탈감작을 위한 Carfilzomib 및 Belatacept (ADAPT)
예비 신장 이식 수혜자의 동종 탈감작에 대한 카르필조밉 및 벨라타셉트의 영향 측정(ITN089ST)
Some kidney transplant candidates have a very low chance of getting a kidney transplant because their immune systems are "highly sensitized" to most kidney donors. Being "highly sensitized" means that they will likely have to wait a long time (more than 5 years) before an acceptable donor is found for them or, they never receive a compatible donor, and die while on the kidney transplant waitlist.
The purpose of this study is to find out whether two drugs, carfilzomib (Kyprolis®),and belatacept (Nulojix®), can make these kidney transplant candidates less sensitized, and make it easier and quicker to find a kidney donor for them.
연구 개요
상태
상세 설명
This study enrolled 21 eligible participants, 18 to 65 years of age, with end stage renal failure on dialysis who are on the waiting list for a deceased donor transplant with calculated panel reactive antibodies (cPRA) ≥99.9% or >98% (with >5 years of waiting time) or, those with cPRA >98% and an human leukocyte antigen (HLA)-incompatible approved living donor who have not received a transplant after 1 year in a paired kidney exchange program. The study will evaluate whether the study treatment is safe and can lower the participant's immune system's sensitization to kidney donors, making it easier to find a well-matched kidney for them.
Participants in the study were enrolled in two consecutive Cohorts. The total duration of participation in the study will be 76 weeks for Cohort 1 and 68 weeks for Cohort 2. Participants who undergo kidney transplantation while enrolled in the study will have 52 weeks of follow up post-transplant.
The duration of participation for living donors is one study visit. Their participation in the study ends upon completion of this study visit.
연구 유형
등록 (실제)
단계
- 2 단계
- 1단계
연락처 및 위치
연구 장소
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North Carolina
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Durham, North Carolina, 미국, 27710
- Duke Transplant Center, Duke University Medical Center
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Inclusion Criteria:
Individuals who meet all of the following criteria are eligible for enrollment as study subjects-
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Subject must be able to understand and provide informed consent
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End stage renal disease (ESRD) on dialysis
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United Network for Organ Sharing (UNOS) listed for a kidney transplant with any one of the following:
- Current calculated panel reactive antibodies (cPRA) ≥ 99.9 percent awaiting deceased donor transplant
- Current cPRA >98 percent (with >5 years of waiting time) awaiting deceased donor transplant
- Current cPRA >98 percent with Human Leukocyte Antigen (HLA)-incompatible approved living donor and has not received a transplant after 1 year in a kidney paired exchange program
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Evidence of established immunity to Epstein-Barr virus (EBV) as demonstrated by serologic testing
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Negative result of most recent tuberculosis (TB) testing or appropriately completed latent tuberculosis infection (LTBI) therapy.
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Testing should be conducted using either a purified protein derivative (PPD) or interferon-gamma release assay (i.e. QuantiFERON-TB, T-SPOT.TB).
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Negative results from tests performed within 12 months prior to study entry are acceptable in the absence of any intervening exposure to TB.
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Subjects with a positive test result must have completed appropriate therapy for LTBI.
- Note: LTBI treatment regimens should be among those endorsed by the Centers for Disease Control and Prevention (CDC), url: https://www.cdc.gov/tb/topic/treatment/ltbi.htm
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Negative Food and Drug Administration (FDA)-approved test for human immunodeficiency virus (HIV) diagnosis (at screening or as documented in medical record, up to 6 months prior to screening)
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Negative Hepatitis C antibody test at screening or as documented in medical record, up to 6 months prior to screening.
--If there is a history of treated hepatitis C then documentation of two consecutive negative HCV quantitative ribonucleic acid (RNA) polymerase chain reaction (PCR) tests separated by at least 6 months is required. Untreated subjects with positive HCV antibody and a single negative HCV quantitative HCV RNA are eligible.
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Negative result for SARS-CoV-2 by an FDA-authorized molecular diagnostic test. Examples include, but are not limited to RT-PCR, LAMP, TMA, and qSTAR. Candidates with a history of recent COVID infection may proceed despite a positive result if they have had complete clinical recovery and it has been >/= 21 days since the initial diagnosis.
