Patients with moderately to severely active Crohn’s disease who took adalimumab as maintenance therapy for 1 year showed improved mucosal healing compared with those who took placebo, Dr. Paul Rutgeerts and his colleagues reported in the May issue of Gastroenterology.
"Historically, clinical response and remission have been the primary treatment goals for patients with Crohn’s disease. Recently, with the availability of more potent therapies, physicians are proposing that treatment goals focus on disease-modifying outcomes such as mucosal healing," said Dr. Rutgeerts, of the University Hospital of Gasthuisberg, Leuven (Belgium), and his associates (Gastroenterology 2012 Feb. 12 [doi:10.1053/j.gastro.2012.01.035]).
The EXTEND (Extend the Safety and Efficacy of Adalimumab Through Endoscopic Healing) trial involved 135 adults who had a long disease duration and had failed to improve on conventional therapy. The authors described it as "the first prospective, placebo-controlled, double-blind study designed with mucosal healing as the primary end point." All the study subjects consented to undergo up to four endoscopies during the trial.
The study also was unique in that patients were permitted to continue taking concomitant medications such as azathioprine, 6-mercaptopurine, methotrexate, aminosalicylates, antibiotics, prednisone, or budesonide. The protocol also allowed tapering of steroid therapy as patients improved, as well as resumption of steroid therapy if they subsequently worsened, and permitted patients in the placebo group who were unresponsive to switch to open-label "rescue" therapy with the active agent.
The study was sponsored by Abbott Laboratories, maker of adalimumab, and was conducted at 19 sites in Europe, the United States, and Canada.
All the study subjects received open-label induction therapy with subcutaneous adalimumab (160 mg at baseline and 80 mg at week 2) for 1 month. At that time their clinical response was assessed and they were randomly assigned to either continue adalimumab as maintenance therapy (40 mg every other week) or to receive placebo for the remainder of the year-long study.
After week 8, patients who had Crohn’s disease flares or did not respond to treatment could switch to open-label adalimumab, 40 mg every other week, for the remainder of the year. If they continued to worsen, the dose could be escalated to 40 mg every week.
The primary efficacy end point, complete mucosal healing on endoscopy at week 12, was achieved by 27% of patients who received continuous adalimumab, compared with only 13% of those who received placebo. This difference "narrowly missed statistical significance," Dr. Rutgeerts and his associates said.
However, at 1 year the difference in rates of mucosal healing did reach statistical significance, at 24% in the adalimumab group and 0% in the placebo group, they noted.
In addition, rates of remission as defined by scores on the Crohn’s Disease Endoscopic Index of Severity (CDEIS) were significantly higher with active treatment at both 12 weeks and 1 year. And significantly more patients on active treatment achieved a 75% response in CDEIS score at both 12 weeks and 1 year.
Thus, "the ability of adalimumab to maintain mucosal healing was confirmed by two endoscopic measures," the authors noted.
The rates of mucosal healing also were significantly higher at week 12 with active therapy in the subgroup of patients who strictly complied with the study protocol. The findings at week 12 were similar across several subgroups of patients. For example, the rate of mucosal healing was 25% in patients who were using steroids at baseline and who took maintenance adalimumab vs. 13% in steroid users on placebo.
And the rate of mucosal healing was 28% in patients who didn’t use steroids at baseline but took maintenance adalimumab vs. 14% in patients who didn’t use steroids and took placebo. Mucosal healing rates also were higher with adalimumab than placebo in the subgroup of patients who had high C-reactive protein levels at baseline and in the subgroup who were taking immunosuppressants at baseline.
At 1 year, 36% of patients taking maintenance adalimumab achieved a decrease in Crohn’s Disease Activity Index (CDAI) score of at least 100 points from baseline, compared with only 14% of those taking placebo. And 41% of patients taking maintenance adalimumab achieved a CDAI decrease of at least 70 points from baseline, compared with only 14% of those taking placebo.
The most common adverse events were infections, and they were more common in the adalimumab group (55%) than in the placebo group (34%). There were five serious infections during the study: one case each of anal abscess, perianal abscess, vulvar abscess, herpes zoster, and tonsillitis.
There were no deaths and no cases of cancer, demyelinating disorder, allergic reaction, lupus-like syndrome, or tuberculosis.