코르티코스테로이드를 사용한 현재 표준 급성 이식편대숙주병(GVHD) 1차 치료에 대한 메토트렉세이트(MTX) 추가의 효능 비교 (MTX-aGVHD)
동종 줄기세포 이식 후 급성 이식편대숙주병의 1차 치료를 위한 표준 치료 요법 단독과 코르티코스테로이드 및 저용량 메토트렉세이트(MTX)를 비교하는 이중 맹검 3상 연구에서 무작위 다기관
Phase III randomized double-blinded trial designed to compare the efficacy of the addition of MTX to current standard acute GVHD first-line treatment with corticosteroids. The protocol will use a novel endpoint for benchmarking interventions based on a composite primary endpoint of GVHD-free and corticosteroids-free survival.
The primary endpoint of the trial will be the assessment of a composite endpoint of graft-versus-host disease-free and corticosteroids-free survival at 12 months after randomization
연구 개요
상태
상태
정황
정황
개입 / 치료
개입 / 치료
상세 설명
This is a phase III randomized, multicenter, double blinded controlled study. Patients who develop clinically meaningful acute GVHD and who meet all other entry criteria will be randomized 1:1 to receive either corticosteroids and placebo ("standard of care", control arm) or the combination of low-dose MTX with corticosteroids as first-line therapy for acute GVHD (MTX; "experimental arm").
The primary analysis of this hypothesis generation study is to estimate the composite endpoint of GVHD-free and corticosteroids-free survival at 12 months after randomization in both treatment arms. In fact, it is more and more established that such composite endpoint is a clinically very relevant one because it represents ideal recovery from allo-SCT (Stem Cell transplantation) (at 1 year after acute GVHD diagnosis) and a measure of cure without ongoing morbidity.
연구 유형
연구 유형
등록 (실제)
등록
단계
단계
- 3단계
연락처 및 위치
연구 장소
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Paris, 프랑스, 75012
- Saint Antoine Hospital - Hematology Department
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참여기준
자격 기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Inclusion Criteria:
- Adults patients (>=18 years old) with hematological diseases, who develop a first episode of acute GVHD (grade II-IV) requiring systemic therapy
- First allo-SCT, with any type of donor, stem cell source, GVHD prophylaxis or conditioning regimen
- Biopsy of acute GVHD target organ is recommended, but not required. Enrollment should not be delayed awaiting biopsy or pathology results
- The patient must have received no previous systemic immune suppressive therapy for treatment of acute GVHD, except for a maximum 72 hours of prior corticosteroid therapy
- Absolute neutrophil count (ANC) greater than 0.5 G/L
- Platelets count greater than 20 G/L
- Signed informed consent
- Affiliation to a social security system (recipient or assign)
- Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception until 6 months after the end of treatment.
Men with a partner of childbearing potential must agree to use a medically acceptable method of contraception until 6 months after the end of treatment.
Exclusion Criteria:
- Hyper-acute GVHD as defined by the MD Anderson's criteria (Saliba, de Lima et al. 2007)
- Flare of GVHD in a patient already on corticosteroid treatment
- Overlap chronic GVHD as defined by the NIH Consensus Criteria (Jagasia, Greinix et al. 2015)
- MTX given within 7 days of enrollment
- Active uncontrolled infection
- Relapsed/persistent malignancy requiring rapid immune suppression withdrawal
- Acute GVHD after donor lymphocytes infusion (DLI)
- Other systemic drugs for GVHD treatment (including extra-corporeal photopheresis)
- If any prior steroid therapy (for indication other than GVHD), treatment at doses > 0.5 mg/kg/day methyl-prednisolone within 7 days prior to onset of acute GVHD
- Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study
- Patient on dialysis
- Patients with veno-occlusive disease of the liver or with significant liver abnormalities who in the judgment of the treating physician cannot receive MTX
- Patients requiring after inclusion in the protocol the continuation of one or more of the following medication: probenecide, trimethoprime (alone or in combination with sulfametoxazole), phenylbutazone or yellow fever vaccine
- Patients with a history of intolerance/allergy to MTX
- Hypersensitivity to the active substance or to any of the excipients
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 무작위
- 중재 모델: 병렬 할당
- 마스킹: 더블
팔의 수
무기와 개입
참가자 그룹 / 팔참가자 그룹 / 팔 |
개입 / 치료개입 / 치료 |
|---|---|
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실험적: Methotrexate
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Methotrexate 3 mg/m2 will be given once week for 4 weeks, then 3 mg/m2 every two weeks for 12 weeks. Body surface area will be capped at 2 m2. Methotrexate will be given as an IV infusion over 15 minutes. All patients will received prednisone 2 mg/kg.day PO (or methylprednisolone 1.6 mg/Kg/day) for 3 days. For responding patients between day 4 and 28, the dose of prednisone must be at least 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone). All patients should receive a folinic acid supplementation 24 hours after each MTX/placebo administration. Lederfoldin 10 mg po or iv will be administered on days 2, 9, 16 and 23. Lederfoldin 10 mg po or iv will be administered on days 37, 51, 65, 79, 93 and 103. |
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위약 비교기: Placebo
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Placebo 3 mg/m2 will be given once week for 4 weeks, then 3 mg/m2 every two weeks for 12 weeks. Body surface area will be capped at 2 m2. Placebo will be given as an IV infusion over 15 minutes. All patients will received prednisone 2 mg/kg.day PO (or methylprednisolone 1.6 mg/Kg/day) for 3 days. For responding patients between day 4 and 28, the dose of prednisone must be at least 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone). All patients should receive a folinic acid supplementation 24 hours after each MTX/placebo administration. Lederfoldin 10 mg po or iv will be administered on days 2, 9, 16 and 23. Lederfoldin 10 mg po or iv will be administered on days 37, 51, 65, 79, 93 and 103. |
