Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Evaluating the Safety and Effectiveness of Bone Marrow Transplants in Children With Sickle Cell Disease (BMT CTN 0601) (SCURT)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00745420
Recruitment Status : Completed
First Posted : September 3, 2008
Results First Posted : December 26, 2017
Last Update Posted : May 10, 2018
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Sickle Cell Disease Clinical Research Network
Information provided by (Responsible Party):
Medical College of Wisconsin

Tracking Information
First Submitted Date  ICMJE August 29, 2008
First Posted Date  ICMJE September 3, 2008
Results First Submitted Date  ICMJE August 23, 2017
Results First Posted Date  ICMJE December 26, 2017
Last Update Posted Date May 10, 2018
Study Start Date  ICMJE August 2008
Actual Primary Completion Date July 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 9, 2018)
Percentage of Participants With Event-Free Survival (EFS) [ Time Frame: 2 years ]
EFS is defined as percentage of participants that have not had an event. Primary or secondary graft rejection, disease recurrence, or death will count as events for this endpoint.
Original Primary Outcome Measures  ICMJE
 (submitted: August 29, 2008)
Event-free survival [ Time Frame: Measured at Year 2 ]
Change History Complete list of historical versions of study NCT00745420 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • Percentage of Participants With Overall Survival (OS) [ Time Frame: 2 years ]
    OS is defined as the percentage of participants that have not died.
  • Neutrophil and Platelet Recovery [ Time Frame: Up to 100 days ]
    Time to neutrophil recovery is defined as the time of the first of three measurements on consecutive days where the patient has an absolute neutrophil count of >= 500/uL following conditioning regimen induced nadir. Time to platelet recovery is defined as the time of the first of three measurements on consecutive days where the patient has achieved a platelet count > 50,000/uL and is platelet transfusion independent for a minimum of seven days following conditioning regimen induced nadir.
  • Graft Rejection [ Time Frame: 1 year ]
    Primary graft rejection is defined as the presence of less than 20% donor cells as assessed by peripheral blood or bone marrow chimerism assays on or after Day 42. Secondary graft rejection is defined as the presence of less than 20% donor derived hematopoietic cells in peripheral blood or bone marrow that occurs after prior evidence of 20% or greater donor cells.
  • Percentage of Participants With Acute Graft-vs-Host-Disease (GVHD) [ Time Frame: 100 days ]
    Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash
    1. Rash <25% of body surface area
    2. Rash on 25-50% of body surface area
    3. Rash on > 50% of body surface area
    4. Generalized erythroderma with bullous formation
    Liver stage (based on bilirubin level)*: 0: <2 mg/dL
    1. 2-3 mg/dL
    2. 3.01-6 mg/dL
    3. 6.01-15.0 mg/dL
    4. >15 mg/dL
    GI stage*: 0: No diarrhea or diarrhea <500 mL/day
    1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD
    2. Diarrhea 1000-1499 mL/day
    3. Diarrhea >1500 mL/day
    4. Severe abdominal pain with or without ileus * If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.
    GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4
  • Percentage of Participants With Chronic GVHD [ Time Frame: 1 year post-transplant ]
    Chronic GVHD is defined per NIH 2005 Consensus Criteria.
  • Number of Participants With Chronic GVHD by Severity [ Time Frame: 1 year post-transplant ]
    Chronic GVHD severity is defined per NIH 2005 Consensus Criteria.
  • Percentage of Participants With Posterior Reversible Encephalopathy Syndrome (PRES) [ Time Frame: 1 year ]
  • Change From Baseline to Day 100 in Participant Reported Health-Related Quality of Life (HRQL) [ Time Frame: 100 days post-transplant ]
    HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in participant reported scores on these HRQL subscales from a pre-transplant baseline assessment to day 100 post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.
  • Change From Baseline to Day 100 in Parent Proxy Reported Health-Related Quality of Life (HRQL) [ Time Frame: 100 days post-transplant ]
    HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in parent proxy reported scores on these HRQL subscales from a pre-transplant baseline assessment to day 100 post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.
  • Change From Baseline to Day 180 in Participant Reported Health-Related Quality of Life (HRQL) [ Time Frame: 180 days post-transplant ]
    HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in participant reported scores on these HRQL subscales from a pre-transplant baseline assessment to day 180 post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.
  • Change From Baseline to Day 180 in Parent Proxy Reported Health-Related Quality of Life (HRQL) [ Time Frame: 180 days post-transplant ]
    HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in parent proxy reported scores on these HRQL subscales from a pre-transplant baseline assessment to day 180 post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.
  • Change From Baseline to 1 Year in Participant Reported Health-Related Quality of Life (HRQL) [ Time Frame: 1 year post-transplant ]
    HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in participant reported scores on these HRQL subscales from a pre-transplant baseline assessment to 1 year post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.
  • Change From Baseline to 1 Year in Parent Proxy Reported Health-Related Quality of Life (HRQL) [ Time Frame: 1 year post-transplant ]
    HRQL will be assessed using the Self-Esteem, General Health Perception, and Change in Health subscales of the Child Health Questionnaire (CHQ Child Form 87). The changes in parent proxy reported scores on these HRQL subscales from a pre-transplant baseline assessment to 1 year post-transplant will be evaluated. Each subscale is scored is scored in the range 0-100, with higher scores indicating better health and well-being. Therefore, a negative mean change in score denotes worsening HRQL score and positive mean change in score denotes an improved HRQL score over time.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 29, 2008)
  • Survival; red blood cell, neutrophil, and platelet recovery; aGVHD; cGVHD; hepatic veno-occlusive disease; idiopathic pneumonia syndrome; and central nervous system toxicity [ Time Frame: Measured at Year 2 ]
  • Neurocognitive dysfunction; cytomegalovirus, adenovirus and fungal infections; Epstein Barr virus post-transplant lymphoproliferative disease; chimerism; immune reconstitution; and quality of life [ Time Frame: Measured at Year 2 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluating the Safety and Effectiveness of Bone Marrow Transplants in Children With Sickle Cell Disease (BMT CTN 0601)
Official Title  ICMJE Unrelated Donor Reduced Intensity Bone Marrow Transplant for Children With Severe Sickle Cell Disease (BMT CTN #0601)
Brief Summary Sickle cell disease (SCD), also known as sickle cell anemia, is an inherited blood disease that can cause organ damage, stroke, and intense pain episodes. A blood stem cell transplant is a treatment option for someone with a severe form of the disease. Prior to undergoing a transplant, people typically receive a conditioning regimen of high doses of chemotherapy and other medications to prepare the body to accept the transplant. A conditioning regimen that uses lower doses of chemotherapy and medications may be safer for transplant recipients. This study will evaluate the safety and effectiveness of blood stem cell transplants, using bone marrow from unrelated donors, in children with severe SCD who receive a reduced intensity conditioning regimen prior to the transplant.
Detailed Description

