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Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease (STRIDE)

This study has been completed.
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Lakshmanan Krishnamurti, Emory University
ClinicalTrials.gov Identifier:
NCT01565616
First received: March 26, 2012
Last updated: July 18, 2017
Last verified: July 2017
  Purpose

This is a Phase II, single arm, multi-center trial. It is designed to estimate the efficacy and toxicity of hematopoietic stem cell transplantation (HSCT) in patients with sickle cell disease (SCD) who have high risk features.

The primary goal of this multi-center Phase II study is to determine the safety and feasibility of a conditioning regimen consisting of busulfan (Bu)/ fludarabine (Flu)/ anti-thymocyte globulin (ATG) in adult patients with severe SCD. A two-component design will be used for this study. The first component will be restricted to patients who have an HLA-identical sibling donor. Five patients will be transplanted during the first component of the study. If no more than 2 of the first 5 patients experience unacceptable toxicity, including death, within the first six months after transplantation, then the safety of the regimen will be considered promising in adult SCD patients.

The second component will include patients who have a related or an unrelated human leukocyte antigen (HLA) matched donor. Up to 15 additional patients will be transplanted in this component of the study which will evaluate the safety and feasibility of unrelated donor hematopoietic cell transplantation (HCT) in adults with SCD. Data related to study endpoints for 1 year after transplantation will be collected; however, participating centers will be encouraged to conduct long-term follow-up evaluations of patients according to standard institutional guidelines. The purpose of this pilot safety trial is to see if this approach is feasible and meets accrual goals lending support to the development of a subsequent full scale investigation of HCT and comparing outcomes in a transplantation cohort to a control cohort of adults eligible for, but unwilling or unable to receive HCT treated by supportive therapy with a primary endpoint of five years survival for this full scale comparative trial.


Condition Intervention Phase
Sickle Cell Disease Drug: Conditioning Regimen with Bone Marrow Transplant Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Hematopoietic Stem Cell Therapy for Young Adults With Severe Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by Lakshmanan Krishnamurti, Emory University:

Primary Outcome Measures:
  • Disease-free Survival Rate [ Time Frame: Up to 1 Year Post Study Completion ]
    Disease-free survival is defined as the survival with stable donor erythropoiesis with no new clinical evidence of sickle cell disease. Primary or late graft rejection, with disease recurrence or death also will count as events for this endpoint.

  • Late Graft Rejection Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    The absence of donor hematopoietic cells in peripheral blood or bone marrow beyond Day 42 in a patient who had initial evidence of hematopoietic recovery with > 20% donor cells will be considered a late graft rejection.

  • Disease Recurrence Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    Disease recurrence is defined as the return of sickle erythropoiesis (HbS S level > 70%) and the absence of donor cell representation. This may be accompanied by recurrence of clinical complications of sickle cell disease such as stroke, acute chest syndrome, and veno-occlusive crisis (VOC).


Secondary Outcome Measures:
  • Overall Survival Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    Overall survival is defined as survival with or without sickle cell disease after HCT.

  • Cumulative Incidence of Neutrophil and Platelet Engraftment [ Time Frame: Duration of Study (Up to 4 Years) ]
    Time to neutrophil engraftment is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of greater than 500/µL after conditioning. Time to Platelet engraftment will be defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count > 50,000/µL AND did not receive a platelet transfusion in the previous 7 days. The exception is the case in which a subject is given a platelet transfusion specifically to achieve a platelet threshold to allow an elective invasive procedure, such as a central catheter removal. The cumulative incidence is defined as the number of new onset neutrophil engraftment and new onset platelet engraftment.

  • Grade II-IV Acute Graft-Versus-Host Disease (GVHD) Incidence Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    Incidence of grade II-IV GVHD will be graded according to the CIBMTR consensus criteria.

  • Grade III-IV Acute Graft-Versus-Host Disease (GVHD) Incidence Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    Incidence of grade III-IV GVHD will be graded according to the CIBMTR consensus criteria.

  • Chronic Acute Graft-Versus-Host Disease (GVHD) Incidence Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    Incidence and severity of chronic GVHD will be scored according to the NIH consensus criteria.