연구는 무엇을 측정합니까?
주요 결과 측정
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization.
기간: Evaluation will be performed at time of inclusion
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GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at time of inclusion
|
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (1).
기간: Evaluation will be performed before start of MTX at the randomization.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed before start of MTX at the randomization.
|
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (2).
기간: Evaluation will be performed at Day 8
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 8
|
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (3).
기간: Evaluation will be performed at Day 15
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 15
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (4).
기간: Evaluation will be performed at Day 22
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 22
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (5).
기간: Evaluation will be performed at Day 28
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 28
|
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (6).
기간: Evaluation will be performed at Day 36
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 36
|
|
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (7).
기간: Evaluation will be performed at Day 50
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 50
|
|
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (8).
기간: Evaluation will be performed at Day 56
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 56
|
|
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (9).
기간: Evaluation will be performed at Day 64
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 64
|
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (10)
기간: Evaluation will be performed at Day 78
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 78
|
|
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (11).
기간: Evaluation will be performed at Day 92
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 92
|
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (12).
기간: Evaluation will be performed at Day 102
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 102
|
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (13).
기간: Evaluation will be performed at 5 months after randomization.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at 5 months after randomization.
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (14).
기간: Evaluation will be performed at 6 months after randomization.
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GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at 6 months after randomization.
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Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (17).
기간: Evaluation will be performed at 9 months after randomization .
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at 9 months after randomization .
|
|
Assessment of a composite endpoint of graft-versus-host disease-free at 12 months after randomization (18).
기간: Evaluation will be performed at 12 months after randomization.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at 12 months after randomization.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (19).
기간: Evaluation will be performed at time of inclusion.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at time of inclusion.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).
기간: Evaluation will be performed before start of MTX at the randomization.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed before start of MTX at the randomization.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).
기간: Evaluation will be performed at Day 8.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 8.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (20).
기간: Evaluation will be performed at Day 15.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 15.
|
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Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (21).
기간: Evaluation will be performed at Day 22.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 22.
|
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Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (22).
기간: Evaluation will be performed at Day 28.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 28.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (23).
기간: Evaluation will be performed at Day 36
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 36
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (24).
기간: Evaluation will be performed at Day 50.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 50.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (25).
기간: Evaluation will be performed at Day 56.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 56.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (26).
기간: Evaluation will be performed at Day 64.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 64.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (27).
기간: Evaluation will be performed at Day 78.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 78.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (28).
기간: Evaluation will be performed at D92.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at D92.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (29).
