Trial Outcomes & Findings for Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study) (NCT NCT00627393)

Last Updated: 2015-04-17

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

114 participants

Primary outcome timeframe

Measured at Day 42

Results posted on

2015-04-17

Participant Flow

Participant milestones

Participant milestones
Measure	Control Arm Received antimicrobial therapy alone.	Granulocyte Arm Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Intention-To-Treat Analysis STARTED	58	56
Intention-To-Treat Analysis COMPLETED	49	48
Intention-To-Treat Analysis NOT COMPLETED	9	8
Per-Protocol Analysis STARTED	49	48
Per-Protocol Analysis COMPLETED	39	35
Per-Protocol Analysis NOT COMPLETED	10	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Control Arm Received antimicrobial therapy alone.	Granulocyte Arm Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Intention-To-Treat Analysis Adjudication indeterminate	5	3
Intention-To-Treat Analysis Withdrawal by patient/family/physician	4	5
Per-Protocol Analysis Received unstimulated/no granulocytes	6	3
Per-Protocol Analysis Withdrawal by patient/family/physician	4	10

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Control Arm n=58 Participants Received antimicrobial therapy alone.	Granulocyte Arm n=56 Participants Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.	Total n=114 Participants Total of all reporting groups
Age, Categorical <=18 years	6 Participants n=99 Participants	4 Participants n=107 Participants	10 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	39 Participants n=99 Participants	32 Participants n=107 Participants	71 Participants n=206 Participants
Age, Categorical >=65 years	13 Participants n=99 Participants	20 Participants n=107 Participants	33 Participants n=206 Participants
Age, Continuous	49.1 years STANDARD_DEVIATION 19.8 • n=99 Participants	54.8 years STANDARD_DEVIATION 16.3 • n=107 Participants	51.9 years STANDARD_DEVIATION 18.3 • n=206 Participants
Sex: Female, Male Female	28 Participants n=99 Participants	23 Participants n=107 Participants	51 Participants n=206 Participants
Sex: Female, Male Male	30 Participants n=99 Participants	33 Participants n=107 Participants	63 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=99 Participants	1 Participants n=107 Participants	6 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	40 Participants n=99 Participants	44 Participants n=107 Participants	84 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	13 Participants n=99 Participants	11 Participants n=107 Participants	24 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	4 Participants n=99 Participants	1 Participants n=107 Participants	5 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	1 Participants n=99 Participants	6 Participants n=107 Participants	7 Participants n=206 Participants
Race (NIH/OMB) White	39 Participants n=99 Participants	40 Participants n=107 Participants	79 Participants n=206 Participants
Race (NIH/OMB) More than one race	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	13 Participants n=99 Participants	9 Participants n=107 Participants	22 Participants n=206 Participants
Weight	76.0 kg STANDARD_DEVIATION 23.8 • n=99 Participants	78.7 kg STANDARD_DEVIATION 20.6 • n=107 Participants	77.3 kg STANDARD_DEVIATION 22.2 • n=206 Participants
Cause of neutropenia Chemotherapy only	43 participants n=99 Participants	44 participants n=107 Participants	87 participants n=206 Participants
Cause of neutropenia Infection	7 participants n=99 Participants	3 participants n=107 Participants	10 participants n=206 Participants
Cause of neutropenia HST (or preparation for HST)	8 participants n=99 Participants	9 participants n=107 Participants	17 participants n=206 Participants
ANC prior to randomization	0.046 x10^9 cells/L STANDARD_DEVIATION 0.091 • n=99 Participants	0.058 x10^9 cells/L STANDARD_DEVIATION 0.096 • n=107 Participants	0.052 x10^9 cells/L STANDARD_DEVIATION 0.094 • n=206 Participants
Zubrod score 0 to 2	19 participants n=99 Participants	18 participants n=107 Participants	37 participants n=206 Participants
Zubrod score 3 to 5	39 participants n=99 Participants	38 participants n=107 Participants	77 participants n=206 Participants
Infection type Bacteremia only	16 participants n=99 Participants	17 participants n=107 Participants	33 participants n=206 Participants
Infection type Tissue bacterial infection	15 participants n=99 Participants	13 participants n=107 Participants	28 participants n=206 Participants
Infection type Fungemia only	8 participants n=99 Participants	5 participants n=107 Participants	13 participants n=206 Participants
Infection type Tissue fungal infection	19 participants n=99 Participants	21 participants n=107 Participants	40 participants n=206 Participants

