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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01565616
Recruitment Status : Completed
First Posted : March 28, 2012
Results First Posted : September 29, 2017
Last Update Posted : November 21, 2017
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Lakshmanan Krishnamurti, Emory University

Tracking Information
First Submitted Date  ICMJE March 26, 2012
First Posted Date  ICMJE March 28, 2012
Results First Submitted Date  ICMJE August 29, 2017
Results First Posted Date  ICMJE September 29, 2017
Last Update Posted Date November 21, 2017
Actual Study Start Date  ICMJE March 2012
Actual Primary Completion Date June 30, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 29, 2017)
Event -Free Survival Rate [ Time Frame: 1 year after transplant ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 26, 2012)
Event-free survival (EFS) [ Time Frame: 1 year ]
To determine the safety and feasibility of a Bone Marrow Transplantation (BMT) in young adults with severe sickle cell disease (SCD) using a reduced toxicity conditioning regimen. Event-free survival (EFS) at one year after BMT will be evaluated by determining disease status, engraftment, and mortality.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 19, 2017)
  • Graft Failure [ Time Frame: 1 year after transplant ]
    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) [ Time Frame: 1 year after transplant ]
    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) [ Time Frame: 1 year after transplant ]
    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 [ Time Frame: 1 year after transplant ]
    Overall survival is defined as survival with or without sickle cell disease after hematopoietic cell transplantation (HCT).
  • Time to Neutrophil and Platelet Engraftment [ Time Frame: 1 year after transplant ]
    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 [ Time Frame: 1 year after transplant ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2012)
Transplant-related outcomes [ Time Frame: 1 year ]
The secondary objectives of this protocol are to evaluate the effect of a BMT on the clinical course of patients with severe SCD and determining the incidence of other transplant-related outcomes. Specifically, to determine whether pre-transplant organ dysfunction (brain, heart, lung, kidney, liver, spleen, etc) due to SCD can be reversed after a BMT and the incidence of survival, engraftment, GVHD, and other transplant-related conditions.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease
Official Title  ICMJE A Phase II Study of Hematopoietic Stem Cell Therapy for Young Adults With Severe Sickle Cell Disease
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE 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.

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

Other Names:
  • Busulfan (BU)
  • Myleran
  • Busulfex IV
  • Fludarabine (FLU)
  • Fludara
  • Rabbit Anti-thymocyte globulin (ATG)
  • Thymoglobulin
Study Arms  ICMJE Experimental: Bone Marrow Transplant Recipients
Adults with sickle cell disease undergoing a bone marrow transplant from an HLA-identical sibling donor or an unrelated HLA-matched donor.
Intervention: Drug: Conditioning Regimen with Bone Marrow Transplant
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 12, 2017)
22
Original Estimated Enrollment  ICMJE
 (submitted: March 26, 2012)
15
Actual Study Completion Date  ICMJE June 30, 2016
Actual Primary Completion Date June 30, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01565616
Other Study ID Numbers  ICMJE IRB00068287
1R34HL108761-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Lakshmanan Krishnamurti, Emory University
Study Sponsor  ICMJE Emory University
Collaborators  ICMJE
  • National Institutes of Health (NIH)
  • National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Lakshmanan Krishnamurti, MD Emory University
PRS Account Emory University
Verification Date October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP