INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #26
`
`Seymour Katz, M.D., Series Editor
`
`Remission in Trials of
`Ulcerative Colitis:
`What Does It Mean?
`
`by Simon Travis and Lotte Dinesen
`
`Measurement of disease activity in ulcerative colitis is critical in determining whether
`new therapies are effective, but there is no gold standard for measuring disease activ-
`ity in ulcerative colitis. Not only is no single disease activity index widely accepted, but
`there is also no generally accepted definition of remission. Remission rates vary by as
`much as two-fold depending on the definition of remission. When two trials of 4.8 g
`mesalamine were evaluated according to the remission endpoint used for two trials of
`infliximab for active ulcerative colitis, apparent remission increased from 20.0% to
`44.9%. Physicians and healthcare professionals should pay attention to the definition of
`remission being used as a measure of clinical efficacy in clinical trials. Interobserver
`variation in endoscopy scoring alone can influence the absolute remission rate by
`10%–16%. Registration remission, which depends primarily on endoscopy and absence
`of rectal bleeding, is most subject to this influence. Clinical remission (absence of rec-
`tal bleeding and normal stool frequency) is used in clinical practice. Steroid-free remis-
`sion is what matters to patients. The definition of remission needs to be validated if the
`results of clinical trials are to be compared.
`
`T he natural history of ulcerative colitis is charac-
`
`terized by relapses and remission. We all think we
`know what a relapse means. It’s when a patient
`has symptoms of rectal bleeding diarrhea, tenesmus,
`urgency and abdominal pain before defecation. We all
`know what remission means, don’t we? It’s a normal
`bowel movement, stupid! Would that it were so
`simple—as Bill Clinton must have wished about the
`
`Simon Travis, DPhil, FRCP and Lotte Dinesen, M.D.,
`Gastroenterology Unit, John Radcliffe Hospital,
`Oxford, UK.
`
`U.S. economy. The trouble is that it’s a deal more
`complex, or otherwise clinical trials in ulcerative coli-
`tis wouldn’t make such a meal of defining remission
`as an endpoint.
`The principal aims of medical treatment are to
`induce clinical remission when disease is active, then
`to maintain remission, and to reduce the risk of long-
`term complications (1). How good are we at achieving
`this? Long-term prognostic studies indicate that about
`50% of patients with ulcerative colitis will be in remis-
`sion at any given time, and 50% will relapse during the
`year; of these, 15% will have a severe relapse and 35%
`
`PRACTICAL GASTROENTEROLOGY • DECEMBER 2006
`
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`GeneriCo, Flat Line Capital
`Exhibit 1058 Page 1
`
`

`
`Remission in Trials of Ulcerative Colitis
`
`INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #26
`
`a moderate relapse (2,3). From a patient’s perspective,
`that’s not very impressive. Furthermore, these
`favourable results are based on a treatment regimen of
`out-patient visits at least once yearly, a well defined
`strategy of maintenance mesalamine in all patients
`who can tolerate it and prompt treatment when relapse
`occurs. We have to do better and of course this means
`new treatments, subject to clinical trials.
`The trouble is that there is no gold standard for
`measuring disease activity in ulcerative colitis. There
`are at least nine different scores used for evaluating
`activity (4). But, even before we start worrying about
`how we measure activity, we need to agree on a defin-
`ition of remission. But because it is remission that mat-
`ters to patients, the primary endpoint of clinical trials
`of ulcerative colitis should be steroid-free remission.
`This matters if clinical trials are to have direct rele-
`vance to patient management.
`There are, in turn, at least three definitions of remis-
`sion for ulcerative colitis. These may be termed clinical,
`registration and complete remission. Clinical remission
`is what is used in practice, meaning cessation of rectal
`bleeding and normal stool frequency. This is not the
`same as “registration” remission (the one currently, but
`not exclusively favored by the FDA), which means ces-
`sation of rectal bleeding and a sigmoidoscopy score of 0
`or 1 (that equates to a normal appearance of the rectal
`mucosa, or erythema only). This, in turn is not the same
`as complete remission, which implies normal stool fre-
`quency, no rectal bleeding and a normal or quiescent
`appearances of the mucosa at sigmoidoscopy. The
`potential impact of these three definitions is consider-
`able, but many trials simply use an arbitrary threshold to
`define the “remission” endpoint, either 0, 1 or 2 of one
`of the disease activity indices, or <150 in the complex
`Seo index (4). This makes it difficult to know what a
`trial means, because obscured in these low scores can be
`symptoms (such as bleeding or increased stool fre-
`quency) that clinicians and their patients would not rec-
`ognize as remission. Furthermore, because most trials
`choose different endpoints, let alone different activity
`indices, comparing the results of different trials is
`exceptionally difficult.
