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Outrage of the Month: Unethical, Reckless Sepsis Trial Funded by NIH Must be Halted

Health Letter, October 2018

By Michael Carome, M.D.

sepsis

Image: Chaikom/Shutterstock.com

When the National Institutes of Health funds a large, multimillion-dollar clinical trial testing new treatments for a life-threatening disease at leading medical centers across the U.S., the public assumes the trial is well-designed and adheres to the highest ethical standards. But all too often, those assumptions are wrong.

Among the most egregious examples of poorly designed, unethical human research is the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial (CLOVERS), which is being funded by the National Heart, Lung, and Blood Institute (NHLBI) through its Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. This three-year clinical trial, which began enrolling seriously ill sepsis patients in March, is deeply flawed, riddled with serious regulatory and ethical lapses, and must be stopped.

To understand what is so wrong with CLOVERS, one first needs to understand the nature of sepsis and the usual treatments for it. Sepsis is a life-threatening syndrome that occurs in patients with infections, such as pneumonia, meningitis or kidney infections. The syndrome develops when a patient’s immune system releases a wide array of substances into the bloodstream to combat the infection, which then trigger inflammatory responses throughout the body that can lead to low blood pressure, shock and organ failure.

Sepsis is a medical emergency. Without immediate appropriate treatment, patients can die within a matter of hours. In addition to antibiotics to treat the underlying infection, two therapies, given in appropriate amounts and in a timely manner, can be lifesaving: administration of intravenous (IV) fluids and use of drugs to raise blood pressure (called vasopressors).

According to sepsis experts and evidence-based treatment guidelines issued by national critical care societies, during usual care for early sepsis, doctors initially start with IV fluids, but if the patient does not rapidly improve, doctors then add vasopressor treatment. Doctors subsequently adjust the doses of IV fluids and vasopressors and balance the use of each based on the patient’s sepsis severity and clinical response to treatment. Importantly, giving too little or too much of either of these treatments for this potentially rapidly lethal syndrome can have fatal consequences.

So now let’s look at the design of CLOVERS.

In CLOVERS, patients with sepsis (ranging from mild to the most severe cases) are being assigned randomly to one of two highly unusual treatment strategies for sepsis, both of which are risky. The goal of the trial is to determine whether one of these two experimental strategies results in more patient deaths than the other.

Specifically, half of the sepsis subjects will receive predominantly IV fluids — given more rapidly and in larger amounts than would usually be given in early sepsis care — and the other half will receive predominantly vasopressors. For both groups, the protocol severely restricts use of one of the two lifesaving treatments for sepsis, even in the face of signs of ongoing shock, such as dangerously low blood pressure.

By not allowing doctors to adjust the doses of IV fluids and vasopressors and balance the use of each based on the severity of the subjects’ sepsis and clinical response to treatment, CLOVERS predictably will expose many subjects in both groups to unacceptable dangers, including increased risks of organ failure and death.

It’s obvious that, prior to designing and initiating CLOVERS, the researchers made no effort to understand usual practice for management of early sepsis.

But the design of CLOVERS is even worse. Because the trial does not include a group of patients who receive the usual treatment for sepsis — a usual-care control group — the CLOVERS researchers can’t adequately determine while the trial is ongoing whether either of the experimental treatments is resulting in a higher death rate than usual care for sepsis. What’s more, once CLOVERS is completed, they will have no way to draw any usable conclusions from the trial because they won’t know how the two experimental treatments compare with the usual sepsis treatment.

The consent form for CLOVERS also has serious deficiencies, including a failure to explain to prospective subjects (or their loved ones) the true experimental nature and risks of the two sepsis treatment strategies being tested in the trial.

The design of this disturbing trial is more akin to an experiment that would be conducted on laboratory animals. The human subjects in CLOVERS are unwitting guinea pigs in a physiology experiment that will not advance medical care for sepsis and likely will harm many sepsis patients.

At least sixteen institutions currently are running the trials, including the Ronald Reagan UCLA Medical Center, University of Colorado Hospital, Cleveland Clinic Foundation, Beth Israel Medical Center and Vanderbilt University Medical Center. Stanford University Hospital, Mount Sinai Hospital and 26 other institutions are listed as study sites but as of May 28, had not yet begun enrolling patients. CLOVERS researchers plan to enroll up to 2,320 subjects by the trial’s projected completion in March 2021.

The fact that CLOVERS successfully passed through multiple levels of review and was approved by officials at the NHLBI and the PETAL Network’s institutional review board is yet another troubling example of the dysfunction — at multiple levels — of the U.S. system for protecting human subjects enrolled in complex clinical trials.

On August 28, Public Citizen sent a letter to the U.S. Department of Health and Human Services’ Office for Human Research Protections (OHRP) urging the immediate termination of CLOVERS. In our letter, we emphasized that because the trial’s design was so flawed, CLOVERS could not be salvaged simply by adding a usual-care control group and modifying the consent form. To the best of our knowledge, OHRP has not taken action to terminate CLOVERS, and sepsis patients continue to be enrolled in the trial across the country.

In our letter to OHRP, we also called for a moratorium on all other current PETAL Network clinical trials and any other NHLBI-funded clinical trials testing interventions in critically ill subjects until the multiple systemic breakdowns that permitted CLOVERS to be approved are fully understood and corrected. OHRP also has not taken action on this request.

In the meantime, anyone asked to enroll themselves or a loved one in CLOVERS — or any other NHLBI-funded clinical trial involving critically ill patients — should simply say “no” and ask for the best available usual treatment.