多発血管炎を伴う好酸球性肉芽腫症（E-merge）患者における従来の治療戦略と比較したメポリズマブベースのレジメンの研究 (E-merge)
多発血管炎を伴う好酸球性肉芽腫症患者における寛解導入のための従来の治療戦略と比較したメポリズマブベースのレジメンの評価。前向き無作為対照二重盲検試験
The purpose of this study is to compare mepolizumab-based regimen to conventional therapeutic strategy for remission induction in patients with Eosinophilic Granulomatosis with Polyangiitis.
調査の概要
詳細な説明
Eosinophilic granulomatosis with polyangiitis (EGPA), formerly called Churg-Strauss syndrome, is a rare systemic small-vessel vasculitis, associated with asthma and blood and tissue eosinophilia. EGPA belongs to the group of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), and commonly involves upper and lower respiratory tracts, the lungs, the peripheral nerve and the heart.
Therapeutic management is based on glucocorticoids alone or in combination with conventional immunosuppressive agents, mainly azathioprine, methotrexate or cyclophosphamide, according to disease severity assessed by the Five Factor Score.
Such treatments, in addition to their common side effects, are frequently insufficiently effective to control chronic asthma and/or rhinosinusitis, requiring long-term high-dose corticosteroids. Because EGPA shares common pathophysiological features with eosinophilic disorders and asthma, new therapeutic options used in these conditions could be of interest, in particular mepolizumab, a monoclonal anti-interleukin (IL)-5 antibody, which has shown promising results in two small preliminary studies to control disease activity and decrease glucocorticoids in cortico-dependant patients. In addition, mepolizumab has been recently evaluated in a prospective trial, the MIRRA trial, targeting a small niche of patients, i.e. those with corticodependent asthma unable to achieve disease control with low dose of glucocorticoids. Results published revealed that mepolizumab led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001).
However, these studies did not evaluate the interest of mepolizumab during EGPA flare associating asthma, eosinophilic and vasculitis lesions, in order to induce remission of the disease and rapidly decrease and discontinue glucocorticoids.
Also, recent pathophysiological date strongly support in addition to previous therapeutic studies the major interest to target IL-5 as soon as EGPA is diagnosed: 1) genetic association studies demonstrated that polymorphisms in the IL-5 pathway are associated with EGPA in comparison with controls, 2) increased expression of IL-5 in mice model are able to induce vasculitis lesions as observed in the human diseases.
Patients will receive a standardized glucocorticoid tapering schedule. From day 28 post-baseline onwards, if the subject's BVAS=0 their oral prednisone dose should be tapered downwards. A standardized glucocorticoid tapering schedule provided in the protocol enables a reduction in oral prednisone dose every 2 weeks, with the intention of achieving a prednisone dose of 4 mg/day or less. Once a subject has achieved a dose of 4 mg/day prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 1.0 mg every week.
Upwards dose adjustments within the 0-4.0 mg range are permitted without necessarily being considered a relapse.
研究の種類
入学 (実際)
段階
- フェーズ 3
連絡先と場所
研究場所
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Paris、フランス、75014
- Service de Médecine Interne, Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques "Hôpital Cochin
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Patients with a diagnosis of EGPA independently of ANCA status,
- Patients aged of 18 years or older,
- Patients with newly-diagnosed disease or relapsing disease at the time of screening, with an active disease defined as a Birmingham Vasculitis Activity Score (BVAS) ≥3,
- Patients within the first 21 days following initiation/increase of corticosteroids at a dose ≤ 1 mg/kg/day (pulses of methylprednisolone before oral corticosteroid therapy are authorized)
- Patients having given their written informed consent prior to participation in the study.
