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

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ClinicalTrials.gov Identifier: NCT02766465
Recruitment Status : Recruiting
First Posted : May 9, 2016
Last Update Posted : August 30, 2017
Information provided by (Responsible Party):

Study Description
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: Bone Marrow 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.

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
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

Arms and Interventions

Arm Intervention/treatment
Experimental: Donor Arm
The donor arm will be treated with a preparative regimen of busulfan, fludarabine, and r-ATG before undergoing the bone marrow transplant. Graft-vs-Host-Disease (GVHD) prophylaxis will be tacrolimus combined with methotrexate.
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: Bone Marrow Transplant
Day 0 is the day of bone marrow transplantation.
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 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.

Outcome Measures

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.

Eligibility Criteria

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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 15.00 - 40.99 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. Three or more pain crises per year in the 2-year period preceding referral (required intravenous pain management in the outpatient or inpatient hospital setting)
    4. Administration of regular RBC transfusion therapy, defined as receiving 8 or more transfusions per year for ≥ 1 year 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.
  3. Adequate physical function as measured by all of the following:

    1. Karnofsky/Lansky performance score > or equal to 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: Pulse oximetry with a baseline O2 saturation of ≥ 85% and Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% (corrected for hemoglobin)
    4. 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).
    5. Hepatic function: Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 times upper limit of normal as per local laboratory. Patients with hyperbilirubinemia as a consequence of hyperhemolysis, or who experience a sudden, profound change in the serum hemoglobin after a RBC transfusion are not excluded.

Exclusion Criteria:

  1. HLA typing prior to referral (consultation with HCT physician). However, if a subject has had HLA typing with accompanying documentation that relatives 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.
  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 (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.
  10. Unwillingness to use approved contraception method from time of biologic assignment until discontinuation of all immunosuppressive medications if assignment at biologic assignment would be to donor arm.

Additional Eligibility Criteria for Transplant after Biologic Assignment to the Donor Arm:

Participants assigned to the Donor Arm at the time of biologic assignment are subject to additional transplant eligibility criteria as specified below. Additional, repeat clinical assessments prior to transplant should be obtained in accordance with institutional policies and standards of care in the interest of good clinical practice.

  1. Participants who are receiving ≥8 packed red blood cell transfusions for ≥1 year or have received ≥20 packed red blood cell transfusions (cumulative) will undergo liver MRI for estimation of hepatic iron content. Liver biopsy is indicated for hepatic iron content ≥7 mg Fe/gm liver dry weight. Histological examination 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) as described in the Manual of Operating Procedures.
  2. Cerebral MRI/MRA within 30 days prior to initiation of transplant conditioning. If there is clinical or radiologic evidence of a recent neurologic event (such as stroke or transient ischemic attack) subjects will be deferred for at least 6 months with repeat cerebral MRI/MRA to ensure stabilization of the neurologic event prior to proceeding to transplantation.
  3. Absence of donor specific HLA antibodies (section 2.5)
  4. 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.
  5. The HLA-matched donor must be medically fit to donate and willing to donate bone marrow.
Contacts and Locations

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): NCT02766465

Contact: Jamie Garrison jgarrison@emmes.com
Contact: Adam Mendizabal, PhD amendizabal@emmes.com

  Show 37 Study Locations
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
Study Director: Mary Eapen, MD Center for International Blood and Marrow Transplant Research
More Information

Additional Information:
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov 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: August 30, 2017
Last Verified: August 2017
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
URL: https://biolincc.nhlbi.nih.gov/home/

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:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Fludarabine phosphate
Antilymphocyte Serum
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