Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
New England Research Institutes
ClinicalTrials.gov Identifier:
NCT00627393
First received: February 28, 2008
Last updated: April 16, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Neutropenia
Infection
Drug: Standard antimicrobial therapy
Biological: Granulocyte transfusions
Drug: G-CFS/dexamethasone
Device: Apheresis machine
Phase 3

Study Type: Interventional
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)

Resource links provided by NLM:


Further study details as provided by New England Research Institutes:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]
  • Overall incidence of adverse effects [ Time Frame: Measured through Day 42 ] [ Designated as safety issue: Yes ]
  • Time to resolve fever [ Time Frame: Measured through Day 42 ] [ Designated as safety issue: No ]
  • 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 ]

Enrollment: 114
Study Start Date: April 2008
Study Completion Date: May 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
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.
3
Participants will donate granulocytes after receiving a combination of two drugs, G-CSF and dexamethasone
Drug: G-CFS/dexamethasone
Twelve hours before each donation, participants will be injected with G-CSF and will take one dose of dexamethasone by mouth.
Other Name: Neupogen
Device: 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.

Detailed Description:

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Severe neutropenia (Absolute Neutrophil Count < 500/mm^3) due to marrow failure caused by underlying disease or therapy
  • Must have one of the following: fungemia; bacteremia; proven or presumptive invasive tissue bacterial infection; or proven, probable, or presumptive invasive fungal infection

Exclusion Criteria:

  • Unlikely to survive 5 days
  • Evidence that patient will not be neutropenic at least 5 days
  • Previously enrolled in this study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00627393

Locations
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
Sponsors and Collaborators
New England Research Institutes
Investigators
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
  More Information

No publications provided

Responsible Party: New England Research Institutes
ClinicalTrials.gov Identifier: NCT00627393     History of Changes
Other Study ID Numbers: 557, U01HL072268, HL072268, HL072291, HL072196, HL072248, HL072191, HL072305, HL072028, HL072072, HL072355, HL072283, HL072346, HL072331, HL072290
Study First Received: February 28, 2008
Last Updated: April 16, 2014
Health Authority: United States: Federal Government

Keywords provided by New England Research Institutes:
Granulocyte Transfusions

Additional relevant MeSH terms:
Neutropenia
Agranulocytosis
Leukopenia
Leukocyte Disorders
Hematologic Diseases
Anti-Infective Agents
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
BB 1101
Therapeutic Uses
Pharmacologic Actions
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 29, 2014