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JOURNAL CLUB 2010 - Gastroenterology

February - 2010

Editorial overview

John Marshall, MD, MSc, FRCPC, AGAF,

Head, Clinical Research for the Division of Gastroenterology Member, Farncombe Family Digestive Health Research Institute Associate Professor of Medicine, McMaster University, Hamilton, Ontario

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD). Both are chronic conditions with an unpredictable course of intermittent flares and remission. The immediate treatment goals for acute episodes of either form of IBD are to quickly control symptoms to improve quality of life, and to induce and maintain long-term remission.

Mesalamine (also called 5-aminosalicylic acid or 5-ASA) continues to be the first-line mainstay therapy for mild to moderate UC. Unmodified mesalamine is rapidly absorbed from the proximal gastrointestinal (GI) tract, limiting its availability to the colonic mucosa. Sulfasalazine was developed so that the active ingredient would be linked to a sulfapyridine carrier molecule, protecting it from degradation. However, dose-related toxicity associated with the sulfapyridine moiety was common and divided dosing was necessary. Newer formulations of oral mesalamine have since been developed to exclude sulfapyridine and instead, use technology like delayed-release Eudragit coatings to target delivery to different areas of the GI tract. However, divided dosing administration was well-accepted and persisted both in clinical trials and in practice.

Recently, there has been growing interest in studying the use of once-daily dosing with different oral mesalamine formulations. One such trial examined two doses of multi-matrix (MMX) mesalamine given once or twice daily in active, mild to moderate UC patients, and found both to be effective in inducing remission (Clin Gastroenterol Hepatol 2007;5(1):95-102). The question remains as to whether this dosing is possible with other oral 5-ASAs. In a study looking at plasma pharmacokinetic parameters, investigators found no apparent difference in release profile following dosing with mesalamine administered once-daily as an MMX formulation or a Eudragit-S formulation (Figure 1). The next step was to evaluate the efficacy of this formulation dosed once-daily in a well-designed clinical trial.

Figure 1. Mean 5-ASA Plasma Concentration Time Profile

Adapted from Sandborn et al. ACG2007, abstract 944.

QDIEM Findings

The QDIEM (QD Dosing Investigation for Efficacy in UC Maintenance) study is the largest prospective IBD trial ever conducted. It was recently published in Gastroenterology and was presented in Toronto at the 2010 Canadian Digestive Diseases Week (CDDW).

The goal of QDIEM was to examine the efficacy and safety of once-daily dosing of delayed-release mesalamine (Eudragit-S formulation) compared with twice-daily dosing for maintaining remission in UC patients. The primary efficacy analysis was designed to assess whether the once-daily dosing regimen was noninferior to twice-daily dosing for maintenance of clinical remission at month 6. Patients randomized and dosed (n=1023) had mild to moderate UC maintained in clinical remission for at least 3 months, and were on a stable dose of mesalamine ranging from 1.6 to 2.4 g/day.

At month 6, 90.5% of the once-daily dosing group had maintained clinical remission compared with 91.8% in the twice-daily dosing group (P=0.50). At month 12, 85.4% of patients were still in clinical remission in both treatment arms (P=0.98) (Figure 2). No differences in timeto- relapse or patient-defined remission were reported at any time point. As assessed by the medication adherence report scale (MARS) questionnaire, adherence to the medication was high in both groups, but patients indicated they preferred taking medication fewer times a day.

F
f Clinical Remission

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Adapted from Sandborn et al. Gastroenterology 2010;138:1286-96.

The incidence of withdrawals as a result of adverse events (AEs) was low for both dosing regimens (Table 1). The incidence of serious AEs was 3.5% in the once-daily group and 1.8% in the twice-daily group (but this was not significant). All serious AEs were judged by investigators to be “doubtfully related” to the study drug with the exception of one p
aily group.

Table 1. Adverse Events (AEs) Leading to Withdrawal

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Adapted from Sandborn et al. Gastroenterology 2010;138:1286-96.

