JP6307442B2 - 対象の高感度(hs−crp)のレベルを低下させる組成物および方法 - Google Patents
対象の高感度(hs−crp)のレベルを低下させる組成物および方法 Download PDFInfo
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Description
パラメータ(a)〜(y)は臨床的に許容される任意の方法論に従って測定することができる。例えば、トリグリセリド、総コレステロール、HDL−Cおよび空腹時血糖を血清由来の試料とし、標準的な測光法を用いて分析することができる。VLDL−TG、LDL−CおよびVLDL−Cは、調製用超遠心分離による血清リポタンパク質分画法、次いで屈折率測定法または分析用超遠心分離法による定量分析を用いて計算または決定することができる。Apo A1、Apo BおよびhsCRPは、標準的な比濁分析法を用いて血清から決定することができる。リポタンパク質(a)は、標準的な免疫比濁法を用いて血清から決定することができる。LDL粒子数および粒子径は、核磁気共鳴(NMR)分光法を用いて決定することができる。レムナントリポタンパク質およびLDL−ホスホリパーゼA2は、酵素による免疫分離法を用いて、それぞれEDTA血漿または血清および血清から決定することができる。酸化LDL、細胞間接着分子−1およびインターロイキン−2の値は、標準的な酵素免疫測定法を用いて血清から決定することができる。ここに挙げた手法については、標準的なテキスト、例えば、WB Saunders CompanyのTietz Fundamentals of Clinical Chemistry、第6版(Burtis、AshwoodおよびBorter編)に詳細に記載されている。
一実施形態では、血液試料採取前に最大12時間、例えば約10時間、対象に絶食させる。
1.次に挙げるコンピュータによる一連の認知機能検査に対する96%超E−EPAの効果を判定すること:
・注意課題の持続力;
・作業記憶課題の質;
・エピソード記憶の質;および
・注意課題のスピード;
2.ルーチンの臨床検査、有害事象(「AE」)モニタリングおよびバイタルサインから96%超E−EPAの安全性および忍容性を判定すること;ならびに
3.血漿および赤血球膜中の必須脂肪酸の測定によって、96%超E−EPAの認知評価項目に対する用量−効果関係の可能性を判定すること。
・治験薬の投薬規定に従う見込みがないか、従う能力がない;
・精神疾患簡易構造化面接法(「MINI」)/精神障害の診断・統計マニュアル(Diagnostic and Statistical Manual of Mental Disorders)(第4版)テキスト改訂版(「TR」)の基準に従って定められる大うつ病性障害、アルツハイマー型認知症または血管性認知症と診断される;
・次に挙げる現病歴または既往歴がある:
・認知機能に影響を及ぼす可能性のある神経障害または精神障害;
・クローン病や潰瘍性大腸炎などの炎症性消化器疾患;
・基底細胞癌以外の癌;
・12誘導ECGによって測定される臨床的に重要な心異常;
・十分に管理できない他の任意の医学的状態または併発疾患があり、試験担当者の考えでは、試験に参加すると被験者が危険に曝されるか、試験の結果に影響を及ぼすか、被験者が試験に参加する能力に影響を及ぼす可能性がある;
・対象とする母集団の正常範囲から外れ、試験担当者が被験者の試験への適性に影響を及ぼすと考える臨床的に重要なスクリーニングの結果(例えば、血液学的検査、生化学的検査)またはバイタルサインがみられる;
・ベースライン来院前4週間以内に何らかの医学的状態に対する処方薬を変えた;
・ベースライン来院前4週間以内または試験治療期間中にオメガ−3を補充した;
・現在、抗凝固薬または325mgを超える1日量のアスピリンを服用している;
・ベースライン来院前2週間以内または6週間の治療期間中にオピエートまたは抗ヒスタミン剤を含有する鎮咳薬または感冒薬を服用した;ならびに
・被験薬またはプラセボの任意の成分に対して既知のアレルギーがある。
・単語提示
・即時単語再生
・画像提示
・単純反応時間
・数字覚度(Digit Vigilance)
・選択反応時間
・空間作業記憶
・数値作業記憶
・遅延単語再生
・単語再認
・画像再認
・気分および注意力のBond−Lader視覚的アナログ尺度
・コンピュータのマウスを用いた検査。
ITT集団および試験PP解析集団についての一連のCDR認知機能検査の分析をすべて完了した。
