Clinical trial NCT00627393: Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)
Official title: High Dose Granulocyte Transfusions for the Treatment of Infection in Neutropenia: The RING Study (Resolving Infection in Neutropenia With Granulocytes)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neutropenia
Infection
Keywords: Granulocyte Transfusions
Lead sponsor: Carelon Research
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2008-03-03
Enrollment: 114
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Percentage of Participants Who Are Alive at 42 Days After Treatment and Have Had Microbial Response
timeFrame: Measured at Day 42
Secondary outcomes:
measure: Alloimmunization, Defined as the Appearance of Anti-human Leukocyte Antigen (HLA) or Antineutrophil Antibodies
timeFrame: Measured at Days 14 and 42
measure: Serious Granulocyte Transfusion Reactions, Including Febrile, Allergic, and Pulmonary Reactions (Transfusion Arm Only)
timeFrame: Measured within 6 hours after end of transfusion
measure: Graft Versus Host Disease Among Recipients of Allogeneic Stem Cell Transplantation
timeFrame: Measured at Day 42
measure: Overall Incidence of Adverse Effects
timeFrame: Measured through Day 42
measure: Fever Resolution
timeFrame: Measured through Day 42
measure: Time to Negative Test for Fungal Antigenemia (e.g., Galactomannan Antigenemia Among Participants With Invasive Aspergillosis)
timeFrame: Measured at Days 7, 14, and 42
measure: Time to Negative Blood Culture for Participants With Positive Blood Culture at Baseline
timeFrame: Measured through Day 42
measure: Long-term Survival
timeFrame: Measured at Month 3
measure: Serious Adverse Events in Granulocyte Donors
timeFrame: Measured at Week 1 after G-CSF administration
measure: Donor Availability (Proportion of Scheduled Granulocyte Transfusion Days on Which Granulocytes Were Available)
timeFrame: Measured through study completion
measure: Evaluation of Granulocyte Yield
timeFrame: Measured immediately after each granulocyte donation
measure: Discontinuation of Granulocyte Transfusions Due to Toxicity or Intolerance
timeFrame: Measured through Day 42
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Weill Medical College, Cornell University
state: New York
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Chlidren's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Presbyterian and Shadyside
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin at Madison
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Memorial Lutheran Hospital
state: Wisconsin
Study officials:
affiliation: Carelon Research
name: Susan F. Assmann, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Froedtert Hospital
name: Jan McFarland, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Eliot Williams, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Boston/Brigham and Women's Hospital
name: Ellis Neufeld, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical College, Cornell University
name: James Bussel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Cassandra Josephson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Paul Ness, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Sherrill Slichter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bloodworks
name: Thomas Price, MD
role: STUDY_CHAIR
affiliation: University of Iowa
name: Ronald Strauss, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Jeffrey McCullough, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Oklahoma
name: James George, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Bruce Sachais, MD, PHD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia
name: David Friedman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh Presbyterian and Shadyside/Children's Hospital Pittsburgh
name: Darrell Triulzi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Price TH, Boeckh M, Harrison RW, McCullough J, Ness PM, Strauss RG, Nichols WG, Hamza TH, Cushing MM, King KE, Young JA, Williams E, McFarland J, Holter Chakrabarty J, Sloan SR, Friedman D, Parekh S, Sachais BS, Kiss JE, Assmann SF. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood. 2015 Oct 29;126(18):2153-61. doi: 10.1182/blood-2015-05-645986. Epub 2015 Sep 2.