The QDIEM study reinforces other evidence that once-daily administration of delayedrelease mesalamine is effective for the maintenance of remission in mild to moderate UC. This may be relevant for some patients where dosing frequency is a factor in adherence. However, since adherence is multifactorial, poor adherence is not necessarily resolved by addressing dosing frequency alone. In fact, some studies have shown that once-daily and twicedaily dosing lead to comparable adherence and patient satisfaction rates (Clin Gastroenterol Hepatol 2003;1:170-3, Clin Therapeutics 1984;6(5):592-9). Since poor adherence in UC patients is linked to an increased risk of relapse (Am J Med 2003;114:39-43), a greater need for surgery and a higher risk of colon cancer, it is important to discuss with the patient all the relevant factors and develop an individualized solution.

The Biologic Era

The acute treatment goals of symptom control and improvement in quality of life do not change in more severe forms of IBD, nor does the need to induce and maintain remission. As immunomodulators or biologics become necessary to achieve this, rapid remission induction and maintenance without steroid dependence with minimal side effects remain the key objectives. Here at the CDDW, particular emphasis was placed on the longterm efficacy of some of the newer tumour necrosis factor (TNF) alpha inhibitors.

The ADHERE study was an open-label extension of CHARM, the registration study with adalimumab for CD.

In ADHERE, continued adalimumab therapy was associated with sustained maintenance of remission. Of those in remission after the first year of CHARM, 83% remained in remission for an additional two years. The authors further reported “clinically meaningful” rates of steroid-free remission among those patients who were receiving steroids when they entered CHARM.

In moderate to severe CD, biologics have proven to be an important addition in the induction and maintenance of steroid-free remission. However, loss of response or antibody development over time remains an issue. Switching to another biologic may help reinstate remission. To that end, Fedorak et al. of the WELCOME study assessed the efficacy of certolizumab pegol in patients with moderate to severe CD who had either lost their response to infliximab or who had developed a hypersensitivity reaction to the drug. In WELCOME, 38.3% of the cohort had achieved a clinical response at week 26, and response rates were not different between patients who received the agent every two weeks or those who received it every four weeks. The presence of antibodies at baseline did not affect early response rates. Although some have claimed that certolizumab and adalimumab do not crossreact with antibodies to infliximab, there has been some inconsistency in the literature. Appropriate strategies for ordering anti-TNF agents in the event of a first-line failure are still being evaluated.

Controversy of Moderate Disease

One of the most difficult areas of clinical practice is what to do with patients with IBD who do not have a clear indication for top-down therapy with a biologic agent, but fail first-line therapies. Time-dependent treatment algorithms in moderate CD and UC were proposed by Panaccione et al. (Aliment Pharmacol Ther 2008;28:674-88) where the key to modifying therapy is time to response in the context of disease severity. In this respect, 5-ASA is the first-line option for mild to moderate UC while budesonide or antibiotics can be considered for mild to moderate CD, with the option of more aggressive therapy if adequate control is not achieved or recurrences are frequent. For moderate to severe disease, biologics should be considered as first-line therapy after a time-limited trial of systemic steroids and immunomodulators.

Due to the variability in disease expression, strict indicators for stepping up treatment remain difficult to define, but the goals of rapid mucosal healing, sustained remission and avoidance of steroid dependency are common goals to all treatments.

Summary

The development of delayed-releas e formulations of 5-ASA has been an important step forward for remission and control of mild to moderate UC. New data suggest that patients who respond to these formulations can maintain disease control with once-daily dosing for up to two or more years. As the severity of UC and CD increases, more aggressive therapies are needed, but the goals remain the same—rapid control of symptoms followed by long periods of disease quiescence. The frequent need for steroids to control acute attacks is a signal that patients require more aggressive therapy but with the expanded therapeutic armamentarium for IBD today, physicians should be able to induce and maintain remission for the great majority of patients.

Questions and Answers

Panel

Pierre Paré, MD, FRCPC, FACG CHAUQ-Hôpital du Saint-Sacrement Clinical Professor of Medicine Université Laval Quebec City, Quebec

Flavio M. Habal, MD, PhD, FRCPC Division of Gastroenterology UHN-Toronto General Hospital Associate Professor of Medicine University of Toronto Toronto, Ontario

Bret A. Lashner, MD, MPH Director, Center for Inflammatory Bowel Disease The Cleveland Clinic Foundation Cleveland, Ohio

John Marshall, MD, MSc, FRCPC, AGAF Head, Clinical Research Division of Gastroenterology Member Farncombe Family Digestive Health Research Institute Associate Professor of Medicine McMaster University Hamilton, Ontario

The practice of giving 5-ASA in divided doses for UC began with sulfasalazine and was driven by sulfapyridine toxicity. Do you think physicians still subscribe to the practice of giving 5-ASA in divided doses because of toxicity concerns? How would you reassure them that most 5-ASA formulations are well tolerated and effective when given only once a day?

