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United European Gastroenterology Week (UEGW)

Vienna, Austria / October 19-22, 2008

Previous clinical trials have established biologics, such as infliximab, as an appropriate therapy for Crohn’s disease when immunomodulators such as azathioprine have failed. However, it was unclear whether outcomes could be improved by moving earlier to a biologic. A new study, called SONIC (Study Of patients with crohn’s disease Naive to Immunomodulators and biologiC therapy), has addressed this specific question by randomizing patients who were steroid dependent or steroid failures to an immunomodulator, infliximab, or the combination. All patients eligible for SONIC were naïve to non-steroid immunomodulators. In addition, patients had to meet at least one of four additional criteria: have failed 5-ASA (defined as inadequate response to at least 2.4 g/day for at least four weeks), have failed budesonide (defined as inadequate response to at least 6 mg/day for at least four weeks), have required two or more courses of steroids in the past year, or were steroid-dependent.

The study confirmed that moving immediately to infliximab was more effective than stepping up to the immunomodulator azathioprine. The new study adds an additional piece of the puzzle for an evidence-based therapeutic decision.

“The trial offers data with the potential to challenge the current approach to treatment. The results demonstrate that moving infliximab forward in the treatment algorithm increases the proportion of patients who achieve steroid-free remission as well as the proportion who achieve complete mucosal healing,” reported senior trial investigator Dr. Jean-Frédéric Colombel, Professor of Hepatogastroenterology, Centre Hospitalier Regional Universitaire de Lille, France.

In SONIC, patients with moderate to severe Crohn’s disease were randomized to the TNF-a inhibitor infliximab plus placebo, azathioprine plus placebo, or the combination of infliximab plus azathioprine. At the end of 26 weeks, corticosteroid-free remission was achieved in 56.8% of patients on the combination, 44.4% of those on infliximab, and 30.6% of those on azathioprine. The advantage for both infliximab (P=0.009) and the combination (P<0.001) over azathioprine monotherapy was highly statistically significant (Figure 1).

Figure 1. SONIC: Corticosteroid-free Clinical Remission at Week 26

There were 508 patients randomized on a one-to-one-basis in the three study arms. The dose of orally administered azathioprine was 2.5 mg/kg/day. The dose of infliximab was administered as an infusion of 5 mg/kg on weeks 0, 2, and 6, and every eight weeks thereafter. The same doses of each active therapy were used in the combination.

In the study population, the median duration of disease was 2.3 years in a population with a median age of 34 years and a median weight of 70 kg. There was a relatively even ratio of men to women. The median Crohn’s Disease Activity Index (CDAI) score was approximately 275. The median C-reactive protein (CRP) level was 1.0 mg/L. At entry, slightly more than half of patients were taking a 5-ASA, 28% were taking a systemic steroid such as prednisone, and 14% were taking budesonide.

At the discretion of the treating physician, concomitant steroid use was permitted during the course of the study in all treatment arms, although doses greater than 40 mg of prednisone or an equivalent were not allowed. At week 14, patients taking steroids were required to begin a mandatory tapering at a rate of 5 mg (of prednisone or equivalent) per week.

The primary end point of steroid-free remission was defined as a CDAI of less than 150 points in the absence of any systemic steroids, such as prednisone, within the previous three weeks (budesonide, which was permitted, could not have been administered at a dose of 6 mg or more for at least three weeks). Mucosal healing was defined as a complete absence of mucosal ulcerations in the colon or terminal ileum as assessed by video endoscopy.

The advantage of the infliximab-based regimens was seen in the primary end point of corticosteroid-free remission as well as the secondary end points such as complete mucosal healing. Specifically, complete mucosal healing was confirmed in 43.9% of those on the combination, 30.1% of those on infliximab alone, and 16.5% of those on azathioprine alone, according to Dr. Paul J. Rutgeerts, Professor of Medicine, University of Leuven, Belgium. When compared to azathioprine alone, the advantage of infliximab, whether in the combination (P<0.001) or as a single agent (P=0.023), was statistically significant.

The superior efficacy of the infliximab-based arms was not offset by any increased safety or tolerability concerns. In fact, although the proportion of patients who experienced an adverse event was similar in the three arms, the proportion experiencing at least one serious adverse event was higher in the arm receiving azathioprine alone (24.2%) than on infliximab alone (16%) or the combination (14%). Similarly, the proportion of patients with serious infections was 5% in the azathioprine arm, 2.5% on infliximab alone, and 3.4% on the combination. According to Dr. Colombel, there was one case of tuberculosis on the combination arm and two cases of colon cancer on the azathioprine arm. The only death occurred post-colectomy in a patient randomized to azathioprine monotherapy.

