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An herbal-based intravenous product significantly lowered the risk of death in sepsis patients with moderate to severe illness, according to results of a large randomized trial conducted in China.

At 28 days, 18.8% of patients who received standard care along with 5 days of Xuebijing injections died versus 26.1% in a group receiving standard care plus placebo, for a risk difference of 7.3 percentage points (95% CI 3.4-11.2, P<0.001), reported Haibo Qiu, MD, PhD, of Zhongda Hospital School of Medicine in Nanjing, and fellow EXIT-SEP investigators.

The more-than 1,800-patient study, published in , also demonstrated a greater number of mechanical ventilation-free and intensive care unit (ICU)-free days for those receiving the botanical product, as well as better Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores, among other secondary outcomes analyzed.

"While enormous strides have been made in the understanding of basic molecular mechanisms underlying the pathophysiology of sepsis, a distressingly long list of novel therapeutic agents has been tested in clinical trials over the past 30 years without a single, specific agent showing consistent morality benefit in sepsis trials," Qiu's group wrote. "The study may have identified a clinically important benefit made by [Xuebijing injection]."

Xuebijing is an herbal-based IV medication that has been licensed for use in China since 2004 for sepsis and multiple organ dysfunction syndrome. A prior trial showed benefit over placebo in , while animal models of Xuebijing in sepsis have suggested "anti-inflammatory, anticoagulation, and immunoregulatory effects," wrote Qiu and co-authors.

However, several hurdles would await any potential consideration by the FDA, said Ellis Unger, MD, and David Clissold, JD -- both of the Washington, D.C.-based food and drug law firm Hyman, Phelps, and McNamara, PC -- including that Xuebijing is an herbal preparation supported from just a single efficacy study that was conducted entirely outside the U.S., and in just one nation to boot.

When it comes to approval decisions, the agency holds potential botanical therapies to the same standards as any other drug, they explained in an . But "evidence must be provided that the product tested in the clinic matches the marketed product, and that the marketed product can be manufactured or produced consistently," they noted, factors that can be affected by "agricultural and processing aspects unique to botanicals (e.g., seasonal growing conditions, growing sites)."

Unger and Clissold also listed an array of generalizability issues to the U.S. in EXIT-SEP, such as the high rates of sepsis driven by lung and intra-abdominal infections, primary sites of infection that "seem unusual" for a U.S. population. They further added that not many severe cases were enrolled, with only 3.5% having an APACHE II score of at least 25 at baseline.

Furthermore, they highlighted an imbalance in unknown vital status between arms (3.6% and 2.6% for the study and placebo groups, respectively), an issue they said should be exceedingly rare in a 28-day trial of hospitalized patients.

"Missing efficacy data can undercut the persuasiveness of a trial, especially if there is a difference between treatment groups," wrote Unger and Clissold.

EXIT-SEP (Efficacy of Xuebijing Injection in Patients With Sepsis) was a multicenter, double-blind trial conducted at 45 sites in China from October 2017 to June 2019. Enrollment criteria included age 18 to 75 years, presence of sepsis 3.0 for less than 2 days (mean 1.4), and a SOFA score of 2 to 13.

Overall, 1,817 adults with sepsis were randomized 1:1 to standard of care plus either twice-daily infusions of Xuebijing (100 mL) or volume-matched saline placebo for 5 days.

Participants had a mean age of 56.5 years, two-thirds were men, and 46% had septic shock at enrollment. Mean SOFA score at baseline was 7.1 in each arm, while mean APACHE II scores were about 12.5. As noted, lung (45%) and intra-abdominal (32%) infections were the most common primary infection sites. Comorbid conditions were well balanced between groups, with hypertension in 30%, diabetes in 20%, coronary artery disease in 7%, and a history of stroke in 6%.

Mortality at 28 days was the primary outcome, occurring in 165 of the 878 patients in the Xuebijing arm and 230 of 882 in the placebo arm, with consistent results seen in subgroup analyses, according to Qiu and colleagues. The mortality benefit was seen in both ICU patients (14% with Xuebijing vs 20% with placebo, P=0.001) and those in the general ward (17% vs 23%, P=0.002).

Other secondary outcomes favoring Xuebijing versus placebo, respectively, included the following:

• Length of ICU stay: 9.8 vs 10.6 days (P=0.03)
• Mechanical ventilation-free days: 19.5 vs 17.7 (P<0.001)
• ICU-free days: 14.4 vs 12.4 (P<0.001)
• Change in SOFA score at 6 days: -2.4 vs -1.7 (P<0.001)
• Change in APACHE II score at 6 days: -2.8 vs -2.3 (P=0.046)

Unger and Clissold noted, however, that these should all be considered exploratory as they did not control for type I error rates.

Adverse events (AEs) overall were similar between arms, at 23% in the Xuebijing group and 25.3% in the placebo group. In the Xuebijing arm, increased alanine aminotransferase levels was the most common AE, in 5.8%, with other AEs including increased aspartate aminotransferase levels in 4.4% and high white blood cell counts in 4.1%.

No serious AEs occurred, but the editorialists took issue with how these were reported, noting that the study protocol excluded "events that are part of the natural history of the primary disease process or expected complications of critical illness."

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