A vitamin-based treatment failed to significantly boost ventilator- and vasopressor-free days within 30 days among critically ill patients with sepsis versus placebo, according to results of a trial that was prematurely axed for “administrative reasons.”
In the VICTAS study with 501 participants, the primary outcome of ventilator- and vasopressor-free days was a median of 25 days in the group that received vitamin C, thiamine, and hydrocortisone (HAT) and 26 days in the placebo group, for a median difference of −1 day (95% CI −4 to 2 days, P=0.85), reported Jonathan E. Sevransky, MD, MHS, of Emory University Hospital in Atlanta, and co-authors.
There also was no difference in 30-day mortality (secondary endpoint) between the two groups (22% in the intervention group versus 24% in the placebo group), they wrote in JAMA. But “the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference,” the authors advised.
In an accompanying editor’s note, Howard Bauchner, MD, JAMA editor-in-chief, and co-authors took the trial’s funding agency to task for its sudden withdrawal of support. “Although the funder of the VICTAS trial may have had business reasons, philosophical priorities, or other factors that were considered in its decision, the withdrawal of funding and resultant termination of the trial compromised the integrity of the study, precluded the study from definitively answering an important clinical question, and represented a serious violation of the implicit pact with the study participants who volunteered for the trial,” they argued.
Neither Bauchner’s group nor the study authors detailed what those reasons were. The trial was funded by the Marcus Foundation, which, according to its current website, has two main foci: “Assisting organizations that work to increase awareness of hunger as a critical problem and/or deliver food resources to meet critical short-term needs; and [s]upporting efforts to change underlying structural obstacles and incentives that hinder efforts to bring sustainable practices into the mainstream.” A list of grantees is dominated by environmental and community food non-profits; the search for terms “VICTAS” and “Emory University” turns up no results on the site.
In 2019, Bernie Marcus, a Home Depot founder, announced that he would “sunset” the Marcus Foundation upon his death. Marcus turned 91 in 2020.
Bauchner and co-authors also took issue with the fact that an “individual who served as chair of the DSMB [data and safety monitoring board]… was involved with the initial design of the [VICTAS] study, participated in the statistical analysis and interpretation of the data, and is listed as an author of the article,” although they did not name any names.
However, Baucher’s group defended JAMA’s decision to publish the study results because the authors do not report any commercial interests in the study agents; the trial is one of the largest of it’s kind; the 501 people who agreed to enrollment deserve acknowledgment; and the DSMB chair/study author was not involved in the decision to halt the trial.
On top of all that, vitamin-based sepsis treatment has carried its fair share of controversy, and answers are needed. In a 2020 ACP Hospitalist article, experts weighed in on vitamin C supplementation in sepsis, with opinions ranging from “The final word on vitamin C infusion… is not in,” to “once therapies are proven to not be helpful, I don’t think we should use them.”
Previous studies, such as CITRIS-ALI and VITAMINS, turned in negative findings. Results from the ongoing ASTER trial (estimated completion date July 2022), along with studies in Egypt, Taiwan, Spain, China, and Qatar, as well as two in Greece, may finally settle the debate.
In the meantime, what VICTAS lacked in longevity and definitive data, it made up for with “important results,” noted Kristin L. Walter, MD, MS, Fishbein Fellow at JAMA, and Christopher W. Seymour, MD, MSc, of the University of Pittsburgh School of Medicine, in an accompanying editorial.
“First, the results of this study are consistent with other recent randomized studies that have found no greater effectiveness of HAT versus placebo for various prespecified primary outcomes,” they said.
In addition, the trial confirmed the safety of HAT treatment in critically ill patients with sepsis, and that “underpowered trials fail to provide absolute certainty in their conclusions,” they wrote.
Walter and Seymour pointed out that physicians who already back HAT are not going to be swayed by VICTAS results, while those who take an anti-HAT stand will be assured of their choice. However, they cautioned that “an inflexible approach that holds fast to one piece of evidence versus another is not productive… [f]or HAT, the critical care community must consider all the evidence, trials or not, with intellectual honesty, flexibility, and keen awareness of the strengths and limitations.”
