Ongoing Clinical Trials in Transfusion Medicine: ABLE, TOPPS, RING
Why learn about clinical trials before they are completed? That question was explored at the AABB Annual Meeting session “Ongoing Clinical Trials in Transfusion Medicine,” which featured three studies that could shed new light on the study and practice of transfusion medicine even as they are still being performed.
“Clinical trials take several years — it is interesting to learn what is happening along the way. And sometimes what is learned can be helpful to others for overcoming their own study challenges,” said Heather Hume, MD, of the University of Montreal, who moderated the session.
The investigations discussed at the Annual Meeting session are attempting to answer the following questions: Is there an advantage to using red blood cells stored only for a short amount of time? Do all patients with hematologic malignancies and severe thrombocytopenia need prophylactic platelet transfusions? Are high-dose granulocyte transfusions useful in the treatment of patients with neutropenia and an infection? As they are conducting their trials, the researchers are finding ways to address such challenges as obtaining informed consent from critically ill patients and ensuring study personnel follow the protocol.
In the Age of Blood Evaluation — or ABLE — trial, researchers are investigating the effect of the age of blood on recipients’ 90-day mortality. In particular, they are evaluating a group of critical care patients with a suspected mortality rate of approximately 25 percent, in which the individual patients are receiving either fresh RBCs (defined in the study as less than eight days old) or standard-issue RBCs (on average stored for two weeks, but which may be stored for up to 42 days). “The consequences of red blood cell storage on clinical outcomes had never before been studied in a prospective clinical trial,” said the Ottawa Hospital Research Institute’s Alan Tinmouth, MD, MSc, FRCPC, a principal investigator in the ABLE study, adding that the previous retrospective observational studies could not determine if prolonged storage of RBCs causes adverse outcomes in critically ill patients. Tinmouth and his colleagues are seeking to determine if fresh RBCs result in a decrease in mortality from 25 percent to 20 percent — a significant enough difference that would allow health care personnel to consider changing how RBC inventories are managed and how transfusions are given.
In the ABLE study, as well as all randomized controlled trials, informed consent is a requirement but can represent a substantial hurdle for scientists. The ultimate concern is that the requirement for individual consent could lead to a loss in enrollment, making the study results less significant. In the ABLE trial, patients are in intensive care units, and many are intubated and thus unable to provide consent at the time of first transfusion, disqualifying them from participation in the study. Consent from family members is sought, but there is sometimes difficulty in contacting them in time for the patient to be included in the trial.
The ABLE research team is striving to circumvent these problems mainly by using pre-consent and deferred consent. In pre-consent, patients who are potentially eligible for inclusion in the trial or their surrogate decision-makers are asked to provide consent. However, they are not randomized and enrolled in the study until the moment that they need a transfusion. Additionally, nontransfused patients are not included in the study, as their inclusion could dilute the study results. With pre-consent, next of kin also can be contacted in sufficient time to give the consent needed to allow the patient to participate.
In deferred consent, explained Tinmouth, patients must have a serious threat that requires immediate attention, have to be unconscious or have to lack the capacity to understand details of the study. Additionally, there cannot be a third-party authorization that can be obtained in sufficient time, and there cannot be a prior directive by the patient refusing the study treatment. Also, there must not be any standard care that the patient could receive, or the treatment from the study must offer a possibility of being more beneficial than standard care. The risk of harm may not be greater than that involved in standard care. Consent is still needed, however, to collect a patient’s personal information.
Simon Stanworth, MD, a principal investigator in the Therapeutic or Prophylactic Platelets — or TOPPS — trial, from the U.K.’s National Health Service, Blood and Transplant, discussed the role of prophylactic platelet transfusion. The main question the trial is addressing is whether a no-prophylactic policy for the use of platelet transfusions in patients with hematologic malignancies is as safe as the current standard — that is, a threshold prophylactic policy at 10x109/L. Included in the trial are adults with a confirmed diagnosis of a hematologic malignancy who are undergoing myelosuppressive therapy and who are, or are expected to be, thrombocytopenic. “At its heart, the trial is about individualizing the platelet transfusion decision,” Stanworth said.