スタチン併用療法を受けており空腹時トリグリセリド値が150mg/dl以上499mg/dl未満である患者を対象に、脂質パラメータおよび炎症パラメータに対する96%超E−EPAの効果を評価した。2型糖尿病の患者を無作為に割り付け、96%超E−EPA 2g/日、96%超E−EPA4g/日またはプラセボで12週間治療した。治療期間終了時、TG、LDL−C、非HDL−C、VLDL−C、Lp−PLA2、Apo B、TC、HDL−C、VLDL−TG、hs−CRP、oxLDLおよびRLP−Cを含めた糖尿病の複数の有効性評価項目を評価した。
空腹時トリグリセリド値が500mg/dL以上の患者におけるAMR101の有効性および安全性を評価するため、非盲検延長を加えた12週間の多施設プラセボ対照無作為化二重盲検試験を実施した。本試験の第一の目的は、空腹時TG値が500mg/dL以上、1500mg/dL以下(5.65mmol/L以上、16.94mmol/L以下)の患者の空腹時TG値低下におけるAMR101 2g/日および4g/日の有効性をプラセボと比較して判定することであった。
・AMR101 2g/日および4g/日の安全性および忍容性を判定すること;
・脂質およびアポリポタンパク質プロファイルに対するAMR101の効果を判定すること;
・低密度リポタンパク質(LDL)の粒子数および粒子径に対するAMR101の効果を判定すること;
・酸化LDLに対するAMR101の効果を判定すること;
・空腹時血漿グルコース(FPG)およびヘモグロビンA1c(HbA1c)に対するAMR101の効果を判定すること;
・インスリン抵抗性に対するAMR101の効果を判定すること;
・高感度C反応性タンパク質(hsCRP)に対するAMR101の効果を判定すること;
・赤血球膜内および血漿リン脂質内への脂肪酸取込みに対するAMR101 2g/日および4g/日の効果を判定すること;
・ベースライン空腹時TG値と空腹時TG値低下との間の関係を検討すること;ならびに
・赤血球膜中エイコサペンタエン酸(EPA)濃度の増大と空腹時TG値低下との間の関係を検討すること。
・AMR101 2g/日、
・AMR101 4g/日または
・プラセボ。
・ベースラインから第12週の評価項目までの総コレステロール(TC)、高密度リポタンパク質コレステロール(HDL−C)、計算低密度リポタンパク質コレステロール(LDL−C)、計算非高密度リポタンパク質コレステロール(非HDL−C)および超低密度リポタンパク質コレステロール(VLDL−C)の変化パーセント;
・ベースラインから第12週までの超低密度リポタンパク質TGの変化パーセント;
・ベースラインから第12週までのアポリポタンパク質A−I(apo A−I)、アポリポタンパク質B(apo B)およびapo A−I/apo B比の変化パーセント;
・ベースラインから第12週までのリポタンパク質(a)の変化パーセント(選択された施設のみ);
・核磁気共鳴で測定したLDLの粒子数および粒子径のベースラインから第12週までの変化パーセント(選択された施設のみ);
・ベースラインから第12週までのレムナント様粒子コレステロールの変化パーセント(選択された施設のみ);
・ベースラインから第12週までの酸化LDLの変化パーセント(選択された施設のみ);
・ベースラインから第12週までのFPGおよびHbA1cの変化;
・ホメオスタシスモデル評価によるインスリン抵抗性指数によって評価したインスリン抵抗性のベースラインから第12週までの変化;
・ベースラインから第12週までのリポタンパク質関連ホスホリパーゼA2の変化パーセント(選択された施設のみ);
・ベースラインから第12週までの細胞内接着分子−1の変化(選択された施設のみ);
・ベースラインから第12週までのインターロイキン−6の変化(選択された施設のみ);
・ベースラインから第12週までのプラスミノーゲン活性化因子阻害剤−1の変化(選択された施設のみ);
・ベースラインから第12週までのhsCRPの変化(選択された施設のみ);
・ベースラインから第12週までの血清リン脂質中のEPA含有量の変化;
・ベースラインから第12週までの赤血球膜中のEPA含有量の変化;ならびに
・次に挙げる脂肪酸:ドコサペンタエン酸、ドコサヘキサエン酸、アラキドン酸、パルミチン酸、ステアリン酸およびオレイン酸の血清リン脂質および赤血球膜中の含有量のベースラインから第12週までの変化。
