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临床试验/NCT04046705
NCT04046705尚未招募3 期

A Prospective Multicenter Trial Comparing Allogeneic Matched Related Haematopoietic Stem Cell Transplantation After a Reduced Intensity Conditioning Regimen, With Standard of Care in Adolescents and Adults With Severe Sickle Cell Disease

Assistance Publique - Hôpitaux de Paris0 个研究点目标入组 78 人开始时间: 2019年10月15日最近更新:
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适应症
干预措施

试验速览

阶段
3 期
状态
尚未招募
入组人数
78
主要终点
2 year event-free survival
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者记录与标识符相似试验

研究概览

简要总结

Although the survival of children with sickle cell disease (SCD) has dramatically improved over the last decades in the US and Europe, mortality remains high in adults. Moreover, many children and most adults develop a chronic debilitating condition due to organ damage. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the unique curative approach; it allows the cure of more than 95% of children transplanted from a matched related donor (MRD) after a myeloablative conditioning regimen.To date, few studies have addressed the role of HSCT in SCD adults, due to the risk of graft versus host disease (GVHD) and to the toxicity expected in older patients with a higher risk of organ damage. The development of safe, non-myeloablative conditioning regimens that allow stable mixed chimerism and avoid GVHD appears as an attractive option for HSCT to cure adults with severe SCD. The investigators design a prospective multicenter trial targeting patients over 15 years with severe SCD, and compare non-myeloablative transplant (when a matched related donor (MRD) is identified) versus no HSCT (for patients lacking MRD). The main objective is to assess the benefit of HSCT on the 2-year event free survival compared to standard care. The primary endpoint is the 2-year event free survival.

研究设计

研究类型
Interventional
分配方式
Non Randomized
干预模型
Parallel
主要目的
Treatment
盲法
None

入排标准

年龄范围
15 Years 至 45 Years（Child, Adult）
性别
All
接受健康志愿者
否

入选标准

  • •SCD patients (SS/Sβ0)
  • •Aged :15 to 45 years
  • •With at least one non-SCD sibling > 18 years from the same parental couple
  • •Who presented at least one of the following criteria:
  • •3 VOC requiring hospitalization over one year within the past 2 years and at least a past history of an ACS
  • •At least 1 ACS within the past 2 years requiring transfusions
  • •History of ischemic stroke or cerebral/cervical arterial stenosis > 50%
  • •Pulmonary hypertension defined by mean pulmonary artery pressure ≥ 25 mmHg at rest, determined by right heart catherization
  • •Requiring treatment with Hydroxyurea or chronic transfusion, or already treated by Hydroxyurea or transfusion program (TP) at inclusion.
  • •Patients already receiving chronic transfusions for VOC or ACS not responding to hydroxyurea, will be eligible, provided at least 3 VOC requiring hospitalization/year within the 2 years before initiation of chronic transfusions, and at least past history of an ACS.
  • •Contraception during all the study period by sirolimus for women of child bearing potential
  • •Signed informed consent
  • •Amenable to HLA typing, HSCT if an HLA-identical sibling is available.
  • •Patients affiliated to the French health care insurance

排除标准

  • •Performance status: ECOG scale>1
  • •Pulmonary function: FEV1 et CVF < 50% of the theorical value
  • •Post capillary and severe pre-capillary pulmonary hypertension with measured mean pulmonary artery pressure at rest >35 mmHg
  • •Cardiac ejection fraction < 45%
  • •Estimated glomerular fraction rate (GFR) <50ml/mn /1.73m2
  • •Conjugate bilirubin >50 µmole/L, cirrhosis, ALT>4N
  • •Uncontrolled infection
  • •Known hypersensitivity of alemtuzumab
  • •Known hypersensitivity to murine proteins and to the following excepients: disodium edetate, polysorbate 80, potassium chloride, potassium phosphate monobasic, sodium chloride, dibasic sodium phosphate, water for injections
  • •Positivity for HIV
  • •Pregnancy or breast-feeding women
  • •Alloimmunization or Delayed Hemolytic Transfusion Reaction precluding red cell transfusions

研究组 & 干预措施

HLA matched haematopoietic stem cell transplantation

Experimental

Peripheral blood stem cell from matched HLA related donor.