SCD is an inherited blood disorder. Symptoms include anemia, infections, organ damage, and intense episodes of pain, also called "sickle cell crises." SCD is caused by an abnormal type of hemoglobin, which is a protein inside red blood cells that carries oxygen to vital organs, such as the brain, heart, lungs, and kidneys. Defective hemoglobin damages red blood cells. The damaged cells, in turn, can block blood flow in vessels and block oxygen and nutrients from reaching organs. For people with severe forms of SCD, one treatment option is a bone marrow transplant, which may correct the abnormal blood cell production problem. In most cases, bone marrow transplants are performed in people who have a healthy sibling with the same tissue type. If people do not have a sibling with the same tissue type, it is possible for them to receive a blood stem cell transplant from an unrelated donor through bone marrow transplant .

Traditionally, people with SCD who are undergoing a bone marrow transplant receive high doses of chemotherapy and medications before the transplant as part of the conditioning regimen to prepare their immune system to accept the donor cells. Participants will experience fewer side effects with a reduced intensity conditioning regimen than with a more intense conditioning regimen. The purpose of this study is to determine the safety and effectiveness of blood stem cell transplants, using bone marrow from unrelated donors, in children with severe SCD who receive a reduced intensity conditioning regimen before the transplant. Specifically, researchers will evaluate whether the reduced intensity conditioning regimen is successful in allowing donor cells to settle and grow successfully, in preventing the production of SCD-damaged red blood cells, and in limiting SCD-related organ damage.

This study will enroll children with severe SCD who lack a sibling with the same tissue type who can serve as their donor. Participants will attend a study visit prior to the transplant to undergo a blood collection, neurocognitive testing to measure learning and brain function, and magnetic resonance angiogram (MRA) and magnetic resonance imaging (MRI) scans. Questionnaires to assess quality of life will also be completed. Twenty-two days before the transplant, participants will begin receiving a reduced intensity conditioning regimen of chemotherapy and medications to prepare them for the transplant. Eight days before the transplant, participants will be admitted to the hospital and will continue the conditioning regimen. Participants will then receive the bone marrow transplant. After the transplant, participants will receive immunosuppression medications for at least 6 months to prevent graft-versus-host disease (GVHD), which may occur if the immune cells from the donated bone marrow attacks the body of the recipient. One week after the transplant, participants will receive granulocyte-colony-stimulating factor (G-CSF), which is a natural protein that increases the white blood cell count and helps protect the body against infections. Participants will receive G-CSF until their white blood cell level is normal again. Participants will remain in the hospital and be closely monitored for signs of infection or other complications until study researchers feel it is safe for them to return home.

After leaving the hospital, participants will attend study visits weekly during Weeks 1 to 8, at Day 60, weekly during Weeks 9 to 14, at Day 100, at Month 6, and at Years 1 and 2. At all study visits, a blood collection, medical history review, and physical exam will occur. In addition, at Day 100, Month 6, and Years 1 and 2, questionnaires to assess quality of life will be completed. At select visits the following procedures will also occur: lung function testing, heart function testing, MRA and MRI scans, and neurocognitive testing.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE Biological: Hematopoietic Stem Cell Transplantation

The stem cell transplant preparative regimen is listed below. Day 0 is the day of the transplant. The - sign is the number of days before and the + sign is the number of days after the transplant.