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Subjects must have an echocardiogram within the previous 1 year without any of the following findings:
- severe left ventricular hypertrophy (LVH)
- greater than mild LVH accompanied by diastolic dysfunction
- left ventricular ejection fraction <40 percent
- pulmonary hypertension defined as right ventricular systolic pressure >35 mm Hg or tricuspid regurgitant velocity >2.8 m/s
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Female subjects of reproductive potential must have a negative pregnancy test upon study entry
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All subjects of reproductive potential must agree to use contraception for the duration of the study
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Subjects must have current vaccinations or documented immunity to:
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varicella (chickenpox)
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measles
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hepatitis B
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pneumococcus
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influenza, and
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varicella zoster (if ≥ 50 years old).
- Note: If subjects require administration of either live or killed vaccines to meet eligibility requirements, they must wait at least 2 weeks between vaccination and the baseline visit (i.e., at least 4 weeks before initiation of therapy)
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Living Donor Inclusion Criteria:
Living donors must meet all of the following criteria to be eligible-
- Able to understand and provide informed consent for research
- Meets United Network for Organ Sharing (UNOS) requirements for kidney organ donation
Exclusion Criteria:
Individuals who meet any of these criteria are not eligible for enrollment as study subjects-
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Inability or unwillingness of a subject to give written informed consent or comply with study protocol
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Known active current or history of invasive fungal infection, non-tuberculous mycobacterial infection
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Hepatitis B surface antigen or core antibody positive
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Serious uncontrolled concomitant major organ disease, excluding kidney failure
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Chronic respiratory failure
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Uncontrolled systemic hypertension
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Previous non-kidney solid organ transplant or bone marrow transplant
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Any infection requiring hospitalization and intravenous (IV) therapy within 4 weeks of screening or oral therapy within 2 weeks of screening
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Primary or secondary immunodeficiency
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History of thromboembolism (except thrombosis of dialysis vascular access site)
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Subjects with myocardial infarction within 12 months of screening or cardiac dysrhythmias uncontrolled by medications
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History of plasma cell dyscrasia
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Known bleeding diathesis or coagulation abnormality
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History of active tuberculosis (TB) (even if treated)
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Malignancy within the last 5 years except treated basal and squamous cell cancer of the skin or treated cervical cancer in situ
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Women who are currently pregnant or nursing
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Alcohol, drug, or chemical abuse within 1 year
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Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational drug, whichever is longer) of screening
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Current treatment with other biological drug. If the potential subject receives standard of care antibody treatments for prophylaxis of COVID-19 (permitted in protocol), there must be a minimum interval of 2 weeks after this treatment and before initiation of the study therapy.
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Current treatment with any medication which increases the risk of thromboembolic events including oral contraceptives
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Currently smoking tobacco
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Neutropenia (absolute neutrophil count <1000/microliter) or thrombocytopenia (platelet count <100,000/microliter) within 4 weeks prior to screening
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Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times upper limit of normal (ULN) or total bilirubin ≥ 2 times ULN
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Past or current medical problems or findings from physical examination or laboratory testing not listed above, which, in the opinion of the investigator, may:
- pose additional risks from participation in the study
- interfere with the subject's ability to comply with study requirements, or
- impact the quality or interpretation of the data obtained from the study.
Exclusion Criteria for Living Donors:
1. There are no exclusion criteria for living donors.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 무작위화되지 않음
- 중재 모델: 순차적 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
|---|---|
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실험적: Cohort 1
The two investigational agents used in this study are carfilzomib and belatacept. Per protocol, Carfilzomib administered intravenously:
Per protocol, Belatacept: -Belatacept will be administered intravenously on days 29 (week 4), 33 (week 5), and weeks 6, 8, 12, 16, then at a lower dose at week 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56. Dosing is based on the recommended dose in the package insert. |
Administered: Intravenously (IV). Carfilzomib is administered intravenously, on two consecutive days, each week for three weeks per cycle. In this study, subjects will receive 2 cycles of carfilzomib. Dosing for each cycle is based on the recommended dosing for carfilzomib monotherapy in the package insert. Carfilzomib is a proteasome inhibitor indicated for the treatment of patients with multiple myeloma. In this study, carfilzomib will be used in highly sensitized subjects without myeloma who are awaiting a kidney transplant.
다른 이름들:
Administered: Intravenously (IV). Belatacept is indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. In this study, belatacept will be used in highly sensitized subjects who are awaiting a kidney transplant.