干预措施: Allogeneic matched related haematopoietic stem cell transplantation (Procedure)

Control arm

Other

Best standard care : Patients will receive the best standard care according to their situation and their previous treatment: initiation of Hydroxyurea, continuation or optimization of the dose of Hydroxyurea, initiation or continuation of TP, initiation of a new drug proved to improve SCD and having authorization to use in France.

干预措施: Standard arm (Other)

结局指标

主要结局

2 year event-free survival

时间窗: 2 years post-inclusion

An event will be defined as : * death from any cause * or acute grade II-IV GVHD according to the Magic consortium 2016 classification or a moderate or severe chronic GVHD according to the NIH classification * or 3 hospitalizations for VOC defined according to usual criteria * or one ACS defined by usual clinical criteria and a pulmonary infiltrate on chest film and/or thoracic computed-tomography (CT) scan * or a stroke defined as a clinical event confirmed by an MRI * or a cerebral or cervical stenosis \>25% in a new territory, or increase \>25% of previous stenosis evaluated MRI and MRI * or a increased of at least +10% of tricuspid regurgitation velocity, (confirmed by 2 echocardiography performed with a delay of at least 3 months) compared with pre-inclusion value for patients with TRV≥2.7 at inclusion

次要结局

  • Percentage of transferrin saturation(at 24 months)
  • Proportion of patients with new RBC alloantibodies(at 24 months)
  • Number of vaso-occlusive crisis (VOC) requiring hospitalization(2 years post-inclusion)
  • Number of acute chest syndrome (ACS) requiring hospitalization(2 years post-inclusion)
  • Number of hospitalizations in intensive care unit(2 years post-inclusion)
  • Number of priapism(2 years post-inclusion)
  • Number of stroke episodes(2 years post-inclusion)
  • LDH count(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Percentage of patients with an aminotransferase value higher than five times the normal value(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Percentage of patients with a gamma-GT value higher than five times the normal value(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Percentage of patients with an Alkaline phosphatase value higher than five times the normal value(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Percentage of patients with a bilirubin value higher than three times the normal value(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Percentage of patients with a prothrombin value less than 70%(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Hemoglobin variants(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Reticulocyte count(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • White blood cells count(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • LH count(at 24 months)
  • FSH count(at 24 months)
  • Testosterone count(at 24 months)
  • Spermogram(at 24 months)
  • Oestrogen count(at 24 months)
  • AMH count(at 24 months)
  • Percentage of patients with a proliferative retinopathy(at 24 months)
  • Percentage of patients with a hemorrhagic retinopathy(at 24 months)
  • Percentage of patients with retinal detachment(at 24 months)
  • Proportion of patients with keratitis(at 24 months)
  • Proportion of patients with uveitis(at 24 months)
  • Tricuspid regurgitant jet velocity(at 24 months)
  • Left atrial dimension(at 24 months)
  • Left ventricular dimension(at 24 months)
  • Ventricular mass index value(at 24 months)
  • Left ventricular ejection fraction(at 24 months)
  • Forced Expiratory Volume in one second (FEV)(at 24 months)
  • DLCO(at 24 months)
  • Forced vital capacity(at 24 months)
  • 6 minutes walk test(at 24 months)
  • Overall survival(2 years post-inclusion)
  • Number of days requiring hospitalization(2 years post-inclusion)
  • Activated partial thromboplastin time higher than 1.5 times the normal value(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Rate of hemoglobin(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Hematocrit(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Mean corpuscular volume(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Platelets counts(every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm)
  • Microalbuminuria/creatininuria ratio(at 24 months)
  • Ferritin level(at 24 months)
  • Transferrin saturation level(at 3 months)
  • Incidence of amenorrhea(at 24 months)
