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Bone Marrow Transplantation vs Standard of Care in Patients With Severe Sickle Cell Disease (BMT CTN 1503) (STRIDE2)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02766465
Recruitment Status : Recruiting
First Posted : May 9, 2016
Last Update Posted : September 12, 2019
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
Dana-Farber Cancer Institute
National Marrow Donor Program
Emory University
Information provided by (Responsible Party):
Medical College of Wisconsin

Brief Summary:
This is a clinical trial that will compare survival and sickle related outcomes in adolescents and young adults with severe sickle cell disease after bone marrow transplantation and standard of care. The primary outcome is 2-year overall survival.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Busulfan Drug: Fludarabine Drug: r-ATG Procedure: Hematopoietic Cell Transplant Drug: Tacrolimus Drug: Methotrexate Procedure: Standard of Care Phase 2

Detailed Description:

This is a prospective phase II multi-center trial of hematopoietic stem cell transplantation or standard of care based on availability of HLA-matched related or unrelated donor after confirmation of clinical eligibility. In order to minimize bias assignment to either treatment arm, clinical eligibility to both treatment arms are similar and donor availability is not known at referral. HLA typing and donor search is initiated upon confirmation of clinical eligibility for the study. Additionally, all analyses of primary and secondary endpoints will follow the Intent-to-Treat principle to address potential bias introduced by participants with donors not proceeding to transplantation or those without a matched donor receiving transplantation with less well-matched donors.

The primary outcome is 2-year overall survival. Our hypothesis is that patients who receive bone marrow transplantation will experience early deaths but that this will plateau by 2 years after transplantation. Patients who receive standard of care will not experience early death but will succumb to their disease at a rate much higher than the general population. Therefore, the goal of the study is to establish that the difference in the proportion of patients surviving is not significantly more than 15% lower in the donor arm at 2-years after assignment to treatment arm.

Secondary endpoints will compare changes in sickle cell disease related events (pulmonary hypertension, cerebrovascular events, renal function, avascular necrosis, leg ulcer) and functional outcomes [6-minute walk distance (6MWD), health-related quality of life, cardiac function, pulmonary function, and mean pain intensity as assessed by a multidimensional electronic pain diary] from baseline to 2-years after assignment to treatment arms.

Additionally for patients assigned to the donor arm and expected to undergo transplantation, hematopoietic recovery, graft rejection, acute and chronic graft-versus-host disease, other significant transplant-related complications and disease-free survival will be reported.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients are enrolled without a known donor. All patients have 180 days from confirmation of eligibility to confirm a donor. Patients with a donor will be assigned to the Donor Arm and receive HCT; patients without a donor will be assigned to the no donor arm and continue receiving standard of care for their SCD.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Study to Compare Bone Marrow Transplantation to Standard Care in Adolescents and Young Adults With Severe Sickle Cell Disease (BMT CTN #1503)
Actual Study Start Date : November 2016
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Donor Arm
Donor Arm patients will undergo hematopoietic cell transplant
Drug: Busulfan
Busulfan dose will be 3.2 mg/kg administered as a single daily dose IV on days -8 through -5 with dosing adjusted using targeted pharmacokinetics.
Other Name: Busulfex

Drug: Fludarabine
Fludarabine dose will be 35 mg/m^2/day administered IV on days -7 through -3 (total fludarabine dose is 175 mg/m^2).
Other Name: Fludara

Drug: r-ATG
r-ATG will be administered IV on day -6 at 0.5mg/kg, on day -5 at 1 mg/kg and on days -4, -3 and -2 at 1.5mg/kg (total r-ATG dose is 6 mg/kg).
Other Name: Rabbit antithymocyte globulin

Procedure: Hematopoietic Cell Transplant
Day 0 is the day of transplantation.
Other Name: Bone Marrow Transplant; BMT; HCT

Drug: Tacrolimus
Tacrolimus commences on day -3 and extends through day +180 after transplantation with doses adjusted to maintain appropriate levels according to institutional guidelines.
Other Name: Prograf®

Drug: Methotrexate
Methotrexate will be administered intravenously on day+1 at 15mg/m^2, day+3 at 10mg/m^2, day+6 at 10mg/m^2, and day+11 at 10mg/m^2.
Other Name: MTX

Active Comparator: No-Donor Arm
No-donor arm patients will continue with standard of care per their SCD physician.
Procedure: Standard of Care
Continue to receive standard of care treatment per patient's SCD physician.

Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 2 Years ]
    OS will be compared between treatment arms using a point-wise comparison at 2-years, and the survival curves will be estimated using the Kaplan Meier product limit estimator.

Secondary Outcome Measures :
  1. Occurrence of Sickle Cell Disease (SCD) related events [ Time Frame: 2 Years ]
    Examination of the occurrence of the SCD-related events will be performed. Exact logistic regression will be used to estimate an odds ratio of each of these events between treatment groups, assuming that at least one event occurs on study in each of the treatment groups, controlling for other patient related characteristics and individual history of the event of interest.