다른 이름들:
Subjects will undergo a bone marrow aspiration prior to starting the study regimen and at 16 weeks after starting the study regimen. In subjects who undergo a kidney transplant during the study, another bone marrow aspiration will be done if it has been >4 weeks since the previous bone marrow aspiration. |
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실험적: Cohort 2
The enrollment of ten additional subjects and dosing regimen is dependent on the results in Cohort 1.° Per protocol, Carfilzomib administered intravenously:
Per protocol, Belatacept: -Belatacept will be administered intravenously on days 28 (week 4), 33 (week 5), and weeks 6, 8, 12, 16, then at a lower dose at week 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56. Dosing is based on the recommended dose in the package insert. ° May be modified based on the safety and efficacy analysis of Cohort 1. |
Administered: Intravenously (IV). Carfilzomib is administered intravenously, on two consecutive days, each week for three weeks per cycle. In this study, subjects will receive 2 cycles of carfilzomib. Dosing for each cycle is based on the recommended dosing for carfilzomib monotherapy in the package insert. Carfilzomib is a proteasome inhibitor indicated for the treatment of patients with multiple myeloma. In this study, carfilzomib will be used in highly sensitized subjects without myeloma who are awaiting a kidney transplant.
다른 이름들:
Administered: Intravenously (IV). Belatacept is indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. In this study, belatacept will be used in highly sensitized subjects who are awaiting a kidney transplant.
다른 이름들:
Subjects will undergo a bone marrow aspiration prior to starting the study regimen and at 16 weeks after starting the study regimen. In subjects who undergo a kidney transplant during the study, another bone marrow aspiration will be done if it has been >4 weeks since the previous bone marrow aspiration. |
연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Proportion of subjects who do not meet a stopping rule for safety and remain free of all of the following through 20 weeks (Cohort 1) after starting treatment or until receiving a transplant, whichever occurs earlier.
기간: Up to 26 weeks post treatment initiation
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Proportion of subjects who have not met a subject stopping rule, and remain free of all of the following through Week 26 post treatment initiation or until receiving a transplant, whichever occurs earlier:
The study site will grade the severity of adverse events experienced by the study subjects according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (Published November 27, 2017). |
Up to 26 weeks post treatment initiation
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Proportion of subjects who do not meet a stopping rule for safety and remain free of all of the following through Week 24 (Cohort 2) post treatment initiation or until receiving a transplant, whichever occurs earlier.
기간: Up to 24 weeks post treatment initiation
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Proportion of subjects who have not met a subject stopping rule, and remain free of all of the following through Week 24 post treatment initiation or until receiving a transplant, whichever occurs earlier:
The study site will grade the severity of adverse events experienced by the study subjects according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (Published November 27, 2017). |
Up to 24 weeks post treatment initiation
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Proportion of subjects who achieve any one of the following compared to Baseline - Cohort 1
기간: Baseline (Visit 0) to Week 20 post treatment initiation
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Proportion of subjects who achieve any one of the following compared to Baseline (Visit 0):
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Baseline (Visit 0) to Week 20 post treatment initiation
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Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline to Week 24 post treatment initiation - Cohort 2
기간: Baseline (Visit 0) to Week 24 post treatment initiation
|
Proportion of subjects who meet any one of the following compared to Baseline (Visit 0):
|
Baseline (Visit 0) to Week 24 post treatment initiation
|
2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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치료 시작 후 24주 이내에 발생한 거대세포바이러스(CMV) 감염 사건의 수
기간: 치료 시작 후 24주 이내
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치료 시작 후 24주 이내
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치료 시작 후 52주 내의 거대세포바이러스(CMV) 감염 사건 수
기간: 치료 시작 후 52주 이내
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치료 시작 후 52주 이내
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이식 후 52주 내 발생한 이식 후 림프증식질환(PTLD) 사건 수
기간: 이식 후 52주 이내
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이식 후 52주 이내
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치료 시작 후 52주 이내에 이식 시점에 기증자 특이 항체(DSA)가 이전에 양성이었고
≥50% 감소된 기증자로 이식받은 대상자의 비율
기간: 이식 후 52주 이내
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이식 후 52주 이내
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Proportion of subjects transplanted with a DSA-negative donor to whom DSA was previously positive, within 52 weeks after starting treatment
기간: Within 52 weeks post treatment initiation
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Clinical outcome measure. Subjects may receive a kidney transplant while in the study, either from a living or deceased donor to whom they were previously compatible, or from a previously incompatible donor in case there is a significant reduction in HLA antibody. |
Within 52 weeks post treatment initiation
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Proportion of subjects with biopsy-proven acute or chronic antibody mediated rejection (AMR) within 52 weeks post-transplant in subjects who undergo a kidney transplant
기간: Within 52 weeks post-transplant