PRIMARY outcome

Timeframe: Measured at Day 42

Population: All adjudicated or deceased subjects in intention-to-treat analyses.

Outcome measures

Outcome measures
Measure	Control Arm n=49 Participants Received antimicrobial therapy alone.	Granulocyte Arm n=48 Participants Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Percentage of Participants Who Are Alive at 42 Days After Treatment and Have Had Microbial Response	42.9 percentage of participants	41.7 percentage of participants

SECONDARY outcome

Timeframe: Measured at Days 14 and 42

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Measured within 6 hours after end of transfusion

Population: Subjects who received granulocyte transfusions. Six subjects in the control group received granulocyte transfusions in violation of the protocol.

Outcome measures

Outcome measures
Measure	Control Arm n=6 Participants Received antimicrobial therapy alone.	Granulocyte Arm n=51 Participants Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Serious Granulocyte Transfusion Reactions, Including Febrile, Allergic, and Pulmonary Reactions (Transfusion Arm Only) No events reported	5 participants	19 participants
Serious Granulocyte Transfusion Reactions, Including Febrile, Allergic, and Pulmonary Reactions (Transfusion Arm Only) Grade 1	0 participants	7 participants
Serious Granulocyte Transfusion Reactions, Including Febrile, Allergic, and Pulmonary Reactions (Transfusion Arm Only) Grade 2	1 participants	14 participants
Serious Granulocyte Transfusion Reactions, Including Febrile, Allergic, and Pulmonary Reactions (Transfusion Arm Only) Grade 3	0 participants	10 participants
Serious Granulocyte Transfusion Reactions, Including Febrile, Allergic, and Pulmonary Reactions (Transfusion Arm Only) Grade 4	0 participants	1 participants

SECONDARY outcome

Timeframe: Measured at Day 42

Population: Subjects who had 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.

Outcome measures

Outcome measures
Measure	Control Arm n=8 Participants Received antimicrobial therapy alone.	Granulocyte Arm n=7 Participants Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Graft Versus Host Disease Among Recipients of Allogeneic Stem Cell Transplantation	0.67 proportion of subjects, GVHD incidnence	0.40 proportion of subjects, GVHD incidnence

SECONDARY outcome

Timeframe: Measured through Day 42

Population: All randomized subjects.

Outcome measures

Outcome measures
Measure	Control Arm n=58 Participants Received antimicrobial therapy alone.	Granulocyte Arm n=56 Participants Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Overall Incidence of Adverse Effects 1 Event	21 participants	20 participants
Overall Incidence of Adverse Effects 0 Event	33 participants	30 participants
Overall Incidence of Adverse Effects 2 Events	2 participants	5 participants
Overall Incidence of Adverse Effects 3 Events	1 participants	0 participants
Overall Incidence of Adverse Effects 6 Events	0 participants	1 participants
Overall Incidence of Adverse Effects 9 Events	1 participants	0 participants

SECONDARY outcome

Timeframe: Measured through Day 42

Population: Subjects who had fever at baseline.

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

Outcome measures

Outcome measures
Measure	Control Arm n=53 Participants Received antimicrobial therapy alone.	Granulocyte Arm n=47 Participants Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Fever Resolution	0.89 proportion of subjects, resolved fever	0.94 proportion of subjects, resolved fever

SECONDARY outcome

Timeframe: Measured at Days 7, 14, and 42

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Measured through Day 42

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Measured at Month 3

Population: All randomized subjects.