The main trial outcome is bleeding at World Health Organization grade 2, 3 or 4, up to 30 days after randomization, and Stanworth discussed some of the difficulties and challenges in collecting this data consistently between different recruiting centers. Data-collection strategies include clearly agreeing on definitions in the preparatory work, centralizing the training of research nurses, and instituting a program to ensure that the research nurses receive continuing education.
One of the other challenges in the TOPPS study, as well as many other trials, is ensuring that all health care personnel follow the protocol. “We spent a great deal of time educating all staff on the wards at centers. It is important that nurses as well as physicians understand what the trial is trying to achieve,” Stanworth said.
The next speaker, Thomas Price, MD, from the Puget Sound Blood Center and the University of Washington School of Medicine, discussed the Reducing Infection With Granulocytes, or RING, study — a phase III randomized controlled trial examining the clinical efficacy of high-dose granulocyte transfusion therapy in people with infections and neutropenia. “Treatment-related neutropenia with aggressive chemotherapy or stem cell transplantation continues to be the major risk factor for severe bacterial or fungal infection,” Price said, adding that invasive fungal infection plays an increasingly important role in post-hematopoietic stem cell transplant morbidity and mortality. “Thus, it seems logical to provide patients with normal functioning granulocytes, which has been done for about 30 years, but treatment results have been disappointing, likely because the dose of the granulocytes has not been adequate.” The response to this has been to increase the dose of the granulocytes, but the clinical efficacy of this procedure has not yet been determined.
In the RING trial, in which the efficacy of the treatment is being evaluated, patients are chosen for inclusion if they have neutropenia from chemotherapy or a hematopoietic stem cell transplant conditioning regimen and a proven or probable fungal or bacterial infection. They are randomized to receive either standard antimicrobial therapy or such therapy and daily granulocyte transfusions from donors who had been administered granulocyte-colony stimulating factor, or G-CSF, and dexamethasone. The daily transfusions would continue until either recovery from neutropenia, a complete or partial response to the infection or some serious adverse event. The primary endpoint is survival and a microbial response at 42 days after randomization.
One of the main challenges in the initial implementation of the RING trial was the time needed to get it up and running. Part of the delay was due to the fact that each clinical site in the study needed to get institutional review board approval, which took a year in some instances. Also, granulocytes needed to be obtained for some clinical sites from the American Red Cross, but the organization did not have a program for collecting them from donors who had been given G-CSF. Red Cross officials expressed enthusiasm about helping but required some time to work with their legal department and IRB. Moreover, the investigators needed to work with the Food and Drug Administration to determine that an investigational new drug application was not needed. “Altogether, it took five-and-a-half years to go from original proposal to implementation,” said Price.
He also noted that since implementation, patient accrual has been lower than expected. “One of the reasons for this may be that fungal prophylaxis therapy has improved in recent years, which means that there are fewer people with fungal infections than anticipated,” Price said. He added that his research team’s randomization of patients may have been too strict initially. The original rule stated that once a patient becomes eligible, the person needs to be randomized to a study arm within 24 hours. However, this proved impractical and required modification.
Based on his research team’s experiences thus far with the RING study, he recommends keeping the study question simple, learning how clinicians actually behave, actively involving subject experts, and managing the length of debates to get the final protocol going. He further recommends actively engaging the study coordinators, usually the nurses. “These are the people who will make or break the study,” he said. “It is also advantageous not to have the treatment available off protocol and to understand that proposals to amend the protocol do not end with implementation. But changing the protocol should only be done after careful scientific and statistical analysis.”
ABLE, TOPPS and RING, even though they are ongoing trials, are offering great examples of how scientists are overcoming important challenges in transfusion medicine research.
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