Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)
Neutropenia, a condition characterized by an abnormally low number of infection-fighting white blood cells called neutrophils, commonly develops in people who have undergone chemotherapy or hematopoietic stem cell (HSC) transplantation. The severely reduced immunity of those with neutropenia can put them at risk of entry of life-threatening infections, making the implementation of treatments that increase white blood cell numbers important. Several studies have shown that the transfusion of donor granulocytes, a type of white blood cell that includes neutrophils, is effective in promoting the recovery of adequate numbers of granulocytes. However, granulocyte transfusions can cause side effects, and it is not known whether the success of the therapy outweighs the health risks of the side effects. This study will evaluate the safety and effectiveness of granulocyte transfusions in treating people with a bacterial or fungal infection during neutropenia.
Drug: Standard antimicrobial therapy
Biological: Granulocyte transfusions
Device: Apheresis machine
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||High Dose Granulocyte Transfusions for the Treatment of Infection in Neutropenia: The RING Study (Resolving Infection in Neutropenia With Granulocytes)|
- Percentage of Participants Who Are Alive at 42 Days After Treatment and Have Had Microbial Response [ Time Frame: Measured at Day 42 ] [ Designated as safety issue: No ]
Microbial response was defined as follows:
- A negative blood culture test at 42 days after randomization for subjects with fungemia (candidemia or fusariosis) or bacteremia.
- Improvement of signs and symptoms of infectious disease (complete or partial response) at 42 days after randomization.
- Alloimmunization, Defined as the Appearance of Anti-human Leukocyte Antigen (HLA) or Antineutrophil Antibodies [ Time Frame: Measured at Days 14 and 42 ] [ Designated as safety issue: Yes ]
- Serious Granulocyte Transfusion Reactions, Including Febrile, Allergic, and Pulmonary Reactions (Transfusion Arm Only) [ Time Frame: Measured within 6 hours after end of transfusion ] [ Designated as safety issue: Yes ]
- Graft Versus Host Disease Among Recipients of Allogeneic Stem Cell Transplantation [ Time Frame: Measured at Day 42 ] [ Designated as safety issue: Yes ]Time to GVHD incidence between the two treatment groups was compared using Gray's model that takes into account death as a competing risk.
- Overall Incidence of Adverse Effects [ Time Frame: Measured through Day 42 ] [ Designated as safety issue: Yes ]
- Fever Resolution [ Time Frame: Measured through Day 42 ] [ Designated as safety issue: No ]Fever resolution between the two treatment groups was compared using Gray's model that takes into account death as a competing risk.
- Time to Negative Test for Fungal Antigenemia (e.g., Galactomannan Antigenemia Among Participants With Invasive Aspergillosis) [ Time Frame: Measured at Days 7, 14, and 42 ] [ Designated as safety issue: No ]
- Time to Negative Blood Culture for Participants With Positive Blood Culture at Baseline [ Time Frame: Measured through Day 42 ] [ Designated as safety issue: No ]
- Long-term Survival [ Time Frame: Measured at Month 3 ] [ Designated as safety issue: No ]
- Serious Adverse Events in Granulocyte Donors [ Time Frame: Measured at Week 1 after G-CSF administration ] [ Designated as safety issue: Yes ]
- Donor Availability (Proportion of Scheduled Granulocyte Transfusion Days on Which Granulocytes Were Available) [ Time Frame: Measured through study completion ] [ Designated as safety issue: No ]
- Evaluation of Granulocyte Yield [ Time Frame: Measured immediately after each granulocyte donation ] [ Designated as safety issue: No ]
- Discontinuation of Granulocyte Transfusions Due to Toxicity or Intolerance [ Time Frame: Measured through Day 42 ] [ Designated as safety issue: Yes ]
|Study Start Date:||April 2008|
|Study Completion Date:||May 2013|
|Primary Completion Date:||April 2013 (Final data collection date for primary outcome measure)|
Participants will receive granulocyte transfusions in addition to standard antimicrobial therapy
Drug: Standard antimicrobial therapy
Antimicrobial therapy is broadly defined as therapy within the standard of care for a particular infection and should be consistent within a given institution. Participants will undergo the recommended therapy for specific infections for 42 days.Biological: Granulocyte transfusions
Participants will receive one granulocyte transfusion per day until one of the following occurs: recovery from neutropenia, life-threatening toxicity, resolution or improvement of infection, or Day 42 after treatment. Granulocyte content of each transfusion is targeted to be at least 4 x 10^10 per collection (or proportionately less for participants less than 30 kg in weight).
Active Comparator: 2
Participants will receive standard antimicrobial therapy alone
Drug: Standard antimicrobial therapy
Antimicrobial therapy is broadly defined as therapy within the standard of care for a particular infection and should be consistent within a given institution. Participants will undergo the recommended therapy for specific infections for 42 days.
Participants will donate granulocytes after receiving a combination of two drugs, G-CSF and dexamethasone
Twelve hours before each donation, participants will be injected with G-CSF and will take one dose of dexamethasone by mouth.
Other Name: NeupogenDevice: Apheresis machine
Participants will undergo a procedure using an apheresis machine for granulocyte collection. The procedure will last 3 to 4 hours and will involve the drawing of blood from each arm, the separation of granulocytes from the red cells and plasma in the machine, and the return of the red cells and plasma to the participants.