Outcome measures

Outcome measures
Measure	Control Arm n=58 Participants Received antimicrobial therapy alone.	Granulocyte Arm n=56 Participants Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Long-term Survival	30 participants	20 participants

SECONDARY outcome

Timeframe: Measured at Week 1 after G-CSF administration

Population: 237 subjects consented to G-CSF and dexamethasone administration prior to granulocyte donation.

Outcome measures

Outcome measures
Measure	Control Arm n=237 Participants Received antimicrobial therapy alone.	Granulocyte Arm Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Serious Adverse Events in Granulocyte Donors Myalgia and backpain of unexpected duration	1 participants	—
Serious Adverse Events in Granulocyte Donors Abnormal nucleated red blood cell differential	1 participants	—

SECONDARY outcome

Timeframe: Measured through study completion

Population: The unit of analysis is patient-days where a granulocyte transfusion was scheduled.

Outcome measures

Outcome measures
Measure	Control Arm n=543 Patient-days Received antimicrobial therapy alone.	Granulocyte Arm Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Donor Availability (Proportion of Scheduled Granulocyte Transfusion Days on Which Granulocytes Were Available)	62.62 percentage of available granulocyte days	—

SECONDARY outcome

Timeframe: Measured immediately after each granulocyte donation

Outcome measures

Outcome measures
Measure	Control Arm n=340 Granulocyte Donations Received antimicrobial therapy alone.	Granulocyte Arm Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Evaluation of Granulocyte Yield	174.75 Granulocyte Yield (billion cells/liter) Interval 89.76 to 242.41	—

SECONDARY outcome

Timeframe: Measured through Day 42

Outcome measures

Outcome data not reported

Adverse Events

Control Arm

Serious events: 25 serious events

Other events: 1 other events

Deaths: 0 deaths

Granulocyte Arm

Serious events: 26 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Control Arm n=6 participants at risk；n=58 participants at risk Received antimicrobial therapy alone.	Granulocyte Arm n=51 participants at risk；n=56 participants at risk Received G-CSF/dexamethasone-mobilized granulocyte transfusions in addition to antimicrobial therapy.
Immune system disorders Allergic reaction/ hypersensitivity	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	9.8% 5/51 • Number of events 5 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
Cardiac disorders Sinus bradycardia	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	0.00% 0/51 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
Cardiac disorders Sinus tachycardia	16.7% 1/6 • Number of events 3 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	33.3% 17/51 • Number of events 36 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
General disorders Hypertension	16.7% 1/6 • Number of events 1 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	17.6% 9/51 • Number of events 15 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
General disorders Hypotension	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	19.6% 10/51 • Number of events 14 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	5.9% 3/51 • Number of events 3 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	15.7% 8/51 • Number of events 16 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
General disorders Headache	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	2.0% 1/51 • Number of events 1 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	2.0% 1/51 • Number of events 1 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	0.00% 0/51 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
Blood and lymphatic system disorders Hemolysis	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	0.00% 0/51 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
Musculoskeletal and connective tissue disorders Rigors and Chills	0.00% 0/6 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	29.4% 15/51 • Number of events 42 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).
General disorders Fever	16.7% 1/6 • Number of events 2 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).	54.9% 28/51 • Number of events 81 • Serious adverse events were reported up to 42 days after randomization. Serious adverse events and other adverse events (i.e. granulocyte transfusion related events) data were collected. The number of participants at risk for other adverse events corresponds to the number of participants who received granulocyte transfusions (6 control arm subjects and 51 granulocyte arm subjects).

Additional Information

Susan Assmann, PhD

New England Research Institutes, Inc.

Phone: 617-972-3048

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee All publications and presentations resulting from studies from the TMH Network must be approved by the Publications and Presentations Committee before submission. The Sponsor (NERI) and funding agency (NHLBI) both are represented on the P\&P Committee along with Network Investigators. Members of the P\&P Committee can recommend changes to publications.
Publication restrictions are in place

Restriction type: OTHER