Journal of Crohn's and Colitis Advance Access published May 28, 2015 Journal of Crohn's and Colitis, 2015, 1–9 doi:10.1093/ecco-jcc/jjv074 Review Paper

Review Paper

Clinical Trials in Ulcerative Colitis: A Historical Perspective Pieter Hindryckx1, Filip Baert2, Ailsa Hart3, Fernando Magro4, Alessandro Armuzzi5, Laurent Peyrin-Biroulet6, the Clinical Trial Committee Clincom of the European Crohn’s and Colitis Organisation (ECCO) 1 Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium 2Department of Gastroenterology, AZ Delta, Roeselare, Belgium 3IBD Unit, St Mark’s Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK 4Department of Pharmacology and Therapeutics, Division of Gastroenterology, Hospital de Sao Joao, University of Porto, Porto, Portugal 5IBD Unit, Complesso Integrato Columbus, Catholic University, Rome, Italy 6Inserm U 954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Université de Lorraine, Vandoeuvre-lès-Nancy, France

Corresponding author: Laurent Peyrin-Biroulet, MD, PhD, Inserm U 954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Université de Lorraine, Allée du Morvan, 54511 Vandoeuvre-lès-Nancy, France. Phone: + 33 3 83 15 36 31; Fax: + 33 3 83 15 36 33; Email: [email protected]

Abstract The clinical trial landscape in ulcerative colitis has evolved significantly in recent decades. Study endpoints have been shifting from mere clinical response to mucosal healing. It has become clear that the choice of combined clinical and endoscopic outcome criteria leads to a reduction in placebo responses, especially when central reading of the endoscopic images is performed. Accumulating evidence suggests that histological remission yields better long-term outcomes for ulcerative colitis patients than mucosal healing alone, and clinical trials with prolonged followup will have to address whether histological remission should be the ultimate treatment goal in ulcerative colitis. In recent years there has also been increasing interest in the implementation of patient-reported outcomes in clinical practice and research, and the regulatory authorities have set up guidelines for the development of such outcomes. This paper aims to provide a comprehensive review of historical aspects of clinical trials in ulcerative colitis and to discuss challenges and perspectives for clinical trials in the near future. A  thorough analysis of all available landmark literature (both original papers and reviews) on clinical trials in ulcerative colitis was performed. Keywords: Ulcerative colitis; clinical trials; history; mucosal healing; histological healing

1. Introduction Ulcerative colitis (UC) was described as a disease entity in the 19th century, but it took until the Second World War for the first clinical studies to be conducted. Although various forms of non-contagious chronic diarrhoea were described in ancient times, the term ‘ulcerative colitis’ was first used in a paper by Sir Samuel Wilks in 1859.1,2 He described an autopsy on a 42-year-old woman who died after several months of diarrhoea.2 This woman had, indeed, transmural inflammation of

the terminal ileum and the colon and hence she had succumbed to Crohn’s disease (CD), which was only recognized as a separate entity about 70 years later.3 In the early 1940s, Nanna Svartz published her positive experience with sulphasalazine. About 10 years later, Sir Sidney Truelove opened the gate of evidence-based medicine in UC by conducting the first randomized controlled clinical trial (RCT) with corticosteroids. Unlike CD, UC has for a long time been considered a rather benign disease, though it can be a disabling condition associated with an

Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]

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2 increased risk of colorectal cancer4 and some structural damage.5 As is the case for CD, most therapeutic strategies were based on symptom control until the 2000s. It has now become clear that stringent disease control, including mucosal healing, is the best care for the patient, providing a reduced risk of disease relapse, hospitalization, surgery and cancer.6 Therefore, treatment goals have shifted over time from clinical response to mucosal healing. In this context, endoscopic scores are increasingly used in both clinical practice and clinical trials in UC patients. Finally, there is currently growing interest in histological healing, which might be the ultimate therapeutic goal in UC.7 This article aims to give a comprehensive review of historical aspects of UC clinical trials before discussing some challenges and future perspectives that will shape the clinical trial landscape for UC in the next few years.

