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

Sickle Cell Disease Clinical Trial

— STRIDE2  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02766465
• Other study ID #: BMT CTN 1503
• Secondary ID: 1U01HL128568-01
• Status: Completed
• Phase: Phase 2
• Start date: November 2016
• Est. completion date: May 2, 2023

Study information

• Verified date: August 2023
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 138
• Est. completion date: May 2, 2023
• Est. primary completion date: May 2, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years to 40 Years

Eligibility

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 Sß) 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 with a donor search prior to referral (consultation with HCT physician).

1. If a subject has had HLA typing and a related donor search that did not identify a suitably matched relative (i.e., sibling) at any time, and also did not have an unrelated donor search, the patient will be considered eligible.

2. If a subject has had HLA typing and a related donor search that did not identify a suitably matched relative (i.e., sibling) at any time and had an unrelated donor search that did not identify a suitably matched unrelated donor = 1 year prior to enrollment, the patient will be considered eligible.

3. If a subject has had HLA typing with no related donor search and had an unrelated donor search that did not identify a suitably matched unrelated donor = 1 year prior to enrollment, the patient will be considered eligible.

4. Subjects with a known HLA-identical sibling or HLA-matched unrelated donor are excluded

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.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Busulfan
A: 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.
• Fludarabine
A: Fludarabine dose will be 35 mg/m^2/day administered IV on days -7 through -3 (total fludarabine dose is 175 mg/m^2). C: Fludarabine 30mg/m2 IV dose will be given on Days -8, -7, -6, -5, -4
• r-ATG
A: 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).

Procedure:
• Hematopoietic Cell Transplant
A,B,C: Day 0 is the day of transplantation.

Drug:
• Tacrolimus
A: Tacrolimus commences on day -3 and extends through day +180 after transplantation with doses adjusted to maintain appropriate levels according to institutional guidelines. C: Tacrolimus at therapeutic doses through Day 180, then taper per institutional guidelines
• Methotrexate
A: 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. C: Methotrexate IV 7.5 mg/m2 dose will be given on Days +1, 3, +6 following transplant

Procedure:
• Standard of Care
Continue to receive standard of care treatment per patient's SCD physician.

Drug:
• Alemtuzumab
B: 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 C: 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.
• Total Body Irradiation (TBI)
Total Body Irradiation 300 cGY on Day -2
• Sirolimus
Sirolimus at therapeutic doses through day 180, then taper per institutional guidelines if donor CD3+ >50%
• Melphalan
C: Melphalan 140 mg/m2 IV dose will be given on Day -3
• G-CSF
G-CSF 5 µg/kg/day continue until neutrophil engraftment.

Locations

Country	Name	City	State
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Emory University	Atlanta	Georgia
United States	Grady Memorial Hospital	Atlanta	Georgia
United States	Augusta University Medical Center	Augusta	Georgia
United States	Boston University	Boston	Massachusetts
United States	Dana Farber Cancer Institute/Brigham & Women's Hospital	Boston	Massachusetts
United States	Dana Farber Cancer Institute/Massachusetts General Hospital	Boston	Massachusetts
United States	Montefiore Medical Center/Albert Einstein School of Medicine	Bronx	New York
United States	New York Presbyterian Brooklyn Methodist Hospital	Brooklyn	New York
United States	University of North Carolina Hospital at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Ohio State University	Columbus	Ohio
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida Gainsville	Gainesville	Florida
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Foundation for Sickle Cell Research/Florida Sickle Inc.	Hollywood	Florida
United States	Baylor College of Medicine/The Methodist Hospital	Houston	Texas
United States	University of Texas Health Sciences Center	Houston	Texas
United States	University of Texas/MD Anderson CRC	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	University of Miami	Miami	Florida
United States	Cohen Children's Medical Center	New Hyde Park	New York
United States	Children's Hospital of New Orleans	New Orleans	Louisiana
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Benioff Children's Hospital at Oakland	Oakland	California
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health Sciences University	Portland	Oregon
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Washington University/St. Louis Children's Hospital	Saint Louis	Missouri
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (6)

Lead Sponsor	Collaborator
Medical College of Wisconsin	Blood and Marrow Transplant Clinical Trials Network, Dana-Farber Cancer Institute, Emory University, National Heart, Lung, and Blood Institute (NHLBI), National Marrow Donor Program

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	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.	2 Years
Secondary	Occurrence of Sickle Cell Disease (SCD) related events	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 Years
Secondary	Mean Pain Intensity	Mean pain intensity assessed by an electronic pain diary.	Day 28, 1 year, and 2 years
Secondary	Exercise Capacity	The 6-minute walk distance (6MWD) test will be used to assess exercise capacity.	Day 28, 1 year, and 2 years
Secondary	Cardiac Function	Cardiac function will be assessed by the change from baseline in Tricuspid regurgitant jet velocity (TRJV).	Day 28, 1 year, and 2 years
Secondary	Pulmonary Function	Pulmonary function will be assessed by the change from baseline in Forced Expiratory Volume 1 second (FEV1).	Day 28, 1 year, and 2 years
Secondary	Renal Function	Renal function will be assessed through measurements of albuminuria (urine-albumin creatinine ratio) and serum creatinine.	Day 28, 1 year, and 2 years
Secondary	Health-Related Quality of Life (HRQoL)	HRQoL assessed using the NIH's PROMIS 57 instrument.	Day 28, 1 year, and 2 years

External Links

•   National Marrow Donor Program