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HLA-Identical Sibling Donor Bone Marrow Transplantation for Individuals With Severe Sickle Cell Disease Using a Reduced Intensity Conditioning Regimen

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ClinicalTrials.gov Identifier: NCT02776202
Recruitment Status : Recruiting
First Posted : May 18, 2016
Last Update Posted : May 19, 2016
Sponsor:
Information provided by (Responsible Party):
National Guard Health Affairs

Brief Summary:

Sickle cell disease (SCD) is the most common inherited blood disorder in Saudi Arabia . Its clinical severity is widely heterogeneous among patients who share the same genetic mutation . Severe frequent pain crisis, recurrent acute chest syndrome and stroke are features of severe SCD. Hydroxyurea is an effective treatment of SCD as it ameliorates the severity and frequency of pain crisis and acute chest syndrome and decreases mortality, however, it is less effective in the prevention and treatment of stroke and other end organ dysfunctions . The only readily available cure of SCD is by hematopoietic stem cell transplantation (HSCT) . Most children with SCD who are treated by HSCT receive myeloablative conditioning with excellent results. The application of reduced intensity (RIC) and non-myeloablative (NMA) conditioning regimens are reserved for patients older than 16 years of age because of the increased risks of morbidity and mortality after HSCT6. However, infertility and gonadal failure after myeloablative conditioning are important barriers to the willingness of patients and their families to undergo HSCT . The development of an effective RIC HSCT in SCD that might spare the fertility of SCD patients would have obvious merit.

With the ultimate goal of expanding this curative therapy to SCD patients, we propose to investigate HSCT with a RIC conditioning regimen. We will carry out a pilot study of HSCT from HLA matched sibling donors using thymoglobulin/fludarabine/melphalan conditioning and sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in SCD patients with severe complications such as stroke and other severe complications. We hypothesize that HSCT from HLA matched sibling using thymoglobulin/fludarabine/melphalan conditioning in SCD will maintain a level of stable donor chimerism that is sufficient to cure SCD with minimal toxicity.


Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Fludarabine monophosphate Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: HLA-Identical Sibling Donor Bone Marrow Transplantation for Individuals With Severe Sickle Cell Disease Using a Reduced Intensity Conditioning Regimen
Study Start Date : May 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: Reduced-intensity conditioning regimen

The HSCT preparative regimen will consist of

  • Thymoglobulin: 2.5 mg /kg/day intravenously (IV) on Days -8 through -5
  • Fludarabine: 35 mg/m2/day IV on Days -8 through -4
  • Melphalan: 140 mg/m2 IV on Day -3
  • Rest on Day -2 and -1
  • Day 0 is the day of transplant
  • GVHD prophylaxis: sirolimus beginning on Day -1 for at least one year and mycophenolate mofetil (MMF) from Day -3 to +45 or to 7 days after neutrophil engraftment, whichever is later.
Drug: Fludarabine monophosphate

The HSCT preparative regimen will consist of

  • Thymoglobulin: 2.5 mg /kg/day intravenously (IV) on Days -8 through -5
  • Fludarabine: 35 mg/m2/day IV on Days -8 through -4
  • Melphalan: 140 mg/m2 IV on Day -3
  • Rest on Day -2 and -1
  • Day 0 is the day of transplant
  • GVHD prophylaxis: sirolimus beginning on Day -1 for at least one year and mycophenolate mofetil (MMF) from Day -3 to +45 or to 7 days after neutrophil engraftment, whichever is later.
Other Names:
  • Melphalan
  • Mycophenolate Mofetil
  • Sirolimus




Primary Outcome Measures :
  1. to determine event-free survival (EFS) at 1 year after HLA-Identical sibling donor hematopoietic stem cell transplantation (HCT) using bone marrow (BM) in patients with sickle cell disease (SCD). [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. 1. To determine the effect of HCT on clinical and laboratory manifestations of severe sickle cell disease including stroke. [ Time Frame: 3 years ]
  2. determine the incidence of other transplant-related outcomes. [ Time Frame: 3 years ]


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Ages Eligible for Study:   3 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. SCD patients who are 3-18 years old. 2. SCD (HbSS, HbSβ° thalassemia or any genotype) with at least one of the following conditions:

    1. Clinically significant neurologic event (stroke) or any neurologic defect lasting > 24 hours and accompanied by an infarct on cerebral magnetic resonance imaging (MRI)
    2. Minimum of two episodes of acute chest syndrome within the preceding 2-year period defined as new pulmonary alveolar consolidation involving at least one complete lung segment (associated with acute symptoms including fever, chest pain, tachypnea, wheezing, rales or cough that is not attributed to asthma or bronchiolitis) despite adequate supportive care measures
    3. History of 3 or more severe pain events per year in the 2 years prior to enrollment.

      3. Availability of 10/10 genotypically HLA identical related donor 4. In patients who have been treated by regular RBC transfusions >12 months, with a liver biopsy that shows no evidence of cirrhosis or active hepatitis 5. Patients must have a Karnofsky score ≥ 50 or WHO/ECOG ≥ 2 for patients age ≥ 16, Lansky score ≥ 50 for patients age < 16.

      6. Adequate cardiac function: shortening fraction of > 25% or ejection fraction of > 55% by echocardiogram 7. Adequate renal function: serum creatinine within normal limits or creatinine clearance >70 ml/min/1.73 m2 8. Adequate liver function: Total bilirubin within normal limits and AST/ALT <2.5x upper limit of normal

      Exclusion Criteria:

  • 1. Patients with symptomatic cardiac insufficiency or arrhythmia. 2. Patients with cirrhosis on liver biopsy. 3. Hepatitis B, hepatitis C, or HIV seropositive patients. 4. Patients with other disease that would increase toxicity of transplant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02776202


Locations
Saudi Arabia
King Abdul Aziz Medical City for National Guard Recruiting
Riyadh, Saudi Arabia
Contact: Nagham RZ Sheblaq    009668011111 ext 53352    sheblaqn@ngha.med.sa   
Contact    009668011111 ext 53352    sheblaqn@ngha.med.sa   
Principal Investigator: Nagham RZ Sheblaq, BS.c         
Sponsors and Collaborators
National Guard Health Affairs

Responsible Party: National Guard Health Affairs
ClinicalTrials.gov Identifier: NCT02776202     History of Changes
Other Study ID Numbers: RC15/043/R
First Posted: May 18, 2016    Key Record Dates
Last Update Posted: May 19, 2016
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Fludarabine
Fludarabine phosphate
Sirolimus
Everolimus
Mycophenolic Acid
Melphalan
Vidarabine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antibiotics, Antitubercular
Antitubercular Agents
Enzyme Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents