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

• ClinicalTrials.gov Identifier: NCT02766465
• Recruitment Status: Recruiting
• First Posted: May 9, 2016
• Last Update Posted: September 12, 2019
• Sponsor: Medical College of Wisconsin
• Collaborators: 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

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: 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.

Study Design

• 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

Arms and Interventions

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.

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

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Jamie Garrison; bmtctn1503@emmes.com

Contact: Adam Mendizabal, PhD; amendizabal@emmes.com

  Hide Study Locations

Locations

United States, California

Benioff Children's Hospital at Oakland; Recruiting

Oakland, California, United States, 94609

Contact: Mark Walters MWalters@mail.cho.org

United States, District of Columbia

Children's National Medical Center; Recruiting

Washington, District of Columbia, United States, 20010

Contact: Allistair Abraham AAbraham@childrensnational.org

United States, Florida

University of Florida Gainsville; Recruiting

Gainesville, Florida, United States, 32611

Contact: Paul Castillo castillopa@ufl.edu

Foundation for Sickle Cell Research/Florida Sickle Inc.; Recruiting

Hollywood, Florida, United States, 33021

Contact: Gershwin Blyden GBlyden@fscdr.org

University of Miami; Recruiting

Miami, Florida, United States, 33136

Contact: Lazaros Lekakis LLekakis@med.miami.edu

United States, Georgia

Grady Memorial Hospital; Recruiting

Atlanta, Georgia, United States, 30303

Contact: Fuad El Rassi fuad.elrassi@emory.edu

Children's Healthcare of Atlanta; Recruiting

Atlanta, Georgia, United States, 30322

Contact: Lakshmanan Krishnamurti lakshmanan.krishnamurti@emory.edu

Emory University; Recruiting

Atlanta, Georgia, United States, 30322

Contact: Edmund Waller ewaller@emory.edu

Augusta University Medical Center; Recruiting

Augusta, Georgia, United States, 30912

Contact: Jeremy Pantin JPANTIN@gru.edu

United States, Iowa

University of Iowa; Recruiting

Iowa City, Iowa, United States, 52242

Contact: Arunkumar Modi Arunkumar-modi@uiowa.edu

United States, Louisiana

Children's Hospital of New Orleans; Recruiting

New Orleans, Louisiana, United States, 70118

Contact: Lolie Yu lyu@lsuhsc.edu

United States, Massachusetts

Dana Farber Cancer Institute/Brigham & Women's Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Zachariah Defilipp zdefilipp@mgh.harvard.edu

Dana Farber Cancer Institute/Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02115

Contact: Joseph Antin jantin@partners.org

Boston University; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Elizabeth Klings klingon@bu.edu

United States, Michigan

Barbara Ann Karmanos Cancer Institute; Recruiting

Detroit, Michigan, United States, 48201

Contact: Paul Swerdlow swerdlow@karmanos.org

United States, Missouri

Washington University/St. Louis Children's Hospital; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Mark Schroeder markschroeder@wustl.edu

United States, New Jersey

Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

Contact: Jennifer Krajewski JKrajewski@HackensackUMC.org

Newark Beth Israel Medical Center; Recruiting

Newark, New Jersey, United States, 07112

Contact: Alice J Cohen acohen@barnabashealth.org

United States, New York

Montefiore Medical Center/Albert Einstein School of Medicine; Recruiting

Bronx, New York, United States, 10467

Contact: Murali Janakiram mjanakir06@gmail.com

New York Presbyterian Brooklyn Methodist Hospital; Recruiting

Brooklyn, New York, United States, 11215

Contact: Ayanna Baptiste amb9075@nyp.org

Cohen Children's Medical Center; Not yet recruiting

New Hyde Park, New York, United States, 11040

Contact: Indira Sahdev ISahdev@northwell.edu

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 Tbs2001@med.cornell.edu

United States, North Carolina

University of North Carolina Hospital at Chapel Hill; Recruiting

Chapel Hill, North Carolina, United States, 27516

Contact: Kimberly Kasow kimberly_kasow@med.unc.edu

Duke University Medical Center; Recruiting

Durham, North Carolina, United States, 27705

Contact: Keith Sullivan keith.sullivan@duke.edu

United States, Ohio

Ohio State University; Recruiting

Columbus, Ohio, United States, 43210

Contact: Steven Devine, MD steven.devine@osumc.edu

United States, Oklahoma

University of Oklahoma; Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contact: George Selby, MD 405-271-4022 George-selby@ouhsc.edu

United States, Oregon

Oregon Health Sciences University; Recruiting

Portland, Oregon, United States, 97239

Contact: Trisha Wong wong@ohsu.edu

United States, Pennsylvania

Children's Hospital of Philadelphia; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Tim Olsen olsont@email.chop.edu

Children's Hospital of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Contact: Beth Carella beth.carella@chp.edu

United States, South Carolina

Medical University of South Carolina; Recruiting

Charleston, South Carolina, United States, 29425

Contact: Jennifer Jaroscak jaroscak@musc.edu

United States, Texas

University of Texas Health Sciences Center; Recruiting

Houston, Texas, United States, 77004

Contact: Harinder Juneia harinder.s.juneja@uth.tmc.edu

Baylor College of Medicine/The Methodist Hospital; Recruiting

Houston, Texas, United States, 77030

Contact: Premal Lulla lulla@bcm.edu

University of Texas/MD Anderson CRC; Recruiting

Houston, Texas, United States, 77030

Contact: Uday Popat upopat@mdanderson.org

United States, Virginia

University of Virginia; Recruiting

Charlottesville, Virginia, United States, 22908

Contact: Tamila Kindwall-Keller TLK5DE@hscmail.mcc.virginia.edu

Virginia Commonwealth University; Recruiting

Richmond, Virginia, United States, 23298

Contact: Christina Wiedl cwiedl@vcu.edu

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

Investigators

• Study Director: Mary Eapen, MD; Center for International Blood and Marrow Transplant Research

More Information

Additional Information:

Blood and Marrow Transplant Clinical Trials Network Website  National Marrow Donor Program 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Krishnamurti L, Neuberg DS, Sullivan KM, Kamani NR, Abraham A, Campigotto F, Zhang W, Dahdoul T, De Castro L, Parikh S, Bakshi N, Haight A, Hassell KL, Loving R, Rosenthal J, Smith SL, Smith W, Spearman M, Stevenson K, Wu CJ, Wiedl C, Waller EK, Walters MC. Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study. Am J Hematol. 2019 Apr;94(4):446-454. doi: 10.1002/ajh.25401. Epub 2019 Feb 11.

• 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
• 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
• URL: https://biolincc.nhlbi.nih.gov/home/

• 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:

Anemia, Sickle Cell; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Methotrexate; Fludarabine phosphate; Fludarabine; Busulfan; Tacrolimus; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; 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