A medical watchdog group is calling on the National Institutes of Health to immediately stop the enrollment of patients in a clinical trial of sepsis treatment and launch an investigation of how the study received approval, arguing that it puts patients at risk of serious harm, including death.

The group, Public Citizen, says in a letter dated Tuesday that the study’s protocol is also so “fundamentally flawed” that it will not produce reliable findings.

The problems with the “CLOVERS” study are so serious that “it is difficult to imagine any reasonable person agreeing to enroll … if he or she were fully informed of [its] true nature and risks,” wrote Dr. Sidney Wolfe and Dr. Michael Carome of Public Citizen’s Health Research Group. They contended that patients in the trial are “unwitting guinea pigs in a physiology experiment that will not advance medical care for sepsis,” and that other lapses are “stunning in their breadth and scope.”

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The basis for the central criticism is twofold. First, Carome told STAT, patients are being put at risk because one of the two sepsis treatments in the study could, depending on how seriously ill the patients are, allow their blood pressure to remain dangerously low for hours. In addition, he said, everyone will receive what he called an experimental treatment, rather than some patients receiving the standard of care, as clinical trials generally do to enable researchers to compare results for patients treated with experimental and standard treatments.

CLOVERS scientists rejected that assertion, arguing that the treatment arms are similar to two widely used approaches. “Nothing in the trial is experimental care,” said Dr. Wesley Self, vice chair of research in the department of emergency medicine at Vanderbilt University Medical Center and an investigator in the study.

Trial organizers began recruiting patients in March and aim to enroll up to 2,320 at 44 U.S. hospitals and other medical sites. All of the patients will receive an initial quantity of intravenous fluids recommended by guidelines from the “Surviving Campaign,” from the Society for Critical Care Medicine. After that, about half will get more fluids (the “liberal fluids” group) and the others (the “restrictive fluids” group) will receive vasopressors, drugs that increase blood pressure, if needed.

An institutional review board at Vanderbilt, which is charged with ensuring that human studies are ethical and scientifically rigorous, approved CLOVERS, which is funded by NIH.

The criticism comes two months after NIH terminated another clinical trial, on alcohol, for severe ethical lapses.

Each year some 1.5 million people in the U.S. develop sepsis, in which an infection cascades into a medical emergency of plunging blood pressure, racing heart, and fever. One-quarter million people die of it annually. Despite the prevalence of sepsis, there is no consensus on how best to treat it, Self said.

The main divide is between giving patients large volumes of intravenous fluids immediately and then vasopressors, or smaller quantities of IV fluids followed more quickly by vasopressors. “Both are used fairly routinely,” Self said, and earlier research, including in lab animals, suggests either can be effective.

Observational evidence has linked the “liberal fluids” approach — which some critical care physicians have adopted over the last 15 years or so — to lower mortality from sepsis than the “restrictive fluids” approach. But the decline in death rates from sepsis might also, or instead, be due to something else that hospitals are doing better, not to giving patients large quantities of fluids.

“We’ve never unbundled why mortality has gone down,” Self said. “That’s why we believe a clinical trial is necessary.” Another reason is to determine whether giving patients large volumes of IV fluids might cause edema (swelling), restricting oxygen flow to organs and thereby contributing to organ damage, as some observational evidence suggests.

The two arms of the CLOVERS (“Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis”) trial differ somewhat from the Critical Care Medicine group’s guidelines. Those call for sepsis patients to quickly (within three hours) receive IV fluids, as CLOVERS patients will. But the guidelines also call for physicians to closely monitor patients’ blood pressure, and give additional IV fluids if blood pressure continues to be dangerously low. “The use of IV fluids in the resuscitation of patients is a cornerstone of modern therapy,” the guidelines state, but must be followed by vasopressors if blood pressure remains dangerously low.

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CLOVERS’ “liberal fluids” arm comes closest to today’s standard sepsis care as well as to the usual-care control arm in earlier clinical trials of sepsis treatments. But it differs from all of those in key ways. Patients in the trial will get larger-than-usual volumes of IV fluids and in less time, and will receive “rescue vasopressors” only after getting about 5 quarts of fluids. Public Citizen calls that “not usual care but unusual care.” According to Carome, “Patients could experience up to several hours of blood pressure much lower than would be tolerated in usual care before they receive vasopressors, and that is not acceptable.”

By not having a third group of patients receive usual care, the study could produce dangerously misleading results, he said. If it finds that one treatment has 20 percent mortality, and the other has 25 percent, the first would seem superior. But if a control group received usual care, like that in the Critical Care Medicine guidelines, it might have 15 percent mortality.

“You wouldn’t be able to know that from this trial,” Carome said. “That could adversely affect future patients.”

