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

NCT04046705 | Unknown Phase 3

• 1 other identifier: K170912J
• Study Type: interventional
• Target: 78
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Sickle Cell Disease

Outcome Measures

Primary Outcomes (1)

• 2 year event-free survival

  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

  2 years post-inclusion

Secondary Outcomes (132)

• Overall survival

  2 years post-inclusion

• Number of days requiring hospitalization

  1 year

• Number of days requiring hospitalization

  2 years post-inclusion

• Number of vaso-occlusive crisis (VOC) requiring hospitalization

  1 year post-inclusion

• Number of vaso-occlusive crisis (VOC) requiring hospitalization

  2 years post-inclusion

Study Arms (2)

HLA matched haematopoietic stem cell transplantation

EXPERIMENTAL

Peripheral blood stem cell from matched HLA related donor.

Procedure: Allogeneic matched related haematopoietic stem cell transplantation

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.

Other: Standard arm

Interventions

Allogeneic matched related haematopoietic stem cell transplantation PROCEDURE

Allogeneic matched related haematopoietic stem cell transplantation after a reduced intensity conditioning regimen

HLA matched haematopoietic stem cell transplantation

Standard arm OTHER

In the standard arm, patients who will not be transplanted, 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 transfusion program, initiation of a new drug proved to improve SCD and having authorization to use in France

Control arm

Eligibility Criteria

• Age: 15 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:
• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

MeSH Terms

Conditions

Anemia, Sickle Cell

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Central Study Contacts

Nathalie Dhedin

CONTACT

+33142385127; nathalie.dhedin@aphp.fr

Sylvie Chevret

CONTACT

+33142499742; sylvie.chevret@paris7.jussieu.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2019
• First Posted: August 6, 2019
• Study Start: October 15, 2019
• Primary Completion: October 15, 2024
• Study Completion: October 15, 2024
• Last Updated: September 23, 2019

Record last verified: 2019-07