Clinical trial NCT04046705: Comparison of 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Sickle Cell Disease
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2019-08-06
Enrollment: 78
Sex: ALL
Minimum age (years): 15
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion criteria

* 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

Exclusion Criteria

* 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

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