In 1950, Hench et  al. reported on the effects of cortisone in rheumatoid arthritis, thereby triggering early investigators to test this promising compound in UC.12–15 For example, Palmer and Kirsner published their experience with corticosteroid use in 120 UC patients.15 They demonstrated with their case series that corticosteroids were able to induce a very rapid symptomatic response (referred to as ‘a miracle’ by the authors), but on the other hand the authors were unable to induce permanent healing. Of their 120 patients, 35 went into remission (defined as complete resolution of symptoms) and another 57 patients improved. Besides clinical effects, the common side-effects of corticosteroids were reported (acne, hirsutism, Cushing deformities, hyperglycaemia, hypertension and an increased incidence of common and opportunistic infections, the latter being the cause of one death from overwhelming sepsis).15

2. The Uncontrolled Clinical Trials Era

3.  Randomized Clinical Trials in the Prebiological Era

Before Nanna Svartz, a Swedish rheumatologist, reported on her experience with sulphasalazine in UC, treatment was mostly supportive and several popular hypotheses on the nature of UC (infectious, allergic, psychological) guided any further empirical treatment.8 The first case series describing the use of sulphasalazine in UC were published during and shortly after the Second World War.9,10 Dr Svartz showed that, of 124 consecutive patients with mild to moderate UC that she treated with the drug, 75 (60%) went into clinical remission and another 41 (33%) showed clinical response (defined as resolution and improvement of ‘subjective symptoms’, respectively).10 Remarkably, this early-described remission rate is comparable to the rates observed in the subsequent controlled clinical trials with oral 5-aminosalicylic acid for mild to moderately active ulcerative colitis.11

3.1.  Induction trials (Table 1) It was Sidney Truelove who introduced evidence-based medicine in inflammatory bowel disease (IBD).16 Supported by the Medical Research Council, he conducted the first placebo-controlled clinical trial in UC in the early 1950s.16 It was a large-scale double-blind national multicentre trial that compared the efficacy of cortisone with a dummy preparation in UC. Remarkably, this very first trial already included some kind of rudimentary serial sigmoidoscopic assessments (defined as ‘normal’, ‘improved’ or ‘no change or worse’) in their outcome measures. It was found that cortisone greatly increased the chances of remission or improvement of the disease within a 6-week timeframe.16 Although Dr Truelove should certainly be honoured for his tremendous contribution to clinical IBD research, some methodological flaws hamper the interpretation

Table 1.  Definitions of clinical response and clinical remissions of major ulcerative colitis induction trials in the pre-biological era. Author

Active compound

Year of publication

Definition of clinical response

Definition of clinical remission

Truelove and Witts16

Corticosteroids

1955

Intermediate between no response and remission

Lennard-Jones et al.17

Corticosteroids Sulphasalazine

1960

Lennard-Jones et al.18

Topical corticosteroids

1962

Baron et al.20

1962

Lichtiger et al.23

Sulphasalazine Salicylazosulphadimidine Sulphasalazine Sulphapyridine 5-Aminosalicylic acid Ciclosporin

Reduced frequency of bowel action and bleeding (not further specified) Reduced frequency of bowel action and bleeding (not further specified) Improved symptoms (not further specified) Clinical improvement (not further specified)

All of the following: (1) 1–2 stools a day without blood (2) No fever (3) No tachycardia (4) Haemoglobin and erythrocyte sedimentation rate normal or returning towards normal (5) Gaining weight Absence of symptoms

Oren et al.28

Methotrexate

1996

Ogata et al.27

Tacrolimus

2006

Azad Khan et al.21

1977

1994

Clinical activity index 4 points + improvement of all categories

Absence of symptoms

Absence of symptoms –

– Complete Mayo score ≤3 of Mayo clinical subscore ≤2 without use of steroids Absence of symptoms

