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MEDICAL FRONTIERS - 111th Annual Digestive Disease Week (DDW)

New Orleans, Louisiana / May 1-5, 2010

The same principles found to be important for healing of ulcerative colitis (UC) with a delayed- and an extended-release 5-aminosalicylic acid (5-ASA, mesalamine) formulation appear to apply to a maintenance regimen. A newly completed trial called SIMPLE (Strategies in Maintenance of Patients receiving Long-term thErapy) has demonstrated that mesalamine is effective for sustained healing when given in adequate doses with an appropriate method of delivery among compliant patients, regardless of how the original healing was achieved. SIMPLE used mucosal healing as the criterion for judging efficacy. This is now increasingly regarded as the standard for documenting optimal disease control. However, in maintenance therapy, compliance is an additional key variable for sustained benefit.

“Clinicians are beginning to realize that compliance is the reason why a large proportion of UC patients relapse. This is really the critical clinical issue for improving outcomes,” stated Dr. Sunanda V. Kane, Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota. As senior author of the SIMPLE study, which evaluated compliance as a variable in risk of disease recurrence, Dr. Kane was able to prove that inducing patients to strictly comply with the prescribed regimen had a large impact on sustained benefit, even when using a high concentration agent designed to release mesalamine throughout the colon. She emphasized variables such as once-daily therapy and marked improvement in quality of life as factors that determine both compliance and sustained disease control.

SIMPLE Findings

The SIMPLE trial was a relatively large multicentre phase IV study designed to identify the efficacy of q.d. maintenance mesalamine that employs a multi-matrix system (MMX) to deliver the active drug to the colon. Two sets of patients were evaluated: the first were those with quiescent UC enrolled regardless of prior treatment to achieve quiescence; the second were patients with active UC who were initially enrolled in the acute phase of this same study with MMX mesalamine. The primary end point at 6 and 12 months was clinical recurrence, defined as four or more bowel movements per day above the patient’s normal frequency or as bowel movements associated with urgency, abdominal pain or rectal bleeding. All patients entered with an ulcerative colitis disease activity index (UCDAI) score of 0 for both bowel movements and rectal bleeding at enrolment or after 8 weeks of MMX mesalamine treatment. All patients in this open-label study received 2.4 g of MMX mesalamine q.d.

The overall rates of efficacy at both 6 and 12 months exceeded 60%, whether or not patients entered the study directly with quiescent disease or first achieved quiescence with MMX mesalamine. At 6 months, 76.1% of the direct-entry patients and 77.8% of the acute-phase patients remained without a clinical recurrence (Figure 1). At the end of 12 months, the rates were 63.3% and 67.3%, respectively. Dr. Kane concluded that MMX mesalamine was equally effective whether or not the patient achieved disease control on an initial course of MMX mesalamine. However, she emphasized that the proportion of patients who remained relapse-free was far higher among those who were compliant, defined as taking at least 80% of the q.d. doses of treatment.

Figure 1.

“Whether we compared the patients at 6 or 12 months, the advantage for remaining recurrence-free was significantly greater in those who met the definition for compliance,” Dr. Kane told delegates. While there was no difference in those who entered the study directly or after acute-phase therapy with MMX mesalamine, 79.4% of those who took 80% or more of their medication had not had a recurrence by 6 months vs. 63.9% who took less (P=0.0476). At 12 months, the disparity was even greater at 68.8% and 47.5% (P=0.012
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Figure 2.

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Paradigm Shift in Disease Management

The association between compliance and outcome is not surprising, but the importance of compliance is also relevant to the paradigm shift in the management of UC. While symptom control was once an acceptable criterion for efficacy, the association between complete mucosal healing and a reduction in subsequent complications, including colectomy, has replaced symptom relief as a key criterion of efficacy. There is abundant evidence that mesalamine can achieve complete mucosal healing if administered in a sustained-release system that delivers an adequate dose of active drug along the length of the colon.

In one of two multicentre studies with MMX mesalamine published three years ago, the rate of mucosal healing at the end of eight weeks of therapy was almost double among those patients receiving active therapy than placebo (41% vs. 22%; P=0.007) (Kamm et al. Gastroenterology 2007;132:66-75). An alternative mesalamine preparation in that study healed only 33% and was not superior to placebo.

The second study showed a similar advantage of MMX mesalamine over placebo (34% vs. 13%; P<0.01) (Lichtenstein et al. Clin Gastroenterol Hepatol 2007; 5:95-102). Both of these studies defined complete mucosal healing as no mucosal friability, and at least a 1-point reduction in sigmoidoscopy score from baseline. This definition was unusually rigorous at the time but has subsequently been adopted by other efficacy trials in UC due to the evidence that mucosal healing is prognostically important.

Although the SIMPLE study did not include sigmoidoscopy control, Dr. Kane reported that the previous data confirm that 5-ASA was effective for healing. She told delegates that in her own practice, she now specifically pursues mucosal healing, rather than symptom relief alone, as a therapeutic goal.

