Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

16th United European Gastroenterology Week (UEGW)

Vienna, Austria / October 19-22, 2008

In ulcerative colitis (UC), like many disease states, the opportunity for treatment benefits is interrelated with dosing frequency, potency, side effects, and adherence. New substudies from the multinational PODIUM (Pentasa Once Daily in Ulcerative Colitis for Maintenance of Remission) trial, which tested the efficacy of once-daily mesalazine for UC, have provided additional details with which to consider this interrelationship in order to maximize the proportion of patients on first-line mesalazine. This goal is a priority because strategies to increase the proportion of patients who reach and preserve remission on 5-ASA represent a major step toward improved long-term outcome.

“The PODIUM study demonstrated that once-daily therapy was more effective than a twice-daily regimen, which may be explained in several ways. The most obvious is increased compliance, but new data confirm an increased remission rate on once-daily therapy independent of compliance,” reported Dr. Axel U. Dignass, Medizinische Klinik I, Markus-Krankenhaus, Frankfurt/Main, Germany. “We should employ these opportunities to increase the proportion of patients who can be adequately maintained on 5-ASA because of the tolerability of this approach.”

Maintaining Higher Remission Rate

In PODIUM, 362 UC patients from centres in eight European countries were randomized to receive mesalazine 2-g sachet once daily or 1-g sachet b.i.d. All patients were required to be in remission at entry, and from previous history about two-thirds had left-sided UC and one-third had pancolitis. The study was designed to demonstrate that rates of relapse, defined as a score >2 on the Ulcerative Colitis – Disease Activity Index (UC-DAI), would be no higher in the group receiving once-daily than b.i.d. therapy. Results did more than demonstrate equivalence.

“At the end of the 12-month study, there was a statistically significant 11.9% (70.8% vs. 58.9%; P=0.024) relative advantage for the once-daily regimen in maintaining remission. The secondary UC-DAI subscores of stool frequency, rectal bleeding, and physicians global assessment told the same story,” Dr. Dignass reported. “The safety profile of once-daily mesalazine granules did not differ from the well-established safety profile of b.i.d. mesalazine granules.”

In the newly completed substudies, the proportion of patients who remained on UC-DAI definitions of normal for stool frequency (81.5% vs. 67.7%) and rectal bleeding (79.6% vs. 70.7%) favoured the once-daily regimen as did the proportion of patients considered normal on the basis of physician global assessment (72.4% vs. 62.5%).

Adherence and Compound Dynamics: Possible Synergy

When results were initially presented, it was reasonably concluded that compliance was better on the once-daily therapy and this explained the greater rates of efficacy. Although compliance was better on a numerical basis, it was not statistically greater in the once-daily arm. This led to further analyses to determine if there was another factor involved in the better outcomes. Specifically, results were analyzed by levels of compliance stratified as >70%, >80%, and >90% of prescribed doses over the course of the study. When the primary end point of freedom from relapse was compared at the same level of compliance, the remission rates were higher on the once-daily dose.

“The evidence from this study that the improved remission rates in the once-daily dosing arm cannot be explained by compliance may be important for understanding strategies in UC control,” Dr. Dignass indicated. He suggested that one of the explanations might be found in the dynamics of the once-daily mesalazine granules. For example, the once-daily mesalazine evaluated in PODIUM provides time-released medication to maintain active drug levels over each 24-hour dosing period, which may avoid a trough in twice-daily regimens, while the initial bolus of drug at the start of each dosing period may provide a more favourable elimination of inflammatory signals.

The advantage of the once-daily regimen in the trial was significant, but it is reasonable to anticipate an even greater advantage outside of the frequent surveillance and monitoring inherent in clinical studies that would favour compliance regardless of dosing regimen. There is abundant evidence that once-daily therapies are easier to incorporate into daily schedules, permitting adherence even when symptoms are controlled and no longer providing an active reminder to take the medication. By itself, once-daily therapy is often considered a quality-of-life advantage over more frequent dosing, but greater protection from relapse is key to preserved quality of life, another outcome evaluated in the PODIUM substudies.

“In those who had a relapse over the course of the study, there was a stepwise reduction in quality of life that correlated with the severity of the relapse,” reported a team of investigators that included Dr. Craig J. Currie, Department of Medicine, Cardiff University, UK. When using standardized methodology for measuring quality of life, the results of the PODIUM study suggested that those with a mild-to-moderate relapse had a health-related quality of life comparable to a cardiac dysrhythmia or gout, while those with a severe relapse had a quality of life similar to emphysema or renal failure. For the simple reason that the once-daily formulation reduced relapse risk, it also provided significantly greater quality of life over the course of the study.

Successful Maintenance and Cost Effectiveness

The cost-analysis substudy of PODIUM generated predictable results by confirming that the greater efficacy of once-daily therapy was cost-saving because of the expense of relapse. This was relatively easy to calculate because the cost of the medications was similar so that any greater expenses incurred by relapses translated into savings for the once-daily regimen. Specifically, based on the probability of relapse, the average per-person savings was £93 (approximately $190 Canadian). In a centre serving 500 patients with UC, the authors predicted a savings of £46,500 ($94,500 Canadian) for employing once-daily therapy rather than b.i.d. treatment.

While most guidelines, such as those from the European Federation of Crohn’s and Ulcerative Colitis (EFCCA), identify 5-ASA therapies as first-line treatment, there is increasing concern that physicians are not giving this therapy a long enough trial or taking steps to maximize the likelihood that patients remain compliant and controlled on this therapy. One major advantage of mesalazine, as demonstrated in PODIUM and previous studies, is its high degree of tolerability, particularly relative to the immunomodulators that are offered to 5-ASA failures. Moreover, 5-ASA provides chemoprophylaxis against colon cancer, for which the risk is significantly increased by the presence of UC. A case-control study has shown a risk reduction for dysplasia and colon cancer of 72% (OR 0.28, 95% CI, 0.09-0.85) in UC patients on 5-ASA (Rubin et al. Clin Gastroenterol Hepatol 2006;11:1346-50).

“PODIUM and other studies have shown that a very substantial proportion of patients can be maintained relapse-free on mesalazine over extended periods. To increase the likelihood of effective maintenance, we now have evidence from a major study that the once-daily formulation of mesalazine 2-g granules further increases the likelihood of successful maintenance,” Dr. Dignass reported. He indicated that this strategy is also reinforced by a safety record no different from the b.i.d. regimen and by the clinical advantage for the once-daily formula when assessed by UC-DAI subcategories, such as rectal bleeding, and lower cost.

Summary

There is abundant evidence that more convenient dosing strategies, particularly once-daily regimens, are associated with improved adherence, but results of the landmark PODIUM study have associated once-daily therapy with a reduced risk of relapse over a study period of 12 months. Unexpectedly, the improvement in compliance does not appear to provide a complete explanation for the differences, based on new data that showed an advantage for the once-daily regimen over the b.i.d. regimen, at all levels of compliance. An advantage in the pharmacodynamics of the once-daily regimen is suspected. Overall, the study outlines a strategy with which to increase the proportion of UC patients who remain well controlled on a first-line well-tolerated 5-ASA.

Note: At the time of printing, once-daily dosing of mesalazine for maintenance of remission in ulcerative colitis is not approved in Canada.