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

Primary Purpose

Sickle Cell Disease

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Conditioning Regimen with Bone Marrow Transplant
Sponsored by
Emory University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring 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

Eligibility Criteria

16 Years - 40 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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 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 ≥ 38.5 Celsius, 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 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 red blood cell (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 multigated acquisition (MUGA) scan.
    3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of greater than or equal to 85% and diffusing capacity of the lungs for carbon monoxide (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 glomerular filtration rate (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 alanine aminotransferase (ALT) and aspartate aminotransferase (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).
  • 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

Sites / Locations

  • Children's Hospital of Oakland
  • Children's National Medical Center
  • University of Miami
  • Children's Healthcare of Atlanta
  • Emory University
  • Duke University Medical Center
  • Chidren's Hospital of Pittsburgh
  • Virginia Commonwealth University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bone Marrow Transplant Recipients

Arm Description

Adults with sickle cell disease undergoing a bone marrow transplant from an HLA-identical sibling donor or an unrelated HLA-matched donor.

Outcomes

Primary Outcome Measures

Event -Free Survival Rate
Event-free survival is defined as stable donor erythropoiesis with no new clinical evidence of sickle cell disease. Primary or late graft rejection, disease recurrence, and death are considered events for this endpoint.

Secondary Outcome Measures

Graft Failure
Primary graft failure occurs when a transplant recipient does not achieve donor chimerism following a bone marrow transplant. Secondary graft failure occurs when graft fails after donor chimerism had initially occurred.
Acute Graft Versus Host Disease (GVHD)
Acute GVHD was graded according to the Center for International Blood and Marrow Transplant Research (CIBMTR) consensus criteria. Clinical manifestations of acute GVHD include skin, liver, and gastrointestinal symptoms. Grading of acute GVHD is determined by size of maculopapular rash, bilirubin and stool output. Acute GVHD grades range from 0 to 4 with 0 indicating no GVHD and 4 representing the most severe grade. Grade II is defined as a maculopapular rash over 25-50% of body surface area (BSA), bilirubin of 3.1 to 6 mg/dL, and stool output of 1000-1500 mL/d (for adults). Grade III is defined as a maculopapular rash over more than 50% of BSA, bilirubin of 6.1 to 15 mg/dL, and stool output of greater than 1500 mL/d (for adults). Grade IV is defined as generalized erythroderma with bullous formation, bilirubin greater than 15 mg/dL, and severe abdominal pain with or without ileus.
Chronic Graft Versus Host Disease (GVHD)
Chronic GVHD was graded according to the National Institutes of Health (NIH) 2014 Consensus Criteria Diagnosis and scoring the severity of chronic GVHD is determined by evaluating symptoms of the skin, nails, hair, mouth, eyes, genitalia, gastrointestinal tract, liver, lungs, muscles, fascia and joints, immune function as well as other symptoms such as ascites and neuropathy. Chronic GVHD is graded as mild, moderate or severe based on the number of organ sites impacted and the severity of symptoms.
Overall Survival
Overall survival is defined as survival with or without sickle cell disease after hematopoietic cell transplantation (HCT).
Time to Neutrophil and Platelet Engraftment
Time to neutrophil engraftment is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of at least 500/µL after conditioning. Time to Platelet engraftment is 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, without receiving a platelet transfusion in the previous 7 days.
Transplant Related Outcomes
Common transplant related complications were monitored as a secondary outcome measure of this study. These transplant related complications include hepatic veno-occlusive disease (VOD), idiopathic pneumonia syndrome (IPS), central nervous system (CNS) toxicity complications of posterior reversible encephalopathy syndrome (PRES), hemorrhage, and seizures, cytomegalovirus (CMV) infection, adenovirus infection, Epstein-Barr virus (EBV) infection, post-transplant lymphoproliferative disease (PTLD), and invasive fungal infection.