  • Idiopathic pneumonia syndrome (IPS) Rate [ Time Frame: Duration of Study (Up to 4 Years) ]

    The number of IPS incidents. IPS is defined as the following:

    Evidence of widespread alveolar injury

    1. Radiographic evidence of bilateral, multi-lobar infiltrates (by chest x-ray or CT scan), AND
    2. Evidence for abnormal respiratory physiology, based upon oxygen saturation (SpO2) < 93% on room air, or the need for supplemental oxygen to maintain oxygen saturation greater than or equal to 93%.
    3. Absence of active lower respiratory tract infection

  • Veno-occlusive Disease (VOD) Rate [ Time Frame: Duration of Study (Up to 4 Years) ]

    Veno-occlusive disease (VOD) is diagnosed by the presence of two or more of the following with no other identifiable cause for liver disease:

    1. Jaundice (direct bilirubin > 2 mg/dL or > 34 μmol/L)
    2. Hepatomegaly with right upper quadrant pain
    3. Ascites and/or weight gain (> 5% over baseline)

  • Central Nervous System (CNS) Toxicity Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    CNS toxicity will be defined as seizures, CNS hemorrhage, or Reversible posterior leukoencephalopathy syndrome (RPLS). RPLS is defined as an increased diffusion coefficient in areas of T2 hyperintensities on diffusion-weighted imaging in the context of clinical symptoms or physical findings including headache, seizures, visual disturbances, and altered level of consciousness.

  • Infection Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    Significant infections will be recorded including but not limited to bacterial or fungal sepsis, CMV reactivation with/without clinical disease, adenovirus infection, EBV PTLD, other significant viral reactivations or community-acquired viral infections and invasive mold infections.

  • Stroke Rate [ Time Frame: Duration of Study (Up to 4 Years) ]
    An overt stroke is defined as a focal neurologic event and neurologic deficit lasting more than 24 hours with neuroimaging changes. Adults with new MRI lesions and ongoing neurologic injury to the brain that does not result in focal motor impairment are referred to as having silent cerebral infarcts. These lesions are defined as a MRI signal abnormality measuring at least 3 mm visible on two views on T-2 weighted images. Both forms of neurologic injury that develop, as a new event post-transplant will be considered a disease related complication.

  • Proportion of Patients still on Immunosuppression 1 Year after Bone Marrow Transplant (BMT) [ Time Frame: Duration of Study (Up to 4 Years) ]
    Proportion of patients still receiving immunosuppressive therapy because of GVHD or concern about graft rejection will be determined.


Enrollment: 22
Actual Study Start Date: March 2012
Study Completion Date: June 30, 2016
Primary Completion Date: June 30, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Subjects with an HLA-identical Sibling Donor
Five participants with an HLA-identical sibling donor, and are undergoing bone marrow transplant for sickle cell disease, will receive a reduced toxicity conditioning regimen of medications.
Drug: Conditioning Regimen with Bone Marrow Transplant

The bone marrow transplant regimen is below. Day 0 is the day of the transplant. The - sign is the number of days before and the + sign is the number of days after the transplant.

SCHEMA OF CONDITIONING REGIMEN Day Treatment (BU- Busulfan, FLU-Fludarabine, ATG-Rabbit Anti-thymocyte globulin)

Day -8 BU 3.2 mg/ kg/dose IV

Day -7 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV

Day -6 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV, ATG 0.5mg/kg IV

Day -5 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV, ATG 1.0mg/kg IV

Day -4 FLU 35mg/m2 IV, ATG 1.5mg/kg IV

Day -3 FLU 35mg/m2 IV, ATG 1.5mg/kg IV

Day -2 ATG 1.5mg/kg IV

Day -1 Rest

Day 0 Stem cell infusion

GVHD Regimen

Day -3 Calcineurin Inhibitor (Cyclosporine or Tacrolimus) therapeutic doses through day 180, then taper