Dr. Marshall: I think the multiple daily dosing of 5-ASA is in large part based on tradition and derived from experience with sulfasalazine. This experience was translated to newer 5-ASA formulations when they first arrived without much thought about whether multiple daily dosing was still required, and I think many physicians are hesitant to break with established practice. So to have new data [supporting once-daily dosing] is very reassuring. I think the QDIEM study adds to other studies and the consistency in these studies showing that once-daily therapy is at least as effective as split dosing. I am not aware of any safety signals in any of these trials which have looked at once-daily dosing so this is also reassuring.

Dr. Habal: I’ve been practicing for 25 years and I’ve always used b.i.d. dosing, never three or four times a day, because the more you split the dose, the less likely patients are to take it, so they end up taking the medication only twice a day anyhow. For a lot of patients who travel or who start early and get home late, I have used once-daily dosing over the years and I’ve never had problems with oncedaily dosing. So even before the QDIEM study, I’ve had patients on once-daily maintenance dosing. The QDIEM study found that oncedaily dosing is as good as twice a day. There was another study assessing the newer MMX molecule of 5-ASA showing the once-daily dose was as good as well.

Dr. Lashner: There is no evidence that giving mesalamine twice a day has a different toxicity profile as giving it once a day. It looks like the serious AEs like renal failure reported in one patient in the QDIEM study are not related to dosing or total dose. The study may not change anything physicians are already doing, but if they aren’t doing it yet, they should be using once-a-day mesalamine for maintenance.

Dr. Paré: No, physicians should not be concerned because of toxicity while prescribing 5-ASAs once daily. For several years, prescribing 5-ASAs twice a day was the routine practice for many clinicians. Now well-designed studies have shown that oncea- day 5-ASAs are both effective and well tolerated.

Are there patients in whom you would not want to use once-daily dosing?

Dr. Marshall: Some patients are reluctant to change their treatment routine, and I certainly share their reluctance to “fix what isn’t broken” if they are in stable remission on multiple daily doses. However, I think most patients could tolerate once-daily dosing and to date, no increase in toxicity or compromise of efficacy has been associated with oncedaily dosing. So I really do consider it a viable option for all patients on oral 5-ASA therapy.

Dr. Habal: If you take the medications we have, for example, the 400-mg or the 500-mg enteric-coated tablets, some patients require 10 tablets a day. It’s a large pill burden for patients and many have a hard time doing it; that is why twice-daily is more acceptable for many patients. So when you offer the option as to which dosing regimen patients might prefer, some still like to take the drug twice a day. What matters is the total amount of drug patients take, not how they take it.

Dr. Lashner: No. For maintenance therapy, they should be on once-daily dosing of a 5-ASA. To induce remission, that is a different story. The only once-a-day agent that is indicated for inducing remission is MMX mesalamine; the rest are multiple times per day. So it depends on what you choose, but to induce remission, most patients will need twice-daily medication.

Dr. Paré: The once-a-day prescribing offers convenience to patients and ensures compliance. If a patient would consider it more convenient to take the therapy in divided doses per day, I do respect this preference while I make sure that he/she is well educated on the efficacy and tolerability of once-a-day dosing.

Non-adherence is an issue across medicine but what are the particular consequences for UC patients? What strategies do you recommend to improve adherence among UC patients?

Dr. Marshall: First of all, compliance is a difficult thing to measure but when you are treating active disease, compliance is probably better than when you are maintaining remission and some of the symptoms have gone away. In that situation, it is very difficult to motivate people to continue taking medication, particularly taking medication more than once a day. So there may be differences in compliance when you are talking about induction vs. maintenance of remission. That said, there are good data from observational studies correlating poor compliance with disease activity over time and there is more and more concern that disease activity is a predictor of long-term complications such as surgery and cancer in UC. So, perhaps better compliance maintains better control of disease which could influence those end points as well.