Thousands of people each year are hospitalized for neutropenia, which continues to cause substantial morbidity and mortality for those affected. Neutropenia is primarily caused by chemotherapy and various other cancer treatments, such as radiation therapy, biotherapy, and HSC transplantation. Signs and symptoms of neutropenia may include high fever, chills, sore throat, and diarrhea. In neutropenia, the number of neutrophils, a type of granulocyte, is greatly reduced, weakening the body's immune system and increasing the risk of infection. Therefore, a method to provide adequate numbers of functional granulocytes to people with neutropenia could be of greatest benefit for recovery. Administration of a combination of two drugs, granulocyte colony-stimulating factor (G-CSF) and dexamethasone, has been show to stimulate the body to produce a large number of granulocytes. Granulocyte transfusions obtained from donors who have received these two drugs may help people with low white blood cell counts fight infections until their own white blood cell counts recover. However, it is not clear whether the benefits of granulocyte transfusions outweigh the risks of side effects. This study will compare the safety and effectiveness of granulocyte transfusions with standard antimicrobial therapy versus the safety and effectiveness of standard antimicrobial therapy alone in increasing granulocyte numbers and in improving survival rates in people with bacterial or fungal infection during neutropenia.
Participation in the research portion of this study will last about 3 months. All participants who were not previously receiving treatment with standard antimicrobial therapy will begin therapy immediately upon study entry. Participants will then be assigned randomly to receive either granulocyte transfusion plus continued antimicrobial therapy or continued antimicrobial therapy alone. All participants will be monitored for a maximum of 42 days, during which they will provide information on medical history and ongoing status of antimicrobial therapy. Daily blood samples to measure white blood cell count will be obtained from participants until samples show that participants are making their own granulocytes. Samples will then be collected weekly until Day 42. There may be additional blood draws depending on the type of infection present in participants.
Granulocyte transfusions will be given daily during the 42-day treatment period, depending on granulocyte donor availability. Blood counts will be checked immediately before and after each transfusion to measure granulocyte levels. Transfusions will be stopped if participants start making their own granulocytes, experience serious side effects, or show a reduction in infection. At Month 3 after study entry, follow-up information will be collected about all participants' health status through reviewing their medical records and contacting their physicians.
Participation for granulocyte donors will last 1 week from the time of donation. Community donors may provide more than one granulocyte donation, but no more than one donation every 3 days. Frequency of donation from a family member will be according to local blood bank criteria with approval from a blood bank physician. Both community donors and family donors are limited to eight donations each year. Twelve hours before each donation, participants will be injected with Neupogen, which contains G-CSF, and they will take one dose of dexamethasone by mouth. Participants will then undergo a blood draw, followed by a procedure using an apheresis machine for granulocyte collection. The procedure will last 3 to 4 hours and will involve the drawing of blood from each arm, the separation of granulocytes from the red blood cells and plasma in the machine, and the return of the red blood cells and plasma to the participants.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00627393
|United States, Iowa|
|University of Iowa Hospitals and Clinics|
|Iowa City, Iowa, United States, 52242|
|United States, Maryland|
|Johns Hopkins Hospital|
|Baltimore, Maryland, United States, 21267|
|United States, Massachusetts|
|Children's Hospital Boston|
|Boston, Massachusetts, United States, 02115|
|United States, Minnesota|
|University of Minnesota|
|Minneapolis, Minnesota, United States, 55455|
|United States, New York|
|Montefiore Medical Center|
|Bronx, New York, United States, 10461|
|Weill Medical College, Cornell University|
|New York, New York, United States, 10021|
|United States, Oklahoma|
|University of Oklahoma Health Sciences Center|
|Oklahoma City, Oklahoma, United States, 73104|
|United States, Pennsylvania|
|University of Pennsylvania|
|Philadelphia, Pennsylvania, United States, 19104|
|Chlidren's Hospital of Philadelphia|
|Philadelphia, Pennsylvania, United States, 19104|
|University of Pittsburgh Presbyterian and Shadyside|
|Pittsburgh, Pennsylvania, United States, 15213|
|United States, Washington|
|University of Washington Medical Center|
|Seattle, Washington, United States, 98195|
|United States, Wisconsin|
|University of Wisconsin at Madison|
|Madison, Wisconsin, United States, 53792|
|Froedtert Memorial Lutheran Hospital|
|Milwaukee, Wisconsin, United States, 53201|
|Principal Investigator:||Susan F. Assmann, PhD||New England Research Institutes|
|Principal Investigator:||Jan McFarland, MD||Froedtert Memorial Lutheran Hospital|
|Principal Investigator:||Eliot Williams, MD||University of Wisconsin, Madison|
|Principal Investigator:||Ellis Neufeld, MD||Children's Hospital Boston/Brigham and Women's Hospital|
|Principal Investigator:||James Bussel, MD||Weill Medical College, Cornell University|
|Principal Investigator:||Cassandra Josephson, MD||Emory University|
|Principal Investigator:||Paul Ness, MD||Johns Hopkins University|
|Principal Investigator:||Sherrill Slichter, MD||University of Washington|
|Study Chair:||Thomas Price, MD||Puget Sound Blood Center|
|Principal Investigator:||Ronald Strauss, MD||University of Iowa|
|Principal Investigator:||Jeffrey McCullough, MD||University of Minnesota - Clinical and Translational Science Institute|
|Principal Investigator:||James George, MD||University of Oklahoma|
|Principal Investigator:||Bruce Sachais, MD, PHD||University of Pennsylvania|
|Principal Investigator:||David Friedman, MD||Children's Hospital of Philadelphia|
|Principal Investigator:||Darrell Triulzi, MD||University of Pittsburgh Presbyterian and Shadyside/Children's Hospital Pittsburgh|