Full Information

First Posted
March 26, 2012
Last Updated
October 19, 2017
Sponsor
Emory University
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01565616
Brief Title
Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease
Acronym
STRIDE
Official Title
A Phase II Study of Hematopoietic Stem Cell Therapy for Young Adults With Severe Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
March 2012 (Actual)
Primary Completion Date
June 30, 2016 (Actual)
Study Completion Date
June 30, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Emory University
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
22 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bone Marrow Transplant Recipients
Arm Type
Experimental
Arm Description
Adults with sickle cell disease undergoing a bone marrow transplant from an HLA-identical sibling donor or an unrelated HLA-matched donor.
Intervention Type
Drug
Intervention Name(s)
Conditioning Regimen with Bone Marrow Transplant
Other Intervention Name(s)
Busulfan (BU), Myleran, Busulfex IV, Fludarabine (FLU), Fludara, Rabbit Anti-thymocyte globulin (ATG), Thymoglobulin
Intervention Description
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. 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 Graft Versus Host Disease (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
Primary Outcome Measure Information:
Title
Event -Free Survival Rate
Description
Event-free survival is defined as stable donor erythropoiesis with no new clinical evidence of sickle cell disease. Primary or late graft rejection, disease recurrence, and death are considered events for this endpoint.
Time Frame
1 year after transplant
Secondary Outcome Measure Information:
Title
Graft Failure
Description
Primary graft failure occurs when a transplant recipient does not achieve donor chimerism following a bone marrow transplant. Secondary graft failure occurs when graft fails after donor chimerism had initially occurred.
Time Frame
1 year after transplant
Title
Acute Graft Versus Host Disease (GVHD)
Description
Acute GVHD was graded according to the Center for International Blood and Marrow Transplant Research (CIBMTR) consensus criteria. Clinical manifestations of acute GVHD include skin, liver, and gastrointestinal symptoms. Grading of acute GVHD is determined by size of maculopapular rash, bilirubin and stool output. Acute GVHD grades range from 0 to 4 with 0 indicating no GVHD and 4 representing the most severe grade. Grade II is defined as a maculopapular rash over 25-50% of body surface area (BSA), bilirubin of 3.1 to 6 mg/dL, and stool output of 1000-1500 mL/d (for adults). Grade III is defined as a maculopapular rash over more than 50% of BSA, bilirubin of 6.1 to 15 mg/dL, and stool output of greater than 1500 mL/d (for adults). Grade IV is defined as generalized erythroderma with bullous formation, bilirubin greater than 15 mg/dL, and severe abdominal pain with or without ileus.
Time Frame
1 year after transplant
Title
Chronic Graft Versus Host Disease (GVHD)
Description
Chronic GVHD was graded according to the National Institutes of Health (NIH) 2014 Consensus Criteria Diagnosis and scoring the severity of chronic GVHD is determined by evaluating symptoms of the skin, nails, hair, mouth, eyes, genitalia, gastrointestinal tract, liver, lungs, muscles, fascia and joints, immune function as well as other symptoms such as ascites and neuropathy. Chronic GVHD is graded as mild, moderate or severe based on the number of organ sites impacted and the severity of symptoms.
Time Frame
1 year after transplant
Title
Overall Survival
Description
Overall survival is defined as survival with or without sickle cell disease after hematopoietic cell transplantation (HCT).
Time Frame
1 year after transplant
Title
Time to Neutrophil and Platelet Engraftment
Description
Time to neutrophil engraftment is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of at least 500/µL after conditioning. Time to Platelet engraftment is 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, without receiving a platelet transfusion in the previous 7 days.
Time Frame
1 year after transplant
Title
Transplant Related Outcomes
Description
Common transplant related complications were monitored as a secondary outcome measure of this study. These transplant related complications include hepatic veno-occlusive disease (VOD), idiopathic pneumonia syndrome (IPS), central nervous system (CNS) toxicity complications of posterior reversible encephalopathy syndrome (PRES), hemorrhage, and seizures, cytomegalovirus (CMV) infection, adenovirus infection, Epstein-Barr virus (EBV) infection, post-transplant lymphoproliferative disease (PTLD), and invasive fungal infection.
Time Frame
1 year after transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of severe sickle cell disease and have one or more of the following: Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours 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 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 ≥ 38.5 Celsius, 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. 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 as new onset of pain that last for at least 2 hours for which there is no other explanation (i.e. vaso-occlusive, priapism). Administration of regular red blood cell (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) 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: Karnofsky performance score greater than or equal to 60 Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction > 26% by cardiac echocardiogram or by multigated acquisition (MUGA) scan. Pulmonary function: Pulse oximetry with a baseline O2 saturation of greater than or equal to 85% and diffusing capacity of the lungs for carbon monoxide (DLCO) > 40% (corrected for hemoglobin) 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 glomerular filtration rate (GFR); or GFR > 70 mL/min/1.73 m2 by radionuclide GFR. Hepatic function: Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory; and alanine aminotransferase (ALT) and aspartate aminotransferase (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 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). 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lakshmanan Krishnamurti, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
Children's National Medical Center
City
Washington, D.C.
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Children's Healthcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Chidren's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Links:
URL
http://www.chp.edu/CHP/stride
Description
Website with more information about the STRIDE study as well as other clinical trials being conducted at the Children's Hospital of Pittsburgh

Learn more about this trial

Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease

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