Day 0 Stem cell infusion

Day +1 Methotrexate 7.5 mg/m2 IV

Day +3 Methotrexate 7.5 mg/m2 IV

Day +6 Methotrexate 7.5 mg/m2 IV

Day+11 Methotrexate 7.5 mg/m2 IV

Other Names:
  • Busulfan
  • Myleran
  • Busulfex IV
  • Fludarabine
  • Fludara
  • Rabbit Anti-thymocyte globulin
  • Thymoglobulin
Experimental: Subjects with a Related or Unrelate HLA-matched Donor
Participants who have a related or an unrelated HLA-matched donor, and are undergoing bone marrow transplant for sickle cell disease, will receive a reduced toxicity conditioning regimen of medications.
Drug: Conditioning Regimen with Bone Marrow Transplant

The bone marrow transplant regimen is below. Day 0 is the day of the transplant. The - sign is the number of days before and the + sign is the number of days after the transplant.

SCHEMA OF CONDITIONING REGIMEN Day Treatment (BU- Busulfan, FLU-Fludarabine, ATG-Rabbit Anti-thymocyte globulin)

Day -8 BU 3.2 mg/ kg/dose IV

Day -7 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV

Day -6 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV, ATG 0.5mg/kg IV

Day -5 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV, ATG 1.0mg/kg IV

Day -4 FLU 35mg/m2 IV, ATG 1.5mg/kg IV

Day -3 FLU 35mg/m2 IV, ATG 1.5mg/kg IV

Day -2 ATG 1.5mg/kg IV

Day -1 Rest

Day 0 Stem cell infusion

GVHD Regimen

Day -3 Calcineurin Inhibitor (Cyclosporine or Tacrolimus) therapeutic doses through day 180, then taper

Day 0 Stem cell infusion

Day +1 Methotrexate 7.5 mg/m2 IV

Day +3 Methotrexate 7.5 mg/m2 IV

Day +6 Methotrexate 7.5 mg/m2 IV

Day+11 Methotrexate 7.5 mg/m2 IV

Other Names:
  • Busulfan
  • Myleran
  • Busulfex IV
  • Fludarabine
  • Fludara
  • Rabbit Anti-thymocyte globulin
  • Thymoglobulin

Detailed Description:

This is a Phase II, single arm, multi-center trial. It is designed to estimate the efficacy and toxicity of hematopoietic stem cell transplantation (HSCT) in patients with sickle cell disease (SCD) who have high risk features.

The primary goal of this multi-center Phase II study is to determine the safety and feasibility of a conditioning regimen consisting of busulfan (Bu)/ fludarabine (Flu)/ anti-thymocyte globulin (ATG) in adult patients with severe SCD. A two-component design will be used for this study. The first component will be restricted to patients who have an HLA-identical sibling donor. Five patients will be transplanted during the first component of the study. If no more than 2 of the first 5 patients experience unacceptable toxicity, including death, within the first six months after transplantation, then the safety of the regimen will be considered promising in adult SCD patients.

The second component will include patients who have a related or an unrelated human leukocyte antigen (HLA) matched donor. Up to 15 additional patients will be transplanted in this component of the study which will evaluate the safety and feasibility of unrelated donor hematopoietic cell transplantation (HCT) in adults with SCD. Data related to study endpoints for 1 year after transplantation will be collected; however, participating centers will be encouraged to conduct long-term follow-up evaluations of patients according to standard institutional guidelines. The purpose of this pilot safety trial is to see if this approach is feasible and meets accrual goals lending support to the development of a subsequent full scale investigation of HCT and comparing outcomes in a transplantation cohort to a control cohort of adults eligible for, but unwilling or unable to receive HCT treated by supportive therapy with a primary endpoint of five years survival for this full scale comparative trial.

The primary objective is to determine event-free survival (EFS) at 1 year after Hematopoietic cell transplantation (HCT) using bone marrow in patients with sickle cell disease. Death, disease recurrence or graft rejection by 1 year will be considered events for this endpoint.

Secondary objectives include determining the effect of HCT on clinical and laboratory manifestations of severe sickle cell disease and determining the incidence of other transplant-related outcomes.

  Eligibility

Ages Eligible for Study:   16 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of severe sickle cell disease and have one or more of the following:

    1. Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours
    2. History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea). Acute Chest Syndrome (ACS) is defined by the following criteria.