Dr. Nathan Shapiro of Beth Israel Deaconess Medical Center in Boston and co-leader of the CLOVERS trial, said in a statement that, to the contrary, “Our study will provide clinicians with authoritative data on which approach leads to better patient outcomes. The study protocol was designed by expert clinicians in emergency and critical care medicine,” and “follows a well-accepted design” that was reviewed not only by Vanderbilt’s IRB but also by a data safety and monitoring board appointed by NIH’s National Heart, Lung, and Blood Institute, the study’s funder.

Bioethicists argue that no human study should be conducted unless it is designed to yield useful results. “If a trial is bad science, it should not be done,” said clinical trials scholar and bioethicist Karen Maschke of the Hastings Center, who has not looked into the CLOVERS study. “The IRB has an ethical obligation to make sure the science is good.”

The consent form for the CLOVERS trial does not specify risks like those Public Citizen alleged. Instead, it says that any risks come from receiving extra IV fluids and vasopressors. There is no mention of possibly having severely low blood pressure for hours, a condition that can cause septic shock and organ failure.

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  • I agree that an arm which compares to current care is important. While I agree with the goal to distinguish which of the two interventions (liberal IVF vs vasopressors) has a relative greater contributory weight to sepsis outcomes, it may be that the combined strategy (liberal IVF and vasopressors) offer yet greater degree of clinical response (i.e., the sum is equal to, lesser than, or greater than the parts). That third arm deserves investigation.

  • I have grave concerns about the ethical standards of the experimental treatment. I think we know what works in sepsis Mgt already Early identification, Good IV access, early boluses of fluids,fluids,fluids, Abx, Pressors, fluids, steroids orb, oxygen support, and close monitoring focus on heart, kidneys and lungs.
    why do we need another risky study to screw people?
    We should advise patients not to consent across the country as potential patients are already too sick to make decisions.

  • I respect the efforts and intentions of the trialists and IRB. They are following the standard “one size fits all” treatment approach to septic shock.

    However the trial uses a guessed, capricious, unified definition of “septic shock typical of virtually all sepsis RCT since the 1980s. None of these have produced reproducibly positive results in 30yrs & mortality in the control groups accross such trials varies by over 400%.

    Infection + hypotension unresponsive to 1 liter of fluid is such a profoundly diverse and heterogeneous population with so many hidden phenotypes that randomization cannot be relied on to balance the groups.

    Of course one cannot guess a disease and then study the guess for 30yrs. It is rather pivotal to study a massive population, identify the phenotypes, and then study treatment of each of the phenotypes in RCT.

    Imagine this was AKI and we guessed a simple unified clinical definition for all of AKI in 1980s as “a severe rise in creatinine unresponsive to 1 liter of fluid”. Then we lumped all the hidden phenotypes together and tried different treatments in massive RCTs.

    The same nonreproducibility and variation of mortality in controls would occur over 30ys depending on the hidden phenotypic mix and randomization would not solve this problem.

    So the question they ask: Is liberal fluid or restrictive fluid best in patients with infection and hypotension unresponsive to 1 liter of fluid? Thats not the right question.

    The right question is the same as for AKI, CHF, & malignancy. What are the phenotypes? Then we can ask: Which phenotypes have better outcomes with liberal fluid & which with restrictive fluid & does this dynamically change in some phenotypes & how do we tell.

    It’s time to reform sepsis science.

    No matter how well meaning the IRB, they have to look at the fundamentals. Thought leaders must have courage and accept the truth. The past methods of sepsis research were not correct and have failed. Patients volunteering to take risk and they are helping mankind should not be subject to futile trial protocols which use guessed one-size-fits-all 1980s research standards which have failed to render reproducibly positive results for
    30 years.

    Only political expediency is holding this outdated threshold science as valid. Time for the young and old sepsis scientists and the awareness group to step up and say we are going to chart a new research course.

  • Multiple organ system failure precipitated by the coagulation cascade is usually the culprit resulting in sepsis related death. Regardless of the treatment one must keep the patient alive long enough for any treatment to be effective. 10 or 15 years ago there was a drug that reversed or delayed the coagulopathy. I saw dramatic improvement and reversal in multiple instances. The product is no longer available due to cost and litigation. Sad.

  • There are simply too many drugs and treatments which are being used WITHOUT FDA AUTHORIZATION OR ONGOING CHECKS THAT THINGS ARE WORKING WELL. When I had Chemotherapy Treatments the involved cancer doctor AUTHORIZED ME HAVING TWO TREATMENTS IN ONE WEEK BECAUSE AN UPCOMING HOLIDAY WOULD HAVE DELAYED MY TREATMENT FOR A WEEK. As a result after six-6-weeks my Blood Count DID NOT RETURN TO A NORMAL LEVEL-the final Chemotherapy Treatment was chosen to be eliminated by the oncologist. Doesn’t sound PROFESSIONAL OR RESPONSIBLE. For the ten years since-my hair in back grows faster than on the sides-a reason has not been provided by-the oncologist, the radiologist, the surgeon who performed the surgery, my primary care doctor, my neurologist, my epilepsy specialist, or the beautician. Who is to say how many other cases of this kind have taken place. Linda M. Ennis

  • This is different from VICTAS trial testing the Marik protocol, right? Perhaps you could write about that one as well.