  2. Mean Pain Intensity [ Time Frame: Day 28, 1 year, and 2 years ]
    Mean pain intensity assessed by an electronic pain diary.

  3. Exercise Capacity [ Time Frame: Day 28, 1 year, and 2 years ]
    The 6-minute walk distance (6MWD) test will be used to assess exercise capacity.

  4. Cardiac Function [ Time Frame: Day 28, 1 year, and 2 years ]
    Cardiac function will be assessed by the change from baseline in Tricuspid regurgitant jet velocity (TRJV).

  5. Pulmonary Function [ Time Frame: Day 28, 1 year, and 2 years ]
    Pulmonary function will be assessed by the change from baseline in Forced Expiratory Volume 1 second (FEV1).

  6. Renal Function [ Time Frame: Day 28, 1 year, and 2 years ]
    Renal function will be assessed through measurements of albuminuria (urine-albumin creatinine ratio) and serum creatinine.

  7. Health-Related Quality of Life (HRQoL) [ Time Frame: Day 28, 1 year, and 2 years ]
    HRQoL assessed using the NIH's PROMIS 57 instrument.

Information from the National Library of Medicine

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Ages Eligible for Study:   15 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age ≥ 15 and < 41 years
  2. Severe sickle cell disease [Hemoglobin SS (Hb SS), Hemoglobin SC (Hb SC) or Hemoglobin SBeta thalassemia (Hb Sβ) genotype] with at least 1 of the following manifestations (a-e):

    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);
    3. An average of three or more pain crises per year in the 2-year period preceding enrollment (required intravenous pain management in the outpatient or inpatient hospital setting). Clinical documentation of pain management in the inpatient or outpatient setting is required.
    4. Administration of regular RBC transfusion therapy, defined as receiving 8 or more transfusion events per year (in the 12 months before enrollment) to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome)
    5. An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity ≥ 2.7 m/sec.
    6. Ongoing high impact chronic pain on a majority of days per month for ≥ 6 months as defined as ONE or more of the following: Chronic pain without contributory SCD complications, OR Mixed pain type in which chronic pain is occurring at site(s) (arms, back, chest, or abdominal pain) unrelated to any sites associated with Contributory SCD complications (e.g. leg ulcers and/or avascular necrosis).

    i. High impact chronic pain is identified as those reporting "severe interference" with life activities OR "usually or always" experiencing a limitation of their life or work activities including household chores. (See guidelines for identifying HICP in the BMT CTN 1503 Manual of Procedures) ii. Contributory SCD complications are defined as clinical signs (e.g. presence of leg ulcers) or clinical assessments (e.g. imaging confirmation of splenic infarct or avascular necrosis). Chronic pain attributed solely to contributory SCD complications is excluded.

  3. Adequate physical function as measured by all of the following:

    1. Karnofsky/Lansky performance score ≥ 60
    2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction > 26% by cardiac echocardiogram or by Multi Gated Acquisition Scan (MUGA).
    3. Pulmonary function:

    a. Pulse oximetry with a baseline O2 saturation of ≥ 85% b. Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% (corrected for hemoglobin) d. Renal function: Serum creatinine ≤ 1.5 x the upper limit of normal for age as per local laboratory and 24 hour urine creatinine clearance >70 mL/min; or GFR > 70 mL/min/1.73 m2 by radionuclide Glomerular Filtration Rate (GFR).

    e. Hepatic function:

    1. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory. Participants are not excluded if the serum conjugated (direct) bilirubin is >2x the upper limit of normal for age as per local laboratory and: There is evidence of a hyperhemolytic reaction after a recent RBC transfusion, OR there is evidence of moderate direct hyperbilirubinemia defined as direct serum bilirubin < 5 times ULN and not caused by underlying hepatic diseasePatients
    2. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 times upper limit of normal as per local laboratory.

Additional inclusion required for donor arm participants to proceed with transplant

  1. Liver MRI (≤ 90 days prior to initiation of transplant conditioning) to document hepatic iron content is required for participants who are currently receiving ≥8 packed red blood cell transfusions for ≥1 year or have received ≥20 packed red blood cell transfusions (cumulative). Participants who have hepatic iron content ≥7 mg Fe/ g liver dry weight by liver MRI must have a liver biopsy and histological examination/documentation of the absence of cirrhosis, bridging fibrosis and active hepatitis (≤ 90 days prior to initiation of transplant conditioning).
  2. Lack of clinical or radiologic evidence of a recent neurologic event (such as stroke or transient ischemic attack) by Cerebral MRI/MRA within 30 days prior to initiating transplant conditioning. Subjects with clinical or radiologic evidence of a recent neurologic event will be deferred for ≥ 6 months with repeat cerebral MRI/MRA to ensure stabilization of the neurologic event prior to proceeding to transplantation
  3. Documentation of participant's willingness to use approved contraception method until discontinuation of all immunosuppressive medications is to be documented in the medical record corresponding with the consent conference.