`Just consider the impact of different definitions of
`remission in one large patient cohort. The ASCEND
`studies included a total of 687 patients with mild to
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`PRACTICAL GASTROENTEROLOGY • DECEMBER 2006
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`moderately active ulcerative colitis, treated with 2.4 g
`or 4.8 g mesalamine (5,6). In an analysis of the results
`using three different definitions of remission, the
`remission rate varied more than two-fold. When the
`Mayo disease activity index (DAI) was 0, it was 22%
`(in other words, “complete remission”; the DAI
`includes stool frequency, rectal bleeding, sigmoi-
`doscopy, patient functional assessment and physician’s
`global assessment); when the DAI was ≤1 the remis-
`sion rate was 28% (meaning no bleeding and normal
`frequency, with at least a 1 point decrease in sigmoi-
`doscopy score), but when “remission” meant a DAI
`≤2, it was 50% (meaning no individual subscore >1)
`(7). This is an extraordinary degree of variation and no
`wonder that doctors and patients are confused by dif-
`ferent activity indices of trials. Confusion is fostered
`by the different names for the different indices: the
`score used in this analysis was the Mayo score, also
`known as the Disease Activity Index, although the
`abstract itself erroneously refers to the Ulcerative Col-
`itis Disease Activity Index (UCDAI) which is slightly
`different (4). At the end of the day, however, it is
`remission and not response that matters to the patient
`who has to get on a bus and travel with confidence. It
`is also steroid-free remission that matters.
`Take the ACT trials of infliximab for ulcerative
`colitis refractory to standard therapy (8). Remission in
`the ACT trials was defined as a Mayo (DAI) score of
`two points or lower, with no individual subscore
`exceeding one point. This is the definition that allowed
`Asacol 4.8 g to score a remission rate of 50% in non-
`refractory ulcerative colitis (7). In the ACT 1 trial, the
`steroid-free remission rate after 7 months’ treatment
`(30 weeks) with infliximab 5mg/kg every 8 weeks was
`24.3% (17/70 patients) and 18.3% (11/60) in the ACT
`2 trial. Of course this was twice that achieved by
`placebo (10.1% and 3.3%, both p < 0.05), but it’s not
`as impressive as some would have us believe.
`Now factor in interobserver-variation in sigmoi-
`doscopy scoring, because this is a subjective assessment
`and inevitably subject to variation between different
`endoscopists. Indeed, Hugh Baron himself validated the
`original sigmoidoscopy scoring system in 1964 based
`on components where there was more than 60% “agree-
`ment” between four observers (9). This was before
`(continued on page 20)
`
`GeneriCo, Flat Line Capital
`Exhibit 1058 Page 2
`
`

`
`Remission in Trials of Ulcerative Colitis
`
`INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #26
`
`(continued from page 18)
`
`kappa statistics were applied to clinical measurement,
`but it illustrates the large potential for disagreement.
`This is a crucial issue for regulatory authorities, since
`the FDA currently favors a definition of remission for
`registration purposes based on sigmoidoscopy and rec-
`tal bleeding alone. When an independent observer eval-
`uated the sigmoidoscopy videos of 335 patients in a
`recent therapeutic trial of ulcerative colitis, the observer
`disagreed with the investigators’ sigmoidoscopy score
`in 12%–23% of cases (10). The impact on the remission
`rates of this variation in the sigmoidoscopy score was a
`median difference of 19.0% (range: 10.0% to 22.4%)
`for absolute clinical, complete and registration remis-
`sion. If results were then analyzed according to the inde-
`pendent observer’s score, remission rates were reduced
`in absolute terms by 10%–16% for registration, but by
`<3% for clinical or complete remission. It is not sur-
`prising that registration remission rates were most
`affected. The implications are substantial. It has the
`potential to make the difference between a therapeuti-
`cally significant outcome and no response, and between
`licensed approval and no license.
`Whilst addressing endpoints that matter to patients
`(and therefore their physicians), objective endpoints
`other than steroid-free remission should be considered
`when clinical trial measure remission. These include
`time off work or normal activities, hospital admission,
`colectomy and mortality. Of course the reason that these
`endpoints—and even the more readily attainable
`steroid-free remission—are not measured is that single
`drugs are unlikely to influence material outcomes that
`are subject to multiple external influences. Most ran-
`domized controlled trials involve single therapies spon-
`sored by industry. That is one of the limitations of
`single-agent randomized controlled trials and is a reason
`for considering therapeutic strategies with several inter-
`ventions, such as the chemotherapy regimens that have
`proved successful in haematological malignancies.
`Such trials are more complex with fewer vested interests
`from industry, but they bring clinical trials closer to the
`outcomes that matter to patients and their physicians.
`Everyday clinicians need to stand up and say that we
`don’t like (or understand!) outcomes in clinical trials of
`ulcerative colitis and won’t take it anymore.
`So what is remission in ulcerative colitis? It
`depends on your perspective. It is either a low point in
`
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`PRACTICAL GASTROENTEROLOGY • DECEMBER 2006
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`a scoring system for active disease that has to be used
`in clinical trials by way of necessity. Or it is a construct
`for achieving drug registration for regulatory authori-
`ties such as the FDA. Or it is something that is mean-
`ingful to patients, who can count the number of times
`they have to go to the bathroom each day, see whether
`there is visible blood in their stool, and understand
`what is meant by healing of the rectal mucosa. These
`are different needs: for a Phase II trial, response may
`be an adequate indicator of whether to pursue drug
`development. But for Phase III studies that lead to
`drug registration, steroid-free remission in terms that a
`patient can understand should be the primary endpoint.
`There is no reason that we should not have separate
`clinical, endoscopic, histological and quality of life
`indices of activity, rather than a composite index, as
`long as they are validated. We should start by validat-
`ing remission on behalf of our patients. ■
`
`References
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`adults (update): American College of Gastroenterology, practice
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`
`GeneriCo, Flat Line Capital
`Exhibit 1058 Page 3