“There was no trend for an increased risk of serious infections in the arm receiving the biologic. Rather, the infection rate was higher in the azathioprine arm,” noted Dr. Colombel, emphasizing that safety issues do not appear to be an important variable in differentiating these strategies.

SONIC Implications

Re-examining what treatment decisions can now be considered evidence-based, Dr. Colombel explained that infliximab, alone or in combination with azathioprine, has previously been established as a superior approach to more aggressive immunomodulators such as methotrexate in patients who are no longer controlled on azathioprine alone. In such patients started on a combination of infliximab and azathioprine, Dr. Colombel advocates withdrawing azathioprine after six months.

Now, there is also controlled evidence to support infliximab in individuals who need to be stepped up from corticosteroids but who have not received a prior course of azathioprine. For these patients, SONIC findings demonstrate that infliximab alone or in combination with azathioprine is superior to azathioprine monotherapy for the key end points of steroid-free remission and complete mucosal healing. Based on the slightly greater activity achieved with infliximab in combination with azathioprine relative to infliximab alone, Dr. Colombel indicated that he would be inclined to offer the combination in patients with high CDAI scores or other risk factors that suggest the need for a more aggressive treatment. Otherwise, he would initiate treatment with infliximab monotherapy.

“When we look at the treatment algorithm, we knew what to do in patients who had been treated with azathioprine and failed. The SONIC infliximab results now tell us which strategy to consider in patients who have not yet been treated with azathioprine but are no longer candidates for steroids,” said Dr. Colombel, who displayed a decision-tree with the new treatment strategy (Figure 2).

Achieving Mucosal Healing and Steroid-free Remission

The SONIC infliximab trial, like many recent studies in inflammatory bowel disease (IBD), included complete mucosal healing as an end point because of the prognostic importance of this outcome. Citing studies in both Crohn’s disease and ulcerative colitis that associated complete mucosal healing with reduced rates of resection, one of the most feared complications of IBD, Dr. Remo Panaccione, Director, Inflammatory Bowel Disease Clinic, University of Calgary, Alberta, confirmed that both steroid-free remission and complete mucosal healing are appropriate goals because of their ability to predict an improved long-term outcome.

Fig
Treatment Algorithm

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“I think early use of therapies that lead to complete mucosal healing will change the natural history of IBD,” suggested Dr. Panaccione, citing several studies that support this premise. In his view, chronic steroid use to maintain control in IBD “is no longer acceptable” and that the time has come “to strive beyond symptomatic remission.” Moreover, he stated that the opportunity to change the natural course of disease with biologics may not persist into late stages of disease.

“All the signals suggest that there is a window in which the biologics work the best,” Dr. Panaccione told delegates. “I think it is time to change the treatment paradigm.”

As Dr. Rutgeerts re-affirmed, that “Complete mucosal healing is the new treatment target” based on evidence that this predicts long-term disease control. Although patients are most concerned about symptom remission, he maintained that the most important risks of disease progression, including colectomy, could be reduced with early aggressive control.

The role of biologics has been in almost permanent transition since their introduction more than 10 years ago. Tracing these changes, Dr. Walter Reinisch, Head, Austrian IBD Study Group, Medical University of Vienna, observed that the initial protocol for biologics was single dose administered on an episodic basis in highly refractory patients. The current therapy is to administer infliximab with induction at zero, two and six weeks and then use scheduled maintenance every-eight-weeks until complete mucosal healing is achieved, and consider intervening at earlier stages when response rates are higher.

“Symptom control is not enough. We have evidence from many trials that if you achieve complete mucosal healing, you are more likely to remain in remission. We need to reconsider where to use these agents on an evidence-based treatment algorithm,” Dr. Reinisch stated.

Summary

The SONIC infliximab study has permitted completion of an evidence-based section of the Crohn’s treatment decision tree. According to the SONIC data, infliximab alone or in combination with azathioprine provides better outcomes than azathioprine alone in patients who have failed steroids. By moving directly to an infliximab treatment-based regimen, Crohn’s disease patients who have failed steroids are more likely to achieve corticosteroid-free remission and to achieve complete mucosal healing. This study fills an important knowledge gap and is likely to alter standard practice in Crohn’s therapy.