Title

Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)
High Dose Granulocyte Transfusions for the Treatment of Infection in Neutropenia: The RING Study (Resolving Infection in Neutropenia With Granulocytes)
  • Phase

    Phase 3
  • Study Type

    Interventional
  • Intervention/Treatment

    urea granulocytes sargramostim ...
  • Study Participants

    114
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.
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.
Study Started
Apr 30
2008
Primary Completion
Apr 30
2013
Study Completion
May 31
2013
Results Posted
Dec 23
2014
Estimate
Last Update
Apr 17
2015
Estimate

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).

Drug G-CSF/dexamethasone

Twelve hours before each donation, participants will be injected with G-CSF and will take one dose of dexamethasone by mouth.

  • Other names: 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.

1 Experimental

Participants will receive granulocyte transfusions in addition to standard antimicrobial therapy

2 Active Comparator

Participants will receive standard antimicrobial therapy alone

3 Other

Participants will donate granulocytes after receiving a combination of two drugs, G-CSF and dexamethasone

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

Summary

Control Arm

Granulocyte Arm

All Events

Event Type Organ System Event Term Control Arm Granulocyte Arm

Percentage of Participants Who Are Alive at 42 Days After Treatment and Have Had Microbial Response

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.

Control Arm

42.9
percentage of participants

Granulocyte Arm

41.7
percentage of participants

Serious Granulocyte Transfusion Reactions, Including Febrile, Allergic, and Pulmonary Reactions (Transfusion Arm Only)

Control Arm

Grade 1

Grade 2

1.0
participants

Grade 3

Grade 4

No events reported

5.0
participants

Granulocyte Arm

Grade 1

7.0
participants

Grade 2

14.0
participants

Grade 3

10.0
participants

Grade 4

1.0
participants

No events reported

19.0
participants

Graft Versus Host Disease Among Recipients of Allogeneic Stem Cell Transplantation

Time to GVHD incidence between the two treatment groups was compared using Gray's model that takes into account death as a competing risk.

Control Arm

0.67
proportion of subjects, GVHD incidnence

Granulocyte Arm

0.4
proportion of subjects, GVHD incidnence

Overall Incidence of Adverse Effects

Control Arm

0 Event

33.0
participants

1 Event

21.0
participants

2 Events

2.0
participants

3 Events

1.0
participants

6 Events

9 Events

1.0
participants

Granulocyte Arm

0 Event

30.0
participants

1 Event

20.0
participants

2 Events

5.0
participants

3 Events

6 Events

1.0
participants

9 Events

Fever Resolution

Fever resolution between the two treatment groups was compared using Gray's model that takes into account death as a competing risk.

Control Arm

0.89
proportion of subjects, resolved fever

Granulocyte Arm

0.94
proportion of subjects, resolved fever

Time to Negative Test for Fungal Antigenemia (e.g., Galactomannan Antigenemia Among Participants With Invasive Aspergillosis)

Outcome Measure Data Not Reported

Time to Negative Blood Culture for Participants With Positive Blood Culture at Baseline

Outcome Measure Data Not Reported

Long-term Survival

Control Arm

30.0
participants

Granulocyte Arm

20.0
participants

Serious Adverse Events in Granulocyte Donors

Granulocyte Donors

Abnormal nucleated red blood cell differential

1.0
participants

Myalgia and backpain of unexpected duration

1.0
participants

Donor Availability (Proportion of Scheduled Granulocyte Transfusion Days on Which Granulocytes Were Available)

Granulocyte Arm

62.62
percentage of available granulocyte days

Evaluation of Granulocyte Yield

Granulocyte Donors

174.75
Granulocyte Yield (billion cells/liter) (Median)
Inter-Quartile Range: 89.76 to 242.41

Alloimmunization, Defined as the Appearance of Anti-human Leukocyte Antigen (HLA) or Antineutrophil Antibodies

Outcome Measure Data Not Reported

Discontinuation of Granulocyte Transfusions Due to Toxicity or Intolerance

Outcome Measure Data Not Reported

Total

114
Participants

Age, Continuous

51.9
years (Mean)
Standard Deviation: 18.3

ANC prior to randomization

0.052
x10^9 cells/L (Mean)
Standard Deviation: 0.094

Weight

77.3
kg (Mean)
Standard Deviation: 22.2

Age, Categorical

Cause of neutropenia

Ethnicity (NIH/OMB)

Infection type

Race (NIH/OMB)

Sex: Female, Male

Zubrod score

Intention-To-Treat Analysis

Control Arm

Granulocyte Arm

Per-Protocol Analysis

Control Arm

Granulocyte Arm

Drop/Withdrawal Reasons

Control Arm

Granulocyte Arm