Sepsis induced hypotension: US consumer group asks regulator to stop trial, arguing flawed design

The US consumer advocacy group Public Citizen has written to the Office for Human Research Protections, which oversees ethical and regulatory issues in biomedical research, asking it to immediately direct the National, Heart, Lung and Blood Institute (NHLBI) to stop enrolment of patients into a clinical trial of sepsis induced hypotension that it is funding and to launch an investigation into how the study was approved.1

The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial is a phase III randomised, non-blinded trial of fluid treatment strategies in the first 24 hours for patients with sepsis induced hypotension.2 The trial plans to assign 2320 adult patients to a restrictive fluids strategy (vasopressors first, followed by rescue fluids) or a liberal fluid strategy (fluids first, followed by rescue vasopressors) and assess the impact on 90 day in-hospital mortality as the primary endpoint.

Public Citizen reviewed the most recent versions of the trial protocol and sample consent form after requesting them from the NHLBI under the Freedom of Information Act, together with the relevant scientific literature. It sought expert advice from Charles Natanson, a senior investigator and chief of anaesthesia in the critical care medicine department at the National Institutes of Health’s Clinical Center; and Peter Eichacker, a senior investigator and head of the critical care medicine section at the Clinical Center. Both are recognised experts in the treatment of sepsis and septic shock.

In its letter to Jerry Menikoff, director of the Office for Human Research Protections, Public Citizen argued that the CLOVERS trial has “serious regulatory and ethical lapses” resulting in “unacceptable risks of harm to subjects enrolled in the trial.”

The letter said that the trial includes only two experimental groups, each involving strategies “that deviate substantially from current usual care and are actually unusual care for the early management of sepsis.” It argued that the trial’s lack of a usual care group “precludes . . . appropriate monitoring to ensure the safety of enrolled human subjects.” It suggested that the design also “precludes . . . the possibility of drawing firm conclusions after the trial is completed that could improve and not worsen clinical practice for future patients.”

Nathan Shapiro, co-principal investigator of the CLOVERS trial from Beth Israel Deaconess Medical Center in Boston, said in a statement, “This study compares two approaches for the treatment of septic shock that are both currently in widespread use. Our study will provide clinicians with authoritative data on which approach leads to better patient outcomes.”

Public Citizen also argued in its letter that the trial’s design does not account for how current usual care varies on the basis of sepsis severity. It suggested that the two strategies under investigation “will lead to inappropriate or misaligned treatment for some subjects in each trial group.” The organisation said that this carries an unacceptable risk of organ failure and death and should be avoided, “but the trial’s design compels such risky deviations from usual care in many septic subjects.”

Michael Carome, director of Public Citizen’s Health Research Group, said, “The design of this trial is more akin to an experiment that would be conducted on laboratory animals. These human subjects are unwittingly guinea pigs in a physiology experiment that will not advance medical care for sepsis and likely will harm many.”

Shapiro said, “The study protocol was designed by expert clinicians in emergency and critical care medicine representing nearly 50 hospitals in the United States and follows a well accepted design.

“To ensure that the study meets the highest scientific and ethical standards, the study was thoroughly reviewed by an independent protocol review committee and a Data Safety and Monitoring Board appointed by the National Heart, Lung, and Blood Institute (the study’s funder), and a central Institutional Review Board before the study began.”