1ce_0.file.base_index_layout.tpl.php
    Line: 88
    Function: instanceBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3cb92fa0_94546305

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 116
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/597cefa22c7600eaa32b117569a9685c70819274_0.file.show.tpl.php
    Line: 71
    Function: endChild

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_675a781dcbf339_49719938

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_templatebase.php
    Line: 238
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_templatebase.php
    Line: 116
    Function: _execute

    File: /www/wwwroot/homev2.kingsoft.jp/application/libraries/SmartyLibrary.php
    Line: 45
    Function: fetch

    File: /www/wwwroot/homev2.kingsoft.jp/application/controllers/ArticleController.php
    Line: 32
    Function: view

    File: /www/wwwroot/homev2.kingsoft.jp/public/index.php
    Line: 292
    Function: require_once

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    Severity: Notice

    Message: Undefined offset: 1

    Filename: smarty/08d1cc69876d91563afb9c1f4d21cc8b7b96caa4_0.file.tips.tpl.php

    Line Number: 41

    Backtrace:

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/08d1cc69876d91563afb9c1f4d21cc8b7b96caa4_0.file.tips.tpl.php
    Line: 41
    Function: _error_handler

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3d14aa11_83151422

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/d064ec4523cd2f49c67136b7b84705846d19c90b_0.file.side.tpl.php
    Line: 43
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b47775ef5_14228348

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/597cefa22c7600eaa32b117569a9685c70819274_0.file.show.tpl.php
    Line: 416
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 248
    Function: callBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 184
    Function: callBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 186
    Function: process

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 156
    Function: process

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/fbdaa42e51518f8881faeabdc1199f6dd175d1ce_0.file.base_index_layout.tpl.php
    Line: 88
    Function: instanceBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3cb92fa0_94546305

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 116
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/597cefa22c7600eaa32b117569a9685c70819274_0.file.show.tpl.php
    Line: 71
    Function: endChild

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_675a781dcbf339_49719938

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_templatebase.php
    Line: 238
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_templatebase.php
    Line: 116
    Function: _execute

    File: /www/wwwroot/homev2.kingsoft.jp/application/libraries/SmartyLibrary.php
    Line: 45
    Function: fetch

    File: /www/wwwroot/homev2.kingsoft.jp/application/controllers/ArticleController.php
    Line: 32
    Function: view

    File: /www/wwwroot/homev2.kingsoft.jp/public/index.php
    Line: 292
    Function: require_once

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    Severity: Notice

    Message: Trying to access array offset on value of type null

    Filename: smarty/49292b3df7e5bd60f7381ff16c5ca4532cf9476f_0.file.card.tpl.php

    Line Number: 24

    Backtrace:

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/49292b3df7e5bd60f7381ff16c5ca4532cf9476f_0.file.card.tpl.php
    Line: 24
    Function: _error_handler

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3d136f97_11902452

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 384
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/08d1cc69876d91563afb9c1f4d21cc8b7b96caa4_0.file.tips.tpl.php
    Line: 41
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3d14aa11_83151422

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/d064ec4523cd2f49c67136b7b84705846d19c90b_0.file.side.tpl.php
    Line: 43
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b47775ef5_14228348

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/597cefa22c7600eaa32b117569a9685c70819274_0.file.show.tpl.php
    Line: 416
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 248
    Function: callBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 184
    Function: callBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 186
    Function: process

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 156
    Function: process

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/fbdaa42e51518f8881faeabdc1199f6dd175d1ce_0.file.base_index_layout.tpl.php
    Line: 88
    Function: instanceBlock

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3cb92fa0_94546305

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_runtime_inheritance.php
    Line: 116
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/597cefa22c7600eaa32b117569a9685c70819274_0.file.show.tpl.php
    Line: 71
    Function: endChild

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_675a781dcbf339_49719938

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_templatebase.php
    Line: 238
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_templatebase.php
    Line: 116
    Function: _execute

    File: /www/wwwroot/homev2.kingsoft.jp/application/libraries/SmartyLibrary.php
    Line: 45
    Function: fetch

    File: /www/wwwroot/homev2.kingsoft.jp/application/controllers/ArticleController.php
    Line: 32
    Function: view

    File: /www/wwwroot/homev2.kingsoft.jp/public/index.php
    Line: 292
    Function: require_once

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    Severity: Notice

    Message: Trying to access array offset on value of type null

    Filename: smarty/49292b3df7e5bd60f7381ff16c5ca4532cf9476f_0.file.card.tpl.php

    Line Number: 29

    Backtrace:

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/49292b3df7e5bd60f7381ff16c5ca4532cf9476f_0.file.card.tpl.php
    Line: 29
    Function: _error_handler

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3d136f97_11902452

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 384
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/08d1cc69876d91563afb9c1f4d21cc8b7b96caa4_0.file.tips.tpl.php
    Line: 41
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
    Line: 123
    Function: content_66f26b3d14aa11_83151422

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_compiled.php
    Line: 114
    Function: getRenderedTemplateCode

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 217
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_internal_template.php
    Line: 386
    Function: render

    File: /www/wwwroot/homev2.kingsoft.jp/application/cache/smarty/d064ec4523cd2f49c67136b7b84705846d19c90b_0.file.side.tpl.php
    Line: 43
    Function: _subTemplateRender

    File: /www/wwwroot/homev2.kingsoft.jp/application/third_party/smarty/libs/sysplugins/smarty_template_resource_base.php
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