“It is not practical to conduct a sigmoidoscopy in all patients to verify healing after an acute course of treatment, but I often evaluate UC patients with endoscopy on a return visit six or more months after starting maintenance therapy to see if the patient remains healed. Obviously, I am more likely to take a second look if patients are experiencing symptoms, but I may modify therapy if I see disease activity even in a patient who is not experiencing symptoms,” Dr. Kane remarked. However, “more often than not, patients have not been compliant so it is not so much a question of modifying therapy [as it is of] educating the patient about the risk of a relapse without good compliance with the regimen.”

A Canadian expert offered a similar view on the role of mucosal healing and the importance of considering therapy strategies in the context of this end point. When asked to comment on this evolution in treatment goals, Dr. Remo Panaccione, Director, Inflammatory Bowel Clinic, University of Calgary, Alberta, stated that there are a variety of factors that contribute to a new emphasis on complete mucosal healing, not only in UC management but also in the management of all inflammatory bowel diseases.

“Mucosal healing has evolved into an important therapeutic goal in IBD, both Crohn’s disease and UC. There is a move from treating only symptoms to treating the disease and that is where assessing for mucosal healing comes into play. In UC, it may be more relevant because UC is a mucosal-based disease and healing the mucosa implies you have adequately treated the disease.  Mucosal healing is also associated with a potential decrease for flares, development of dysplasia or cancer, and a reduction in colectomy,” Dr. Panaccione observed. Although he did not fully endorse Dr. Kane’s approach to a second look endoscopy at six months, he did support her emphasis on healing as an end point.

Dr. Panaccione told delegates that a stringent definition of disease control “does not necessarily mean we should be scoping everyone to see if mucosal healing is present, but the gastroenterologist should be more aware of subtle symptoms that may suggest that there is still active disease and then confirm this with a colonoscopy. Furthermore, clinicians should start reaching for therapies that have not only proven to provide symptomatic relief but also have demonstrated mucosal healing properties when they are making therapeutic decisions.”

Compliance Critical

MMX mesalamine is effective for mucosal healing in the majority of UC patients, but the assumption of healing depends on treatment compliance. Dr. Kane said that qualities such as q.d. dosing have been shown repeatedly to be important to compliance, but she also pointed to other qualities of treatment that may be important in helping patients make the connection between rigorous compliance and improved outcome. In particular, she suggested that the perceived efficacy of the therapy can be a motivation factor. She noted that in the acute phase of the SIMPLE study, 40% of patients had achieved control of bowel movement frequency and rectal bleeding within one week. The median time to resolution of these symptoms was 22 days.

“While there is no clear evidence that the onset of action of UC medication influences patient compliance, the fast onset of action of MMX mesalamine on clinical symptoms is likely to have a positive impact on patients’ attitudes toward treatment,” Dr. Kane observed. She suggested that in educating patients about the importance of compliance, failure to adhere to the same medication that relieved their symptoms might result in a return of the same symptoms. This can be valuable for discouraging patients from becoming less adherent as symptoms resolve.

The connection between remaining on effective treatment and remaining free of the burden of disease is also reflected in the quality of life data generated by the SIMPLE study. In the acute phase of the study, a significant improvement in disease-specific measures of health-related quality of life (HRQoL) was significantly correlated to a reduction in disease activity. Subsequent maintenance data from SIMPLE demonstrated the same significant correlation between a decrease in disease activity and an improvement in HRQoL. The burden of UC on HRQoL is well known, but patients on MMX mesalamine not only achieved a significant improvement in essentially all aspects of HRQoL but achieved a level of HRQoL that was similar or better than that of the general population.

“As clinicians, what we need to do is help patients understand the relationship between the therapy and their ability to stay well. We know that many patients without symptoms for an extended period start to become non-compliant because they think they do not need their medicine any longer. We now have data from the SIMPLE study that suggests many of the failures on 5-ASA maintenance are due to non-compliance. We may be able to address this with better patient counselling,” Dr. Kane suggested.

Compliance may be even more important when the treatment goal is achieving and sustaining mucosal healing. One concept that may explain the importance of mucosal healing is that the homeostasis inherent in normal tissue function produces an obstacle to a return of disease activity. Once the molecular events that drive disease expression emerge, the cascade of inflammatory activity that disrupts mucosal integrity takes time to resolve even with treatment.

“The first-line therapy for UC, 5-ASA, is effective for achieving and sustaining mucosal healing in a high percentage of patients with mild to moderate disease, but it is dependent on choosing a medication that enhances compliance. This is clearly an important issue,” Dr. Kane emphasized.

Summary

New data from a phase IV study that confirm that compliance to 80% or more of prescribed MMX mesalamine reduces risk of recurrence is consistent with the importance of delivering sufficient drug along the length of the colon to produce mucosal healing, a barrier to relapse. The ability of the agent prevent recurrence in almost 70% of compliant patients over 12 months of maintenance therapy was observed, whether patients initially achieved disease quiescence with MMX mesalamine or another 5-ASA agent. The ability to link disease control to the efficacy of a q.d. agent was proposed as a potential tool to educate patients about the importance of compliance for sustained disease control.