スタチン療法を受けていても空腹時トリグリセリド値が200mg/dl以上、500mg/dl未満である患者(2つの適格化参加値の平均値が185mg/dl以上であり、かつ少なくとも一方の値が200mg/dl以上であることが必要)における96%超E−EPAの有効性および安全性を評価するため、12週間の多施設プラセボ対照無作為化二重盲検試験を実施した。本試験の第一の目的は、スタチン療法でLDL−C目標値を目指す治療を受けているが、心血管疾患のリスクが高く、空腹時TG値が200mg/dL以上、500mg/dL未満である患者の空腹時TG値低下における96%超E−EPA 2g/日および4g/日の有効性をプラセボと比較して判定することであった。
・96%超E−EPA 2g/日および4g/日の安全性および忍容性を判定すること;
・総コレステロール(TC)、非高密度リポタンパク質コレステロール(非HDL−C)、低密度リポタンパク質コレステロール(LDL−C)、高密度リポタンパク質コレステロール(HDL−C)および超高密度リポタンパク質コレステロール(VHDL−C)を含めた脂質およびアポリポタンパク質プロファイルに対する96%超E−EPAの効果を判定すること;
・ベースラインから第12週までのリポタンパク質関連ホスホリパーゼA2(Lp−PLA2)に対する96%超E−EPAの効果を判定すること;
・低密度リポタンパク質(LDL)の粒子数および粒子径に対する96%超E−EPAの効果を判定すること;
・酸化LDLに対する96%超E−EPAの効果を判定すること;
・空腹時血漿グルコース(FPG)およびヘモグロビンA1c(HbA1c)に対する96%超E−EPAの効果を判定すること;
・インスリン抵抗性に対する96%超E−EPAの効果を判定すること;
・高感度C反応性タンパク質(hsCRP)に対する96%超E−EPAの効果を判定すること;
・赤血球膜内および血漿リン脂質内への脂肪酸取込みに対する96%超E−EPA 2g/日および4g/日の効果を判定すること;
・ベースライン空腹時TG値と空腹時TG値低下との間の関係を検討すること;ならびに
・血漿中および赤血球膜中脂肪酸濃度の変化と空腹時TG値の低下との間の関係を検討すること。
・休薬が不要な患者:来院1(第−6週)にスクリーニング来院を実施した。適格患者を4週間の食事と生活習慣の安定化の期間に移行させた。スクリーニング来院時、全患者に国立コレステロール教育プログラム(National Cholesterol Education Program)(NCEP)の治療法としての生活改善(Therapeutic Lifestyle Changes)(TLC)による食事療法の重要性に関するカウンセリングを実施し、この食事療法に従う方法について基本的な指導を行った。
・休薬が必要な患者:来院1(第−8週)にスクリーニング来院を実施した。スクリーニング来院時、適格患者に6週間の休薬期間を開始させた(すなわち、最初のLDL−C/TG適格化来院前の6週間の休薬)。患者にNCEPのTLC食事療法に関するカウンセリングを実施し、この食事療法に従う方法について基本的な指導を行ったスクリーニング検査の結果から参加に適格でないと判断された患者には現地職員が連絡を取り、以前服用していた脂質を変化させる薬剤を再開するよう指示した。
・96%超E−EPA 2g/日、
・96%超E−EPA 4g/日または
・プラセボ。
・ベースラインから第12週の評価項目までの総コレステロール(TC)、高密度リポタンパク質コレステロール(HDL−C)、LDL−C、計算非HDL−Cおよび超低密度リポタンパク質コレステロール(VLDL−C)の変化パーセント;
・ベースラインから第12週までの超低密度リポタンパク質TGの変化パーセント;
・ベースラインから第12週までのアポリポタンパク質A−I(apo A−I)、アポリポタンパク質B(apo B)およびapo A−I/apo B比の変化パーセント;
・ベースラインから第12週までのリポタンパク質(a)の変化パーセント;
・核磁気共鳴で測定したLDLの粒子数および粒子径のベースラインから第12週までの変化パーセント;
・ベースラインから第12週までのレムナント様粒子コレステロールの変化パーセント;
・ベースラインから第12週までの酸化LDLの変化パーセント;
・ベースラインから第12週までのFPGおよびHbA1cの変化;
・ホメオスタシスモデル評価によるインスリン抵抗性指数によって評価したインスリン抵抗性のベースラインから第12週までの変化;