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Clinical outcome measure. Antibody mediated rejection (AMR) is an important cause of graft loss after organ transplantation and is caused by anti-donor-specific antibodies, especially anti- human leukocyte antigen (HLA) antibodies. |
Within 52 weeks post-transplant
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Number of biopsy-proven acute or chronic AMR events within 52 weeks post-transplant in subjects who undergo a kidney transplant
기간: Within 52 weeks post-transplant
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Clinical outcome measure. Antibody mediated rejection (AMR) is an important cause of graft loss after organ transplantation and is caused by anti-donor-specific antibodies, especially anti- human leukocyte antigen (HLA) antibodies. |
Within 52 weeks post-transplant
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Proportion of subjects with invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 24 weeks after starting treatment
기간: Within 24 weeks post treatment initiation
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A measure of infection-related morbidity. |
Within 24 weeks post treatment initiation
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Proportion of subjects with invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 52 weeks after starting treatment
기간: Within 52 weeks post treatment initiation
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A measure of infection-related morbidity. |
Within 52 weeks post treatment initiation
|
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Number of invasive fungal infections, mycobacterial infections, or Pneumocystis jirovecii infection events within 24 weeks after starting treatment
기간: Within 24 weeks post treatment initiation
|
A measure of infection-related morbidity. |
Within 24 weeks post treatment initiation
|
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Number of invasive fungal infections, mycobacterial infections, or Pneumocystis jirovecii infection events within 52 weeks after starting treatment
기간: Within 52 weeks post treatment initiation
|
A measure of infection-related morbidity. |
Within 52 weeks post treatment initiation
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Proportion of subjects with cytomegalovirus (CMV) infection and disease within 24 weeks after starting treatment
기간: Within 24 weeks post treatment initiation
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CMV infection confirmed by the presence of detectable CMV in blood by polymerase chain reaction [PCR] diagnostic testing, regardless of whether signs or symptoms are present. |
Within 24 weeks post treatment initiation
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Proportion of subjects with cytomegalovirus (CMV) infection and disease within 52 weeks after starting treatment
기간: Within 52 weeks post treatment initiation
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CMV infection confirmed by the presence of detectable CMV in blood by polymerase chain reaction [PCR] diagnostic testing, regardless of whether signs or symptoms are present. |
Within 52 weeks post treatment initiation
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Proportion of subjects with post-transplant lymphoproliferative disorder (PTLD) within 52 weeks post-transplant
기간: Within 52 weeks post-transplant
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As per diagnosis by local pathologist and treating physician. |
Within 52 weeks post-transplant
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Mean number of Human Leukocyte Antigen (HLA) antibodies eliminated at 16 weeks compared to Baseline (Cohort 1)
기간: Baseline (Visit 0), Week 16 post treatment initiation
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Mechanistic outcome measure focusing on change in donor specific antibodies (DSA). |
Baseline (Visit 0), Week 16 post treatment initiation
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Mean number of Human Leukocyte Antigen (HLA) antibodies eliminated at 52 weeks compared to Baseline (Cohort 2)
기간: Baseline (Visit 0), Week 52 post treatment initiation
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Mechanistic outcome measure focusing on change in donor specific antibodies (DSA). |
Baseline (Visit 0), Week 52 post treatment initiation
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Mean percentage of Human Leukocyte Antigen (HLA) antibodies eliminated at 16 weeks compared to Baseline (Cohort 1)
기간: Baseline (Visit 0), Weeks 16, and 52 post treatment initiation
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Mechanistic outcome measure focusing on change in donor specific antibodies (DSA). |
Baseline (Visit 0), Weeks 16, and 52 post treatment initiation
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Mean percentage of Human Leukocyte Antigen (HLA) antibodies eliminated at 52 weeks compared to Baseline (Cohort 2)
기간: Baseline (Visit 0), Weeks 16, and 52 post treatment initiation
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Mechanistic outcome measure focusing on change in donor specific antibodies (DSA). |
Baseline (Visit 0), Weeks 16, and 52 post treatment initiation
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공동 작업자 및 조사자
협력자
수사관
- 연구 의자: Stuart J. Knechtle, MD, Duke Department of Surgery, Duke University School of Medicine
- 연구 의자: Annette M. Jackson, PhD, Duke Department of Surgery, Duke University School of Medicine
간행물 및 유용한 링크
연구 기록 날짜
연구 주요 날짜
연구 시작 (실제)
기본 완료 (실제)
연구 완료 (추정된)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
기타 연구 ID 번호
- DAIT ITN089ST
- ITN089ST (기타 식별자: Immune Tolerance Network (ITN))
- NIAID CRMS ID#: 38685 (기타 식별자: DAIT NIAID)
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
IPD 계획 설명
The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
IPD 공유 기간
On average, within 24 months after database lock for the trial.
IPD 공유 액세스 기준
Open access.
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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