A national consumer watchdog group is urging federal regulators to immediately halt an “unethical, reckless” clinical trial on sepsis patients being conducted at more than 40 locations nationwide, including two health care systems in the Triangle and one in Winston-Salem.
Public Citizen warned in a letter to federal regulators Tuesday that the clinical trial lacks basic patient safeguards and could expose up to 2,320 patients to organ failure and death. The organization is asking the Office for Human Research Protections, within the U.S. Department of Health and Human Services, to immediately suspend the clinical trial and launch an investigation on how it was approved.
The clinical trial, which began March 7 and is expected to be completed in June 2021, is enrolling patients at Duke University Medical Center, UNC Chapel Hill and Wake Forest Baptist Health, according to a public notice on clinicaltrials.gov. The trial, called CLOVERS, is sponsored by Massachusetts General Hospital and funded by the National Blood, Heart and Lung Institute within the National Institutes of Health. Its aim is to better understand a leading cause of death in U.S. hospitals.
Sepsis is the body’s over-response to a bacterial infection that spreads into the blood and damages the organs. It is one of the leading causes of death in the world. Sepsis, which can lead to septic shock, kills about 250,000 Americans a year out of some 1.5 million people who come down with the infection, according to the Centers for Disease Control and Protection. The CDC says 1 of every 3 patients who dies in a hospital has sepsis.
But Public Citizen, which is based in Washington, D.C., said the clinical trial is exposing sepsis patients to greater risk than they already face and violates core tenets of medical ethics.
“The design of the CLOVERS trial is more akin to an experiment that would be conducted on laboratory animals,” Public Citizen’s letter said. “The human subjects of the CLOVERS trial, as designed and currently conducted, are unwitting guinea pigs in a physiology experiment that will not advance medical care for sepsis. “
The U.S. Department of Health and Human Services said in an emailed statement Tuesday that “The Office for Human Research Protections plans to review the allegations.”
It’s not clear how many patients have participated locally in CLOVERS, which stands for Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis. All three North Carolina health care systems declined to comment on Public Citizen’s letter and the alleged risks of the clinical trial.
UNC spokesman Phil Bridges confirmed that UNC School of Medicine is participating in CLOVERS and referred media queries to Beth Israel Deaconess Medical Center in Boston, which Bridges said is centrally handling media calls.
The Beth Israel Deaconess Medical Center provided a written statement from Nathan Shapiro, a sepsis researcher and professor at Harvard Medical School and the co-principal Investigator for CLOVERS.
“Our study will provide clinicians with authoritative data on which approach leads to better patient outcomes,” the statement 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.”
Wake Forest Baptist Health did not respond to emails. Duke emailed a brief statement: “We really don’t have anything to contribute to this story and would refer you to the overall study PI [principal investigator] or the NIH for any questions or information.”
Craig Coopersmith, a professor of surgery and director of the Emory Critical Care Center in Atlanta, said the study is safe and should help provide important information to help doctors treat sepsis patients. Coopersmith, who is not involved in CLOVERS, has co-authored several key papers on sepsis, including 2017 guidelines establishing standards for the first six hours of treatment that he said is the accepted treatment standard around the world.
“I would feel comfortable enrolling patients in it,” Coopersmith said by phone.
Coopersmith said that in such a clinical trial, many patients would be too disoriented, exhausted or incapacitated to consent to participate — if they were even conscious — and would have to be enrolled by their relatives.
“These are the sickest patients in the world,” he said.
Public Citizen says it received expert advice from two NIH doctors to analyze the flaws in the NIH-sponsored sepsis trial: Charles Natanson, senior investigator and chief of the anesthesia section in NIH’s Critical Care Medicine Department; and Peter Eichacker, senior investigator and head of the Critical Care Medicine Section in the Critical Care Medicine Department at NIH.
While sepsis is a common killer, its treatment is not well understood. The condition leads to a sharp drop in blood pressure, chills, disorientation, sleepiness and unconsciousness. Doctors attack the dangerous infection in two ways: by administering intravenous fluids and by giving the patient blood pressure drugs to constrict blood vessels and increase blood pressure.
Medical experts use the IV fluids and drugs in tandem, unsure which approach works best. In the CLOVERS clinical trial, sepsis patients would be randomly divided into two groups: those primarily treated with blood pressure drugs and those who mostly get IV fluids. The patients would receive one or the other treatment for a period of 24 hours.
The treatment dilemma is explained to patients and family members in the clinical trial’s consent language, which reads: “We do not know which approach is better in this situation. Right now, the choice of approach is left to the doctors.
“We want to find out whether one of these approaches compared to the other can improve a patient’s chances of survival.”
Michael Carome, director of Public Citizen’s Health Research Group, said the clinical trial will deprive highly vulnerable patients of one important treatment and expose patients to dangerously low blood pressure for hours.
“Half are not going to get fluids they need, and instead will get a drug they might not need,” Carome said. “They’re seeing if you’re more likely to die in Experimental Group A or in Experimental Group B.”
But Coopersmith characterized the study differently: He said both groups would get blood pressure medicine and IV fluids, but in different proportions.
Public Citizen’s letter also criticizes the study design because it lacks a control group — patients treated the conventional way with drugs and IV fluids — to compare results. Carome said this is an important omission because it eliminates the established treatment from the trial’s outcomes.
For example, Carome said, if 30 percent of sepsis patients in one group died, and 25 percent of the patients in the other group died, the trial results would indicate that the second group got the better treatment because fewer patients died.
But if only 15 percent die who are treated in the conventional way, that wouldn’t show up in the clinical trial because it is not being measured, Carome said.
Coopersmith said the reason the study lacks a control group is the reason the study is being conducted in the first place: There is no standard way of treating sepsis that can be used as a basis for comparison.