Exclusion Criteria:

  1. HLA typing prior to referral (consultation with HCT physician). If a subject has had HLA typing with accompanying documentation that full siblings were not HLA typed and that a search of the unrelated donor registry was not performed the subject will be considered eligible. Documentation will be reviewed and adjudicated by the Protocol Officer or his/her designee.
  2. Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment.
  3. Seropositivity for HIV.
  4. Previous HCT or solid organ transplant.
  5. Participation in a clinical trial in which the patient received an investigational drug or device must be discontinued at enrollment.
  6. A history of substance abuse as defined by version IV of the Diagnostic & Statistical Manual of Mental Disorders (DSM IV).
  7. Demonstrated lack of compliance with prior medical care as determined by referring physician.
  8. Pregnant or breast feeding females.
  9. Inability to receive HCT due to alloimmunization, defined as the inability to receive packed red blood cell (pRBC) transfusion therapy.

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 identifier (NCT number): NCT02766465

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Contact: Jamie Garrison
Contact: Adam Mendizabal, PhD

  Hide Study Locations
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United States, California
Benioff Children's Hospital at Oakland Recruiting
Oakland, California, United States, 94609
Contact: Mark Walters   
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Allistair Abraham   
United States, Florida
University of Florida Gainsville Recruiting
Gainesville, Florida, United States, 32611
Contact: Paul Castillo   
Foundation for Sickle Cell Research/Florida Sickle Inc. Recruiting
Hollywood, Florida, United States, 33021
Contact: Gershwin Blyden   
University of Miami Recruiting
Miami, Florida, United States, 33136
Contact: Lazaros Lekakis   
United States, Georgia
Grady Memorial Hospital Recruiting
Atlanta, Georgia, United States, 30303
Contact: Fuad El Rassi   
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Lakshmanan Krishnamurti   
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Edmund Waller   
Augusta University Medical Center Recruiting
Augusta, Georgia, United States, 30912
Contact: Jeremy Pantin   
United States, Iowa
University of Iowa Recruiting
Iowa City, Iowa, United States, 52242
Contact: Arunkumar Modi   
United States, Louisiana
Children's Hospital of New Orleans Recruiting
New Orleans, Louisiana, United States, 70118
Contact: Lolie Yu   
United States, Massachusetts
Dana Farber Cancer Institute/Brigham & Women's Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Zachariah Defilipp   
Dana Farber Cancer Institute/Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Joseph Antin   
Boston University Recruiting
Boston, Massachusetts, United States, 02215
Contact: Elizabeth Klings   
United States, Michigan
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Paul Swerdlow   
United States, Missouri
Washington University/St. Louis Children's Hospital Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Mark Schroeder   
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Jennifer Krajewski   
Newark Beth Israel Medical Center Recruiting
Newark, New Jersey, United States, 07112
Contact: Alice J Cohen   
United States, New York
Montefiore Medical Center/Albert Einstein School of Medicine Recruiting
Bronx, New York, United States, 10467
Contact: Murali Janakiram   
New York Presbyterian Brooklyn Methodist Hospital Recruiting
Brooklyn, New York, United States, 11215
Contact: Ayanna Baptiste   
Cohen Children's Medical Center Not yet recruiting
New Hyde Park, New York, United States, 11040
Contact: Indira Sahdev   
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: John Levine, MD         
Weill Cornell Medical College Recruiting
New York, New York, United States, 10065
Contact: Tsiporah Shore   
United States, North Carolina
University of North Carolina Hospital at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27516
Contact: Kimberly Kasow   
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27705
Contact: Keith Sullivan   
United States, Ohio
Ohio State University Recruiting
Columbus, Ohio, United States, 43210
Contact: Steven Devine, MD   
United States, Oklahoma
University of Oklahoma Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: George Selby, MD    405-271-4022   
United States, Oregon
Oregon Health Sciences University Recruiting
Portland, Oregon, United States, 97239
Contact: Trisha Wong   
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Tim Olsen   
Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Beth Carella   
United States, South Carolina
Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Contact: Jennifer Jaroscak   
United States, Texas
University of Texas Health Sciences Center Recruiting
Houston, Texas, United States, 77004
Contact: Harinder Juneia   
Baylor College of Medicine/The Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Premal Lulla   
University of Texas/MD Anderson CRC Recruiting
Houston, Texas, United States, 77030
Contact: Uday Popat   
United States, Virginia
University of Virginia Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Tamila Kindwall-Keller   
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23298
Contact: Christina Wiedl   
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
Dana-Farber Cancer Institute
National Marrow Donor Program
Emory University
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Study Director: Mary Eapen, MD Center for International Blood and Marrow Transplant Research

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Medical College of Wisconsin Identifier: NCT02766465     History of Changes
Other Study ID Numbers: BMTCTN1503
1U01HL128568-01 ( U.S. NIH Grant/Contract )
First Posted: May 9, 2016    Key Record Dates
Last Update Posted: September 12, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Medical College of Wisconsin:
Sickle Cell Disease
Young Adults
Phase II Trial
Hematopoietic Cell Transplantation (HCT)
Human Leukocyte Antigen (HLA)
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Fludarabine phosphate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Calcineurin Inhibitors
Alkylating Agents
Antineoplastic Agents, Alkylating