- Patients affiliated with social security or CMU (profit or being entitled)
Exclusion Criteria:
- Patients with GPA, MPA, or other vasculitis, defined by the ACR criteria and/or the Chapel Hill Consensus Conference,
- Patients with vasculitis in remission of the disease defined as a BVAS <3
- Patients with severe cardiac failure defined as class IV in New York Heart Association
- Patients with acute infections or chronic active infections (including HIV, HBV or HCV and checked in the last 12 months),
- Patients with active cancer or recent cancer (<5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment,
- Pregnant women and lactation. Patients with childbearing potential should have reliable contraception for the 12 months duration of the study,
- Patients with EGPA who have already been treated with mepolizumab within the previous 12 months,
- Patients with hypersensitivity to a monoclonal antibody or biologic agent,
- Patients with contraindication to use mepolizumab, cyclophosphamide, mesna, azathioprine or maintenance therapy used for vasculitis,
- Patients with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol,
- Patients included in other investigational therapeutic study within the previous 3 months,
- Patients suspected not to be observant to the proposed treatments,
- Patients who have white blood cell count ≤4,000/mm3,
- Patients who have platelet count ≤100,000/mm3,
- Patients who have ALT or AST level greater that 3 times the upper limit of normal that cannot be attributed to underlying EGPA disease,
- Patients unable to give written informed consent prior to participation in the study
- Patients under tutorship or curatorship and protected adults.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：Patients with FFS=0 - Mepolizumab
Mepolizumab 300mg every 4 weeks until D336 |
300 mg/month subcutaneous |
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プラセボコンパレーター：Patients with FFS=0 - Placebo
Placebo of Mepolizumab every 4 weeks until D336 |
Patients with FFS=0 will receive placebo |
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実験的：Patients with FFS≥1 - Mepolizumab
Mepolizumab 300mg every 4 weeks until D336 and placebo of Azathioprine 1mg/kg/day from D126 until D360 and placebo of cyclophosphamide/mesna at D1, D15, D28, D56, D84 and D112 |
300 mg/month subcutaneous Patients with FFS=0 will receive placebo |
|
プラセボコンパレーター：Patients with FFS≥1 - Placebo
Placebo of Mepolizumab every 4 weeks until D336, cyclophosphamide and mesna at D1, D15, D28, D56, D84 and D112 and Azathioprine 1mg/kg/day from D126 until D360 |
Patients with FFS=0 will receive placebo Patients with FFS≥1 will receive cyclophosphamide then azathioprine |
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Percentage of patients who achieved a prednisone dose of 4.0 mg or less per day at day 168, without experiencing a relapse
時間枠：Day 168
|
EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterized by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms; OR c) active nasal and/or sinus disease, warranting: i) an increased dose of prednisone compared to previous dosage and at least >4 mg/day prednisone total daily dose or equivalent; OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards |
Day 168
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
168日目と364日目のプレドニゾン投与量
時間枠：168日目と364日目
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168日目と364日目
|
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|
168 日目と 364 日目のコルチコステロイドの曲線下面積
時間枠：168日目と364日目
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168日目と364日目
|
|
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プレドニゾンを 1 日あたり 4.0 mg 以下の用量で 0 週間使用した参加者の割合
時間枠：168日目と364日目
|
168日目と364日目
|
|
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プレドニゾンを 1 日 4.0 mg 以下の用量で 0 週間以上 4 週間未満使用した参加者の割合
時間枠：168日目と364日目
|
168日目と364日目
|
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プレドニゾンを 1 日あたり 4.0 mg 以下の用量で 4 週間以上 12 週間未満使用した参加者の割合
時間枠：168日目と364日目
|
168日目と364日目
|
|
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プレドニゾンを 1 日あたり 4.0 mg 以下の用量で少なくとも 12 週間使用した参加者の割合
時間枠：168日目と364日目
|
168日目と364日目
|
|
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168日目と364日目の両方でプレドニゾンの用量が1日あたり4.0mg以下の参加者の割合。
時間枠：364日目
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364日目
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包含から最初の再発までの時間
時間枠：364日目
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364日目
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血管炎損傷指数 (VDI)
時間枠：168日目と364日目
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168日目と364日目
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HAQアンケート
時間枠：168日目と364日目
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168日目と364日目
|
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SF-36アンケート
時間枠：168日目と364日目
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168日目と364日目
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ANCA 力価の変化 (UI/mL) およびフォローアップ中の臨床イベントとの相関
時間枠：364日目
|
364日目
|
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好酸球の進化 (x10^9/L) とフォローアップ中の臨床イベントとの相関
時間枠：364日目
|
364日目
|
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Proportion of participants experiencing a relapse
時間枠：Day 364
|
EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterized by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms; OR c) active nasal and/or sinus disease, warranting: i) an increased dose of prednisone compared to previous dosage and at least >4 mg/day prednisone total daily dose or equivalent; OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards |
Day 364
|
|
Number of relapse during the study period
時間枠：Day 364
|
EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterized by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms; OR c) active nasal and/or sinus disease, warranting: i) an increased dose of prednisone compared to previous dosage and at least >4 mg/day prednisone total daily dose or equivalent; OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards. |
Day 364
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|
Number of adverse events that result in the cessation of further injections
時間枠：Day 364
|
Number of adverse events is expressed as adverse events according to the CTCAE toxicity grading system per patient-year at days 168 and 364 for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hemorraghic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, injection reactions (within 24 hours of injection). |
Day 364
|
協力者と研究者
捜査官
- スタディディレクター：Loic GUILLEVIN, MD, PhD、Assistance Publique - Hôpitaux de Paris
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
- 血管疾患
- 心血管疾患
- 自己免疫疾患
- 免疫系疾患
- 皮膚疾患
- リンパ疾患
- リンパ増殖性疾患
- 皮膚疾患、血管
- 血管炎
- 抗好中球細胞質抗体関連血管炎
- 肉芽腫
- 全身性血管炎
- 皮膚および結合組織疾患
- ヘミックおよびリンパ疾患
- チャーグ・ストラウス症候群
- 硫黄化合物
- 有機化学物質
- 複素環化化合物
- 複素環化化合物、2リング
- 複素環化化合物、融合リング
- 核酸、ヌクレオチド、およびヌクレオシド
- 炭化水素
- プリン
- ホスホルアミドマスタード
- 窒素マスタード化合物
- マスタード化合物
- 炭化水素、ハロゲン化
- ホスホラミド
- 有機リン化合物
- ヌクレオシド
- チオヌクレオシド
- メルカプトプリン
- シクロホスファミド
- アザチオプリン
- メポリズマブ
その他の研究ID番号
- D20180135
- 2020-003318-10 (EudraCT番号)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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