The multicenter, adaptive-sample size VICTAS enrolled adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction from emergency departments (ED) or ICUs at 43 U.S. hospitals from August 2018 through July 2019. Funding was pulled at the 501-patient mark, the study was halted, and “All study-related follow-up was completed by January 2020,” the authors explained.
Participants were randomized to receive IV vitamin C at 1.5 g, thiamine at 100 mg, and hydrocortisone at 50 mg every six hours (n=252) or matching placebo (n=249) for 96 hours or until ICU discharge or death.
“Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone,” Sevransky’s group noted, adding that open-label corticosteroids were prescribed to 33% and 32% of the intervention and placebo groups, respectively.
Patients’ median age was 62, 46% were female, and 30% were Black. The median Acute Physiology and Chronic Health Evaluation II score was 27 while the median Sequential Organ Failure Assessment score was 9. The majority were admitted to the ICU from the ED and the lungs were the source of infection in more than one-third in both groups.
Finally, the median patient weight in both groups was 80 kg (about 176 lbs.), and the authors found that the primary-outcome model yielded an interaction between treatment and weight (P=0.02).
With regard to long-term outcomes, 180-days mortality in the intervention group was 40.5% versus 37.8% in the placebo group for a 2.7% difference (95% CI −11.3% to 5.8%). Also, a Cox proportional hazard model yielded an unadjusted hazard ratio for death in the intervention group of 1.08 at 180 days (95% CI 0.82-1.43), the authors reported.
As for adverse events (AEs), there were no serious ones reported, although two AEs — hemorrhagic shock and worsening kidney function — in the intervention group were assessed as potentially related to study participation.
Besides the forced stop, other study limitations included the fact that “clinicians were allowed to administer corticosteroids at their discretion. If corticosteroids have a beneficial effect on [the primary outcome], this would bias the trial results toward the null, although a post hoc sensitivity analysis demonstrated similar findings in patients not receiving open-label corticosteroids,” the authors noted.
Also, the median time to receipt of intervention was 14.7 hours “and while this timing was earlier than in the VITAMINS trial, it remains unknown if still earlier administration could improve outcomes,” Sevransky’s group said. In a 2020 NPR interview, Paul Marik, MD, one of the first to study vitamin-based treatment for sepsis, said that therapy should be delivered within six hours after sepsis is suspected in order to be effective.
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In criticially ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not lead to a statistically significant difference in ventilator- and vasopressor-free days within 30 days following randomization versus placebo.
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The VICTAS trial was terminated early when the funding was lost, so it may have been underpowered to detect any clinically important differences.
Shalmali Pal, Contributing Writer, BreakingMED™
VICTAS was funded by the Marcus Foundation/Emory University, and supported by SCCM Discovery, Johns Hopkins, and Vanderbilt University. Hydrocortisone, vitamin C, and thiamine were purchased from McGuff Pharmaceuticals. Nova Biomedical provided support to six sites with point-of-care glucometers.
Sevransky reported serving as a Critical Care Medicine associate editor and support from the CDC Foundation. Co-authors reported relationships with, and/or support from, Hamilton, Oxford University Press/Brigham Young University, New York University, Faron, Sedana, Janssen, the NIH, the U.S. Department of Defense, BARDA DRIVe/Solving Sepsis, Critical Care Medicine, Critical Care Explorations, the Surgical Critical Care Initiative/Uniformed Services University of the Health Sciences, La Jolla Pharmaceutical, Bioxcel, Pfizer, Orion, Eli Lilly, the National Heart, Lung, and Blood Institute, Agency for Healthcare Research and Quality, the CDC, Johnson & Johnson, Nico, United Therapeutics, Janssen, Reata Pharma, Berry Consultants, Entegrion, Endpoint Health Research, bioMérieux, Bioscape Digital, Cincinnati Children’s Hospital Medical Center, Cumberland Pharmaceuticals, Avisa Pharma, Cytovale, Beckman Coulter, Regeneron, and Grifols.
Bauchner and Walter reported no relationships relevant to the contents of this paper to disclose. Co-authors reported serving as JAMA executive editor, deputy editor, and associate editor, as well as support from, and/or relationships with, the NIH, Beckman Coulter, and Edwards Lifesciences.
Cat ID: 500
Topic ID: 498,500,282,290,494,500,503,728,730,190,469,520,192,255,590,60,925