  • Alemtuzumab: Children weighing 10 kg or more will receive 10 mg, 15 mg, and 20 mg intravenously (IV) on Days -21, -20, and -19, respectively
  • Fludarabine: 30 mg/m^2/day IV on Days -8 through -4
  • Melphalan: 140 mg/m^2 IV on Day -3
  • Rest on Days -2 and -1
  • Transplant occurs on Day 0
  • GVHD prophylaxis: Tacrolimus or cyclosporine beginning Day -3, methotrexate (7.5 mg/m2/day) Day 1, 3 and 6 and methylprednisolone/prednisone on Day +7 to +28 followed by a taper if there is no GVHD
Other Name: Bone Marrow Transplant
Study Arms  ICMJE Experimental: Hematopoietic Stem Cell Transplantation
Bone Marrow Transplant with GVHD Prophylaxis Regimen
Intervention: Biological: Hematopoietic Stem Cell Transplantation
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 28, 2017)
30
Original Estimated Enrollment  ICMJE
 (submitted: August 29, 2008)
45
Actual Study Completion Date  ICMJE September 2016
Actual Primary Completion Date July 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • SCD (genotype hemoglobin SS disease [Hb SS], genotype hemoglobin SC disease [HbSC],sickle ß°[Sß°] thalassemia, or sickle ß^+[Sß^+]thalassemia) with one or more of the following:

    1. Patients must have symptomatic SCD (genotype Hb SS, Hb SC, Sß° thalassemia or Sß+ thalassemia), AND have 1 or more of the following clinical complications:(i) Clinically significant neurologic event (stroke) or any neurologic deficit lasting more than 24 hours that is accompanied by an infarct on cerebral MRI; OR (ii) patients who have a Transcranial Doppler (TCD) velocity that exceeds 200 cm/sec by the non-imaging technique (or TCD measurement greater than 185 cm/sec by the imaging technique) measured at a minimum of 2 separate occasions one month or more apart; OR,
    2. Minimum of two episodes of acute chest syndrome in the 2 years before study entry, defined as new pulmonary alveolar consolidation involving at least one complete lung segment (associated with acute symptoms including fever, chest pain, tachypnea, wheezing, rales, or cough that is not attributed to asthma or bronchiolitis) despite adequate supportive care measures
    3. History of 3 or more severe pain events per year in the 2 years before study entry
  • Lansky/Karnofsky performance score greater than or equal to 40
  • Patients must have an unrelated adult bone marrow donor who is Human Leukocyte Antigen (HLA)-matched at 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing.
  • Patients with adequate physical function: a)Cardiac: Left ventricular ejection fraction (LVEF) greater than 40%, or LV shortening fraction greater than 26%; b) Pulmonary: Pulse oxymetry with a baseline O2 saturation of greater than or equal to 85% is required for all patients, Carbon Monoxide Diffusing Capacity (DLCO) greater than 40% (corrected for hemoglobin) for patients in whom pulmonary function testing can be performed; c) Renal: Serum creatinine less than or equal to 1.5 x upper limit of normal for age and glomerular filtration rate (GFR) greater than 100 mL/min/1.73 m. For patients older than or equal to 16 years of age, GFR should be greater than 70 mL/min/1.73 m^2; d) Hepatic: Serum conjugated (direct) bilirubin less than 2x upper limit of normal for age as per local laboratory; alanine transaminase (ALT) and aspartate transaminase (AST) less than 5 times upper limit of normal as per local laboratory.
  • If the patient has been receiving chronic transfusion therapy for more than or equal to 1 year AND has clinical evidence of iron overload (serum ferritin level of greater than 1000 ng/ml), a liver biopsy shall be obtained within 90 days of starting conditioning therapy (alemtuzumab). Histologic exam of the liver must document absence of bridging fibrosis or cirrhosis of the liver. In other cases, a liver biopsy is optional.
  • Hemoglobin S (Hb S) level less than or equal to 45%, seven days prior to initiation of alemtuzumab

Exclusion Criteria:

  • Evidence of uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms) within 1 month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen
  • Pregnant or breastfeeding
  • Patients with 8/8 HLA-matched family donors able to donate
  • Seropositivity for HIV
  • Prior allogeneic marrow or stem cell transplant
  • Iron chelation must be discontinued more than or equal to 48 hours before initiating the conditioning regimen
  • Hydroxyurea (if receiving this therapy) must be discontinued more than or equal to 48 hours before initiating the conditioning regimen
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 19 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00745420
Other Study ID Numbers  ICMJE BMTCTN0601
U01HL069294 ( U.S. NIH Grant/Contract )
5U24CA076518 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
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
Supporting Materials: 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/
Responsible Party Medical College of Wisconsin
Study Sponsor  ICMJE Medical College of Wisconsin
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Blood and Marrow Transplant Clinical Trials Network
  • National Cancer Institute (NCI)
  • National Marrow Donor Program
  • Sickle Cell Disease Clinical Research Network
Investigators  ICMJE
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
PRS Account Medical College of Wisconsin
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP