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 : May 26, 2020
|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 Drug: Alemtuzumab Drug: Total Body Irradiation (TBI) Drug: Sirolimus Drug: Melphalan Drug: G-CSF||Phase 2|
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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||200 participants|
|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)|
|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|
Experimental: Donor Arm
Donor Arm patients will undergo hematopoietic cell transplant. Patients with a matched unrelated donor will receive a bone marrow transplant (unless PBSC graft is pre-approved per section 2.5.1 using a preparative regimen with Busulfan, Fludarabine and rabbit ATG. Patients with an HLA-identical sibling donor can receive a transplant using one of three regimens:
A. Busulfan, Fludarabine, and rabbit ATG using a bone marrow graft (preferred regimen) B. Alemtuzumab/TBI 300 cGy using a peripheral blood graft C. Alemtuzumab, fludarabine, melphalan using a bone marrow graft
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
Fludarabine dose will be 35 mg/m^2/day administered IV on days -7 through -3 (total fludarabine dose is 175 mg/m^2).
Fludarabine 30mg/m2 IV dose will be given on Days -8, -7, -6, -5, -4
Other Name: Fludara
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
Tacrolimus commences on day -3 and extends through day +180 after transplantation with doses adjusted to maintain appropriate levels according to institutional guidelines.
Tacrolimus at therapeutic doses through Day 180, then taper per institutional guidelines
Other Name: Prograf®
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.
Methotrexate IV 7.5 mg/m2 dose will be given on Days +1, 3, +6 following transplant
Other Name: MTX
Alemtuzumab 0.03 mg/kg IV dose will be given on Day -7, Alemtuzumab 0.1 mg/kg IV dose will be given on Day -6, Alemtuzumab 0.3 mg/kg IV dose will be given on Day -5,-4,-3
Alemtuzumab test dose 3 mg IV once 24 hours prior to 1st dose of Alemtuzumab Alemtuzumab 10 mg IV, 15 mg IV, 20 mg IV given on Days -22 through Day -18. Alemtuzumab doses may be administered between Days -22 and -18 but are required to be on three consecutive days.
Other Name: Lemtrada
Drug: Total Body Irradiation (TBI)
Total Body Irradiation 300 cGY on Day -2
Sirolimus at therapeutic doses through day 180, then taper per institutional guidelines if donor CD3+ >50%
Other Name: Rapamune
Melphalan 140 mg/m2 IV dose will be given on Day -3
Other Name: Alkeran
G-CSF 5 μg/kg/day continue until neutrophil engraftment.
Other Name: Granulocyte colony-stimulating factor
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.
- 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.
- 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.
- Mean Pain Intensity [ Time Frame: Day 28, 1 year, and 2 years ]Mean pain intensity assessed by an electronic pain diary.
- 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.
- 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).
- 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).
- 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.
- Health-Related Quality of Life (HRQoL) [ Time Frame: Day 28, 1 year, and 2 years ]HRQoL assessed using the NIH's PROMIS 57 instrument.
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: Dinma Ahaiwefirstname.lastname@example.org|
|Contact: Adam Mendizabal, PhDemail@example.com|
|Study Director:||Mary Eapen, MD||Center for International Blood and Marrow Transplant Research|