  • These criticisms are entirely valid, and point out violations of NIH’s own clinical trial guidelines. In light of the recent scandal addressing the so-called “medical benefits of drinking” alcohol at the institute charged with researching alcoholism (recently soundly refuted by a huge international study in the August 2018 issue of Lancet), the sepsis project raises questions about the quality of the NIH peer review process. Neither this or the NIAAA study should have made it through 3-tier peer review.

    The SRO should have flagged it, the PO should have flagged it, the review committee should have flagged it, the IC director should not have sent it to the advisory council which should have rejected it. That is a lot of review steps that looked the other way — again.

  • Of course if they actually collected correct data, they could back tracks from the death and discharge information. There are no real reporting requirements, so the data is useless. These serious flaws underlie a lot of these “Studies.” The Medical and Hospital Industries will use the information that a provider is enrolled in one of these “Studies” as a Public Relations tool. The people who die due to these protocols with be attributed to underlying causes.
    I watched a friend die from Sepsis after surviving open heart surgery. Sepsis was not mentioned on his Death Certificate. The Hospital that gave him the sepsis, through an incision for a cardiac test was never informed. There is conspiracy of silence going on here, the lack of data proves it. When I told the nurse about the infection she ignored it. That was the hospital protocol, ignore, deny and dissemble. My friends heart surgery was postponed due to “insurance issues” meaning he waited a couple of years, as his health declined. There is no “Research” on that either, postponing a procedure, because the insurance does not want to pay. The hospital waited 24 hours before they began treating him for Sepsis, it was too little too late.
    The Point is that Physician have been silent or encouraged this. They believe from lectures by Industry Insiders that collecting data is ‘”government overreach” or they are told it could lead to liability. These Industries made sure that this data could not be collected, and hospitals could avoid reporting sepsis. 125 million cases sounds serious, and expensive, yet the Industry refuses to be accountable. They have made sure there is no way to count the cases, or look at the treatments. Their profit margin is much more important than “patient safety.” The industry does a really good job keeping the facts out of mass media too. Most Americans have no idea, that the Sepsis rate at their local hospital, is dangerous, or that a lot of it goes unreported. Thanks to corrupt Medical Boards, and local politicians, this is covered up.

  • “…the guidelines also call for physicians to closely monitor patients’ blood pressure” Wrong. NURSES monitor vital signs, mental status, urine output, central venous pressure, etc. in critically ill people. Stop attributing our practice to another profession.

  • I have had about 6-8 sepsis attacks in my life in the last thirty years because of a medical problem in my legs. The WORST problem I’ve had to face in those thirty years was the DOCTORS who treated me. Every 2-3 years for the last thirty or so years my leg will develop cellulitis. The skin on my leg becomes infected and i need antibiotics to fight off the infection. Almost every time this happens to me doctors would prescribe Bactum or Keflex medication to help cure me. However most times I needed other antibiotics to cure my infection but 90% of the doctors who treated me didn’t do the proper medical procedures of doing a culture on the wound, blood test, xrays or other test to see exactly what was the PROPER medicine to fight my infection. Instead of getting immediate proper care my infection developed into septis about 6 times over the last thirty years. Because of these near death experiences of septis I developed over the years my health is shot forever! I am 67 y.o. and I feel like a 90 y.o.an and walk like one too! My advice to ALL of you with conditions that may lead to septis is to go to the nearest EMERGENCY ROOM HOSPITAL EVERY time you feel like you are VERY sick from an infection in your body because going to your doctors office and dealing with a person, a doctor who may cause you more physical harm because that doctor wants to try this or that antibiotic before doing the FULL testing by blood and if necessary xray and whatever else is needed to determine the right medication to properly fight the infection is like a foolish thing to do! I’ve have had to get my latest doctor to agree to inform my health insurance company that my doctor recommends that EVERY time I get a fever, chills and bad sickness and an infection at ythe same time to immediately go to the emergency room and not to the doctors office because doctors offices aren’t equipped to do the right test to determine the right antibiotic for my infection. Also they told me that pills would not heal infection sometimes and that I would need intervenious medication instead and that unfortunately can only be administered in hospitals or nursing homes. So from what I’ve experienced so far in my life I’m sure beyond a doubt that the septis death rate could be dramatically lessened if PROPER medical care is IMMEDIATELY GIVEN!

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