Dr. Habal: Adherence is a very important factor for maintenance of remission in many patients. In my practice I did a survey and I actually have about 70% good compliance. I know this because I renew all of their prescriptions myself and when I renew a prescription, I make a note of how many pills I dispense to a patient, so I know if they have been taking their pills or not. I also see almost all my patients once a year— more often if they flare up—and in patients who are not compliant and who I know have a rocky course with their disease, I see them every three months, at which point I re-emphasize how important it is for them to take their medication. The main problem with colitis is, once the patient is feeling well, they start skipping doses here and there and find they feel no differently so then they may stop for a few months and so on. With the newer data showing chemoprophylaxis of 5-ASA, I bring this up with patients as well, so I tell them why it’s important to get their disease in remission, that it will reduce their chances of developing future cancer—and it works! Another point is patients are not taking the medication because of cost.

Dr. Lashner: Once a day is critical. We also have to stress the importance of taking these medications because those who do take their medication really do have remission better maintained than those who do not; the drugs simply work. And there is also a cancer chemopreventive effect from 5-ASA agents so you make that clear and there is a better chance patients will take their medication.

Dr. Paré: Studies have shown that patient compliance with 5-ASA is poor outside of clinical trials. Adherence to complex 5-ASA dosing has been shown to be as low as 40% in community-based trials. In a large Internet survey by the Crohn’s and Colitis Foundation of America, over 60% of patients reported being non-compliant with 5-ASA; too many pills was the main reason for their non-compliance, much more often than having no symptoms. Non-compliance has the clinical impact of increasing the risk of relapse (five times greater than in compliant patients), resulting in a decreased quality of life. Adherence to 5-ASA also has been associated with a reduced risk of colorectal cancer. Maintaining compliance is an essential component of UC treatment and an open physician-patient dialogue is key to achieving this through counselling, education, eliciting reasons for non-compliance and informing patients of a more convenient 5-ASA dosing regimen. Regular long-term follow-up of patients with quiescent disease will reinforce compliance.

5-ASAs are indicated for the treatment of mild to moderate UC while the biologics are indicated for the treatment of moderate to severe UC. How do you decide when to switch patients to a biologic?

Dr. Marshall: This is a challenging area in IBD partly because it does not lend itself easily to algorithms. But certainly disease severity is one consideration when you are escalating therapy. A bigger consideration is treatment response. Even independent of underlying disease severity, some patients do not respond adequately to what might be thought of as “milder” therapy and require escalation because of refractory symptoms, even if symptoms themselves are not that severe. Some of the standard scores such as the Mayo Index—which is perhaps the most widely cited now—include components that we always ask our patients: stool frequency; rectal bleeding; overall impression of severity. So even if we don’t use official scoring systems, we use some of their components in our practice.

Dr. Habal: The majority of mild to moderate UC patients do quite well on 5-ASA therapy but there is a subgroup of patients who break through so they stop responding to 5-ASA. Occasionally we increase the dose, depending on the dose used. If patients fail to respond, then we usually use corticosteroids as the next drug, such as oral prednisone; it induces remission quickly and then we can start weaning patients off it. The problem with prednisone is that as you decrease the dose, certain patients will flare up. So first of all I stop the 5-ASA when I introduce high-dose steroids and then reintroduce it as I decrease the steroid dose and see how a patient responds. Up to several years ago, patients who started to flare as we dropped the dose of prednisone were put on azathioprine in combination with a steroid at the beginning; then, as we weaned them off the steroid, we hoped azathioprine would get patients back into remission. If they failed that or were unable to tolerate azathioprine, usually we have the option of surgery. The use of the biologics in these patients is still not clear but we do offer them the opportunity to try a biologic to see what happens; if that fails, they will need surgery. So the biologics are left towards the end when everything else fails or they serve as a bridge towards surgery.

Dr. Lashner: If a patient is on maximal doses of mesalamine and it’s not working, then you try something else but the biologic agents are only one of the alternatives. There is no reason to switch to something else if a patient is doing well on mesalamine, so it’s simply if patients are getting maximal doses of mesalamine and they are not doing well, then I will explore the alternative agents for that patient. But the biologics are only one of several options when response to mesalamine is inadequate.

Dr. Paré: Switching directly from 5-ASAs to biologics is unusual. The current practice in case of failure of 5-ASAs to induce clinical remission is to initiate corticosteroids with or without immunosuppressants. The use of biologics is recommended in oral steroid-refractory and immunosuppressive-refractory UC. Inadequate response to conventional therapy, not achieving steroid-free remission or intolerance to such therapy also points to using biologics.