기간: Evaluation will be performed at Day 102.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at Day 102.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (30).
기간: Evaluation will be performed at 5 months after randomization.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at 5 months after randomization.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (31).
기간: Evaluation will be performed at 6 months after randomization.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at 6 months after randomization.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (32).
기간: Evaluation will be performed at 9 months after randomization.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at 9 months after randomization.
|
|
Assessment of a composite endpoint of corticosteroids-free survival at 12 months after randomization (33).
기간: Evaluation will be performed at 12 months after randomization.
|
GVHD-free survival is defined as absence of initiation of additional GVHD therapy or development of chronic GVHD requiring systemic therapy, and corticosteroids-free survival as absence of continuation of corticosteroids above a dose of 0.15 mg/Kg day. |
Evaluation will be performed at 12 months after randomization.
|
2차 결과 측정
2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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무작위 배정 후 첫 12개월 이내에 심각한 부작용 발생률
기간: 무작위 배정 후 12개월
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무작위 배정 후 12개월
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완전 관해(CR), 매우 우수한 부분 반응(VGPR), 부분 반응(PR), 혼합 반응(MR), 무반응(NR) 및 28일, 56일의 진행 및 처음 12개월 내 최고의 반응의 비율 무작위화 후.
기간: 28일째, 56일째 및 무작위화 후 처음 12개월 이내에 가장 좋은 반응을 보였습니다.
|
28일째, 56일째 및 무작위화 후 처음 12개월 이내에 가장 좋은 반응을 보였습니다.
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무작위화 후 처음 12개월 이내에 GVHD 플레어의 비율.
기간: 무작위 배정 후 12개월
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무작위 배정 후 12개월
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무작위 배정 후 처음 12개월 이내에 NIH 합의 기준에 의해 평가된 전체 및 중증 만성 GVHD의 누적 발생률(Jagasia, Greinix et al. 2015, Lee, Wolff et al. 2015).
기간: 무작위 배정 후 첫 12개월 이내
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무작위 배정 후 첫 12개월 이내
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무작위 배정 후 3개월 이내에 전신 감염 및 CMV(cytomegalovirus ) 재활성화 발생률
기간: 무작위 배정 후 3개월 이내
|
무작위 배정 후 3개월 이내
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무작위 배정 후 12개월 이내에 EBV(Epstein-Barr 바이러스) 재활성화 및 이식 후 림프증식성 질환의 발생률
기간: 무작위 배정 후 12개월 이내
|
무작위 배정 후 12개월 이내
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무작위 배정 후 처음 12개월 이내에 재발하지 않은 사망률의 누적 발생률.
기간: 무작위 배정 후 12개월
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무작위 배정 후 12개월
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무코르티코스테로이드, 무질병 및 무작위화 후 처음 12개월 이내에 전체 생존.
기간: 무작위 배정 후 12개월
|
무작위 배정 후 12개월
|
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면역 회복 및 미생물총: 첫 12개월 이내에 완전한 면역 회복(림프구 및 수지상 세포) 및 미생물 불균형 교정 환자 수
기간: 무작위 배정 후 12개월
|
무작위 배정 후 12개월
|
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Quality of Life (QoL)-1
기간: 12 Months
|
Evaluation by 1 questionnaire: EORTC QLQ-C30 (quality of life questionnaire) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) |
12 Months
|
|
Quality of Life (QoL)-2
기간: 12 Months
|
Evaluation by 1 questionnaire: FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant) |
12 Months
|
공동 작업자 및 조사자
수사관
수사관
- 수석 연구원: Mohamad Mohty, PU-PH, Assistance Publique - Hôpitaux de Paris
연구 기록 날짜
연구 주요 날짜
연구 시작 (실제)
연구 시작
기본 완료 (실제)
기본 완료
연구 완료 (실제)
연구 완료
연구 등록 날짜
최초 제출
최초 제출
QC 기준을 충족하는 최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
처음 게시됨
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
마지막 업데이트 게시됨
QC 기준을 충족하는 마지막 업데이트 제출
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
기타 연구 ID 번호
- PHRC-K 16-150
- 2017 (미국 NIH 보조금/계약)
- 2017-002691-98 (EudraCT 번호)
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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