More Disappointing Results for Vitamin C, Thiamine and Hydrocortisone in Sepsis

By Megan Brooks

February 25, 2021

NEW YORK (Reuters Health) - Among critically ill patients with sepsis, treatment with hydrocortisone, vitamin C (ascorbic acid) and thiamine (HAT) did not improve outcome in the randomized controlled VICTAS trial.

"Our study suggested that the large treatment effect seen in a previous observational trial is not likely, but we cannot rule out smaller but still clinically important treatment effect in patients," Dr. Jonathan E. Sevransky, with Emory University School of Medicine in Atlanta, told Reuters Health by email.

In their JAMA paper, the investigators note that the VICTAS trial was stopped early due to withdrawal of funding support and therefore may have been underpowered to detect a clinically important difference.

The VICTAS trial enrolled 501 adults in the intensive-care units at 43 U.S. hospitals with sepsis-induced respiratory dysfunction, cardiovascular dysfunction, or both; 252 were randomly allocated to the combination of vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) and 249 to placebo or placebo every six hours for 96 hours or until death or discharge from the ICU. Patients could receive open-label corticosteroids at the discretion of the clinical team; about a third of patients in each group were given corticosteroids.

The results showed no statistically significant difference in the HAT and placebo groups in the primary outcome, number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization, (median, 25 days with HAT vs. 26 days with placebo; P=0.85).

There were also no differences in any prespecified secondary endpoints, including deaths at 30 days due to any cause (22% in the HAT group vs. 24% in the placebo group). None of the sensitivity analyses substantially changed the main findings.

In addition to early termination of the study, the investigators make note of several other limitations.

One is that the trial used a fixed dose of vitamin C; a higher dose or dosing based on plasma vitamin C concentrations might yield different results. Also, clinicians were allowed to give corticosteroids at their discretion and enrollment was limited to patients with sepsis-induced cardiovascular or respiratory failure; including patients with different types of organ dysfunction may have yielded different results.

They also note that the median time to HAT treatment was 14.7 hours (interquartile range, 7.9 to 20.9 hours) and it's unclear whether earlier administration might improve outcomes.

In email to Reuters Health, Dr. Sevransky noted that "none of the published multicenter studies – including VICTAS – have shown a significant treatment effect in the primary outcome measure tested. All of them, however, were underpowered to show definitively whether a smaller, but still meaningful effect might be present. A large Canadian trial of vitamin C in sepsis is currently underway – and that trial may provide additional guidance to clinicians."

In an editorial, Dr. Kristin Walter, Fishbein Fellow in Medical Journalism at JAMA, and Dr. Christopher Seymour, associate editor at the journal, note that the "debate involving this therapy was at times vociferous, and has yet to be resolved."

"Even though the VICTAS trial may not settle the debate over HAT treatment in sepsis, it provides important results. First, the results of this study are consistent with other recent randomized studies that have found no greater effectiveness of HAT vs placebo for various prespecified primary outcomes," they point out.

"Second, the trial confirms that HAT treatment is safe in critically ill patients with sepsis. Third, and not surprisingly, the VICTAS trial shows that underpowered trials fail to provide absolute certainty in their conclusions," they add.

"For clinicians who consider HAT a low-cost, low-risk, and accessible treatment for sepsis, this study may not change their practice. For clinicians who considered the HAT debate settled when five randomized trials in 2020 failed to demonstrate a mortality benefit, the VICTAS trial will confirm their position," Dr. Walter and Dr. Seymour say.

They also point out that, according to, seven more ongoing randomized trials continue to recruit patients to test HAT in sepsis. To date, six randomized trials (including VICTAS) have yielded results for primary endpoints that do not support HAT treatment, they note.

Funding for the VICTAS trial was provided by the Marcus Foundation to Emory University.

SOURCE: JAMA, February 23, 2021.