麻豆传媒

CHICAGO -- Patients receiving vedolizumab (Entyvio) after undergoing bowel resection for advanced Crohn's disease in a randomized trial were significantly less likely to show endoscopic signs of recurrence compared with placebo, a researcher said here.

Out of 43 patients assigned to vedolizumab, 18 had no Crohn's-like lesions after 6 months, compared with just one of 37 in the placebo group, according to Geert D'Haens, MD, PhD, of Amsterdam University Medical Center in the Netherlands.

At the other end, 11 of the 37 placebo patients were rated as "i4" on the for endoscopic severity in Crohn's disease, versus three patients in the vedolizumab group, D'Haens reported at the annual Digestive Disease Week conference. An i4 rating indicates extensive inflammation with ulcers and/or stenosis.

In fact, D'Haens observed, two of the vedolizumab patients rated at i4 were actually dropouts from the study who were given the i4 rating under the trial's protocol for imputing missing data.

Overall, patients receiving vedolizumab had a 77.8% probability of being rated with a lower Rutgeerts score than patients assigned to placebo, he said, meeting the trial's primary efficacy endpoint. Safety findings, he added, were unremarkable given the drug's established record.

Vedolizumab is an adhesion molecule blocker that is for treating active Crohn's disease as well as ulcerative colitis in adults.

D'Haens explained that drug therapy eventually fails for most Crohn's disease patients, leaving no option but surgical resection. However, recurrence after surgery is common, since resection does not eliminate the immune-system disruption giving rise to the disease in the first place. No therapy is currently approved to prevent recurrence, he noted, creating a significant unmet need.

"Since lymphocyte trafficking is inhibited by vedolizumab, we hypothesized that this treatment could prevent postoperative recurrence," he said.

Patients (n=80) were randomized 1:1 to the active drug or placebo. One of the entry requirements was complete elimination of visible Crohn's lesions and inflammation, as determined by the surgeon. With that in mind, the investigators decided not to start with the vedolizumab dose used to treat active disease, but rather the maintenance dose: 300 mg infused every 8 weeks, starting within 4 weeks of surgery. Patients underwent colonoscopies after 6 months.

To be eligible, patients also needed to have at least one risk factor for recurrence: active smoking, one or more previous bowel resections, surgery for abscess or fistula, or previous use of tumor necrosis factor inhibitors (TNFi). Patients with the latter, however, had to have stopped them at least 6 weeks before eligibility screening.

There were also many exclusion criteria. Participants could not have been on vedolizumab or other non-TNFi biologics previously. Short bowel syndrome, recent history of cancer, lab abnormalities at baseline, and active or suspected Clostridioides difficile infection were also causes for exclusion.

Mean patient age was 36, with disease duration averaging about 9 years. Just under half were women. Among the risk factors for recurrence, the most common was past TNFi exposure (49%), followed by surgery for perforations (36%) and previous bowel resections (35%).

Serious adverse effects were unusual, supporting D'Haens's observation that "vedolizumab is a very safe drug." In the vedolizumab group, three such events were recorded: one each of bilateral tubo-ovarian abscess, thrombosed hemorrhoids, and pancreatic cancer. The latter was not believed to be drug-related. Two serious events occurred in the placebo group -- one intestinal perforation related to Crohn's disease and one case of severe abdominal pain.

The investigators also looked at recurrence of clinical Crohn's symptoms. No difference between groups was seen for this endpoint, at 22% and 21% for placebo and vedolizumab, respectively. This finding prompted a lively discussion after D'Haens's formal presentation, with two audience members asserting that clinical recurrence is not a meaningful outcome in a rigorous trial setting, particularly since bowel resection can itself lead to symptoms such as diarrhea. One called clinical recurrence a "worthless" endpoint, and D'Haens agreed.

But that provoked a rebuke from one of the session's co-moderators, Paul Moayyedi, MBChB, PhD, of McMaster University in Hamilton, Ontario, who argued that "it's a disservice to our patients" to ignore clinical outcomes in treatment trials.

Comment