  • Number of parity(at 24 months)
  • Number of new episodes of avascular osteonecrosis(at 24 months)
  • Number of patients for each location of new episodes of avascular osteonecrosis(at 24 months)
  • Fractures(at 24 months)
  • Central nervous system function(at 24 months)
  • Iron overload(at 24 months)
  • Red blood cell packed transfused(at 24 months)
  • Number of delayed hemolytic transfusion reaction (DHTR)(at 24 months)
  • Percentage of patients with an oral opioid consumption(at 24 months)
  • Quality of life evaluated using MOS SF36 questionnaire(at 24 months)
  • Depression and Anxiety status(at 12 months)
  • Weight(at 24 months)
  • Number of severe infections(at 24 months)
  • GvHD incidence(at 24 months)
  • Grading of GvHD(at 12 months)
  • Chimerism in HSCT(at 24 months)
  • Number of days of hospitalization(Number of days of hospitalization from inclusion at M24)
  • RBC and WBC adherence(at 24 months)
  • Expression of RBC and WBC surface markers(at 24 months)
  • Mast cell mediator release(at 24 months)
  • Inflammatory cytokines(at 24 months)
  • Number of priapism(1 year post-inclusion)
  • Number of stroke episodes(1 year post-inclusion)
  • Microalbuminuria/creatininuria ratio(at 3 months)
  • Percentage of transferrin saturation(at 12 months)
  • Microalbuminuria/creatininuria ratio(at 6 months)
  • Weight(at 3 months)
  • Microalbuminuria/creatininuria ratio(at 12 months)
  • Ferritin level(at 3 months)
  • Ferritin level(at 6 months)
  • Ferritin level(at 12 months)
  • Percentage of transferrin saturation(at 6 months)
  • Number of acute chest syndrome (ACS) requiring hospitalization(1 year post-inclusion)
  • Number of hospitalizations in intensive care unit(1 year post-inclusion)
  • Number of days requiring hospitalization(1 year)
  • Number of vaso-occlusive crisis (VOC) requiring hospitalization(1 year post-inclusion)
  • Percentage of patients with a proliferative retinopathy(at 12 months)
  • Percentage of patients with a hemorrhagic retinopathy(at 12 months)
  • Percentage of patients with retinal detachment(at 12 months)
  • Proportion of patients with keratitis(at 12 months)
  • Proportion of patients with uveitis(at 12 months)
  • Weight(at 6 months)
  • Tricuspid regurgitant jet velocity(at 12 months)
  • Left atrial dimension(at 12 months)
  • Left ventricular dimension(at 12 months)
  • Ventricular mass index value(at 12 months)
  • Left ventricular ejection fraction(at 12 months)
  • Forced Expiratory Volume in one second (FEV)(at 12 months)
  • DLCO(at 12 months)
  • Forced vital capacity(at 12 months)
  • 6 minutes walk test(at 12 months)
  • Central nervous system function(at 12 months)
  • Iron overload(at inclusion)
  • Iron overload(at 12 months)
  • Number of delayed hemolytic transfusion reaction (DHTR)(at 3 months)
  • Number of delayed hemolytic transfusion reaction (DHTR)(at 6 months)
  • Number of delayed hemolytic transfusion reaction (DHTR)(at 12 months)
  • Proportion of patients with new RBC alloantibodies(at 3 months)
  • Proportion of patients with new RBC alloantibodies(at 6 months)
  • Proportion of patients with new RBC alloantibodies(at 12 months)
  • Percentage of patients with an oral opioid consumption(at 3 months)
  • Percentage of patients with an oral opioid consumption(at 6 months)
  • Percentage of patients with an oral opioid consumption(at 12 months)
  • Quality of life evaluated using MOS SF36 questionnaire(at 3 months)
  • Quality of life evaluated using MOS SF36 questionnaire(at 6 months)
  • Quality of life evaluated using MOS SF36 questionnaire(at 12 months)
  • Depression and Anxiety status(at 3 months)
  • Depression and Anxiety status(at 6 months)
  • Weight(at 12 months)
  • GvHD incidence(at 12 months)
  • Chimerism in HSCT(at 1 month)
  • Chimerism in HSCT(at 2 months)
  • Chimerism in HSCT(at 3 months)
  • Chimerism in HSCT(at 6 months)
  • Chimerism in HSCT(at 9 months)
  • Chimerism in HSCT(at 12 months)
  • Chimerism in HSCT(at 18 months)
  • RBC and WBC adherence(at inclusion)
  • RBC and WBC adherence(at 12 months)
  • Expression of RBC and WBC surface markers(at inclusion)
  • Expression of RBC and WBC surface markers(at 12 months)
  • Mast cell mediator release(at inclusion)
  • Mast cell mediator release(at 12 months)
  • Inflammatory cytokines(at inclusion)
  • Inflammatory cytokines(at 12 months)

研究者

申办方类型
Other
责任方
Sponsor

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