      Defined as new pulmonary alveolar consolidation (or infiltrate) involving at least one complete lung segment associated with acute symptoms including one or more of the following: fever ≥ 38.5oC, chest pain, tachypnea per age adjusted normal, intercostal retractions/nasal flaring/use of accessory muscles of respiration, wheezing, rales or cough that is not attributed to asthma or bronchiolitis.

    3. History of three or more severe pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea). Pain Crisis is defined by the following criteria.

      Defined as new onset of pain that last for at least 2 hours for which there is no other explanation (i.e. vaso-occlusive, priapism).

    4. Administration of regular RBC transfusion therapy, defined as receiving 8 or more transfusions per year for greater than or equal to 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome)
    5. Trans-thoracic echocardiograph evidence of tricuspid valve regurgitant jet (TRJ) velocity greater than or equal to 2.7 m/sec.

      Adequate physical function as measured by:

      1. Karnofsky performance score greater than or equal to 60
      2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction > 26% by cardiac echocardiogram or by MUGA scan.
      3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of greater than or equal to 85% and DLCO > 40% (corrected for hemoglobin)
      4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and 24-hour urine creatinine clearance > 70 mL/min/1.73 m2 by radionuclide GFR; or GFR > 70 mL/min/1.73 m2 by radionuclide GFR.
      5. Hepatic function: Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory; and ALT and AST < 5 times upper limit of normal as per local laboratory. Patients whose hyperbilirubinemia is the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded
      6. If the patient has been receiving chronic transfusion therapy for greater than or equal to 1 year and has clinical evidence of iron overload by serum Ferritin (mean of 3 ferritin levels >1000 and chronic transfusions >20 in a lifetime or MRI, evaluation by liver biopsy is required. Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues (1995). Further described in the Manual of Operating Procedures.
  • Patients must have a related or unrelated bone marrow donor with HLA-matched at 8 of 8 HLA-A, B, C, and DRB1 loci by allelic testing. Umbilical cord blood or peripheral blood stem cell donors will not be accepted.

Exclusion Criteria:

  • Patients with cirrhosis of the liver, uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment, or seropositivity for HIV
  • Patients who have received prior HCT
  • Patients who within 3 months of enrollment have participated in another clinical trial in which the patient received an investigational drug or device or off-label use of a drug or device
  • Patients who demonstrate lack of compliance with prior medical care
  • Patients who are unwilling to use approved contraception for at least 6 months after transplant
  • Patients who have a history of substance abuse in the last 5 years that interferes with their care
  • Patients who are pregnant or breast feeding
  • Patients unable to provide consent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01565616

Locations
United States, California
Children's Hospital of Oakland
Oakland, California, United States, 94609
United States, District of Columbia
Children's National Medical Center
Washington, D.C., District of Columbia, United States, 20010
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Georgia
Children's Healthcare of Atlanta
Atlanta, Georgia, United States, 30322
Emory University
Atlanta, Georgia, United States, 30322
Georgia Regents University
Augusta, Georgia, United States, 30912
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Chidren's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15224
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Emory University
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Lakshmanan Krishnamurti, MD Emory University
  More Information

Additional Information:
Responsible Party: Lakshmanan Krishnamurti, Professor, Emory University
ClinicalTrials.gov Identifier: NCT01565616     History of Changes
Other Study ID Numbers: IRB00068287
1R34HL108761-01 ( U.S. NIH Grant/Contract )
Study First Received: March 26, 2012
Last Updated: July 18, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lakshmanan Krishnamurti, Emory University:
Severe Sickle Cell Disease
Hematopoietic cell transplantation (HCT)
Hematopoietic Stem Cell Therapy
Bone Marrow Transplant
Hematologic Diseases
Genetic Diseases
Anemia
Hemolytic
Congenital
Human Leukocyte Antigen
HLA

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Fludarabine
Busulfan
Antilymphocyte Serum
Antineoplastic Agents
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Myeloablative Agonists

ClinicalTrials.gov processed this record on August 18, 2017