・ベースラインから第12週までのリポタンパク質関連ホスホリパーゼA2(Lp−PLA2)の変化パーセント(Lp−PLA2);
・ベースラインから第12週までの細胞内接着分子−1の変化;
・ベースラインから第12週までのインターロイキン−2の変化;
・ベースラインから第12週までのプラスミノーゲン活性化因子阻害剤−1の変化。ただし、このパラメータは適切な保管条件の整った施設でのみ収集する;
・ベースラインから第12週までのhsCRPの変化;ならびに
・EPA、ドコサペンタエン酸(DPA)、ドコサヘキサエン酸(DHA)、アラキドン酸(AA)、ジホモ−γ−リノレン酸(DGLA)、EPA/AAの比、オレイン酸/ステアリン酸(OA/SA)の比および総オメガ−6酸に対する総オメガ−3酸の比を含めたドコサペンタエン酸、ドコサヘキサエン酸、アラキドン酸、パルミチン酸、ステアリン酸およびオレイン酸の血漿中濃度および赤血球膜中含有量のベースラインから第12週までの変化。
Claims (14)
- スタチン併用療法を受けており、2型糖尿病であり、空腹時のトリグリセリド値が約150mg/dl以上約499mg/dl未満であり、かつ6.8%以上のベースラインHbA1c値を有する対象において、高感度CRP(hs−CRP)値を低下させるのに使用するための、エイコサペンタエン酸またはその薬学的に許容されるエステルを含む医薬組成物であって、該対象のhs−CRP値を低下させるのに効果的な期間、約3.5g〜約4gのエイコサペンタエン酸またはその薬学的に許容されるエステルを該対象に連日投与するように用いられる、前記医薬組成物。
- 前記スタチン併用療法が、安定なスタチン療法である、請求項1記載の医薬組成物。
- 存在する全脂肪酸の少なくとも90重量%のエイコサペンタエン酸エチルを含む、請求項1記載の医薬組成物。
- カプセルに封入されている、請求項1記載の医薬組成物。
- 前記カプセルがゼラチンを含む、請求項4記載の医薬組成物。
- 前記対象に1〜4個の前記カプセルを毎日投与する、請求項5記載の医薬組成物。
- 前記期間が約12週間であり、前記対象のhs−CRP値が、安定なスタチン療法を受けておりかつ前記医薬組成物を投与されていないプラセボ対照に比して、少なくとも約5%低下する、請求項1記載の医薬組成物。
- 前記hs−CRP値が、前記プラセボ対照に比して、少なくとも約10%減少する、請求項7記載の医薬組成物。
- 6.8%以上のベースラインHbA1c値、及び約150〜499mg/dlのベースライントリグリセリド値を有すると測定された、安定なスタチン療法を受けている対象において、高感度CRP(hs−CRP)値を低下させるのに使用するための、エイコサペンタエン酸またはその薬学的に許容されるエステルを含む医薬組成物であって、約3.5〜約4gのエイコサペンタエン酸またはその薬学的に許容されるエステルを該対象に約12週間、連日投与して、該対象のhs−CRP値をベースラインに比して減少させるように用いられる、前記医薬組成物。
- 前記医薬組成物の投与後に、少なくとも5%のhs−CRP値の減少が確認される、請求項9記載の医薬組成物。
- 前記hs−CRP値が、安定なスタチン療法を受けており、少なくとも6.8%のベースラインHbA1c値、及び約150〜499mg/dlのベースライントリグリセリド値を有し、前記医薬組成物を投与されていないプラセボ対照に比して、少なくとも5%減少する、請求項10記載の医薬組成物。
- 前記スタチンがアトルバスタチン、ロスバスタチンおよびシンバスタチンからなる群より選択される、請求項11記載の医薬組成物。
- 前記対象および前記プラセボ対照が、ナイアシン併用療法もフィブラート併用療法も受けていない、請求項12記載の医薬組成物。
- 存在する全脂肪酸の少なくとも90重量%のエイコサペンタエン酸エチルを含む、請求項9記載の医薬組成物。
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AU2018260825A1 (en) | 2018-11-22 |
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WO2013103958A1 (en) | 2013-07-11 |
JP2015503593A (ja) | 2015-02-02 |
US9827219B2 (en) | 2017-11-28 |
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