Clinical Trials in Ulcerative Colitis of the results of his first trial. For example, several dosing regimens of cortisone were pooled to compare with placebo, and patients were not randomized for disease activity or for concomitant medication use (every other therapy, including the use of sulphonamides and antibiotics, was allowed at the discretion of the treating physician). Nevertheless, in a subsequent trial performed by Professor John Lennard-Jones and Sir Francis Avery Jones (St Mark’s Hospital, London) and published in 1960, highly comparable remission rates (around 65%) were seen for outpatients with mild UC who received oral prednisone.17 The same authors conducted the first double-blind placebo-controlled trial of topical steroids in UC (proctitis).18 They used both symptomatic and sigmoidoscopic assessment to evaluate outcome and found significant improvement in the patients given steroids topically compared with placebo. Their gradings of sigmoidoscopic appearances were ‘active’, ‘moderately active’, ‘inactive’ and ‘normal’. Until now the results of the aforementioned trials have formed the core scientific basis of corticosteroid use in UC.19 Despite the early positive experiences with sulphasalazine, it was not until 1962 that the first positive double-blind placebo-controlled trial with this compound was published, by Professor John LennardJones and Sir Francis Avery Jones (St Mark’s Hospital, London).20 Notably, the authors expressed their ethical concerns about the use of placebo, given the fact that an established effective therapy was available (namely, corticosteroids). The inclusion criteria were patients with symptoms and ‘active inflammation seen on sigmoidoscopy’ and ‘both the observer who took the history and an independent observer who did not know of the symptoms had to agree that such inflammation was present’; these clinical trials pioneers were very aware of the importance of subjective and objective assessment of disease activity and the need for blinded validation of activity. The trial showed that three-quarters of the included patients with mild UC benefitted from sulphasalazine, whereas this was only the case for 35% of patients treated by placebo. The authors analysed the data with regard to ‘complete symptomatic and endoscopic remission’ and found that 5 out of 20 patients treated with sulphasalazine achieved this endpoint. However, nearly half of the patients experienced unpleasant side-effects of sulphasalazine and 20% of the patients interrupted the treatment for this reason.20 In 1977, the group of Truelove demonstrated that 5-aminosalicylic acid (5-ASA) was the active therapeutic moiety in sulphasalazine, whereas the sulphapyridine component, being responsible for most of the sideeffects, had no impact on colonic inflammation.21 Again, the authors included both endoscopic and histological improvement in their outcome parameters. This paper opened the window for the development of new 5-ASA formulations for oral and topical administration, and a large number of accompanying RCTs. A recent Cochrane review again confirmed the efficacy of 5-ASA in UC.22 Sulphasalazine/5-ASA and corticosteroids formed the therapeutic landscape for UC for many years. Subsequently, in the early 1990s, reports on the use of ciclosporin for steroid-refractory UC began to appear. A trial in the early 1990s that compared ciclosporin 4 mg/ kg intravenously with placebo for severe steroid-refractory UC was terminated early due to a rapid and impressive benefit of ciclosporin treatment, rendering it unethical to proceed with the study.23 In the light of the significant systemic toxicity of ciclosporin, a trial with ciclosporin enemas was performed in parallel by another group, albeit in a completely different study population (mild to moderate left-sided UC). While ciclosporin enemas did not provoke any toxicity, they turned out to be ineffective.24 In 2001, D’Haens and co-workers25 showed that intravenous ciclosporin monotherapy is an effective and safe alternative to intravenous glucocorticosteroids in patients with a severe UC flare-up. About 2 years later, Van Assche

3 et al.26 showed that there was no difference in the clinical response rates between 4 and 2 mg/kg of intravenous ciclosporin, with a trend towards less hypertension for the latter. A few years later, a Japanese study27 demonstrated the effectiveness of oral tacrolimus, another calcineurin inhibitor, for induction of remission in steroid-refractory moderately to severely active UC, with acceptable tolerance of the drug. Shortly after the positive results with ciclosporin, some uncontrolled positive experiences with methotrexate in UC warranted a randomized controlled clinical trial. Sixty-seven UC patients with a total Mayo score of at least 7 despite steroids and/or immunosuppressives were randomized to oral methotrexate 12.5  mg/week or placebo.28 The study failed to demonstrate any effect of methotrexate. However, the dosage and route of administration were chosen based on extensive experience with the drug in rheumatoid arthritis and subsequent reports claimed that a higher dose and parenteral administration might be needed to induce remission in UC.29,30 In this light, GETAID (Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives) compared subcutaneous methotrexate (25 mg every week) with placebo in corticodependent UC patients (METEOR trial). Although the primary endpoint of the study [steroid-free remission defined as a total Mayo score ≤2 with no subscore >1 at week 16 and no need for other immunosuppressives, antitumour necrosis factor (anti-TNF) or colectomy at week 16 and/ or 24] was not met, more patients in the methotrexate group went into steroid-free clinical remission at week 16 and/or 24.31

3.2.  Maintenance trials (Table 2) The observation that the majority of UC patients relapsed in the first months after treatment discontinuation somewhat dampened enthusiasm about the therapeutic effect of corticosteroids and sulphasalazine, as it became rapidly clear that both drugs also had considerable dose-dependent side-effects, especially with long-term use.15,16,32 The maintenance trials tested whether lower, less toxic doses of these two drugs with proven efficacy were able to prevent UC relapses compared with placebo. Whereas it was clear from trials conducted at St Mark’s Hospital and Oxford that corticosteroids failed to maintain remission,33,34 Misiewicz, Lennard Jones and co-workers showed in 1965 that a low dose of sulphasalazine (2 g daily) was able to maintain remission in 24 of 34 (71%) patients with UC after 1 year of treatment, while this was the case for only 8 of 33 (24%) patients who were treated with placebo.35 All patients were in both clinical and endoscopic remission at inclusion in the trial. In 1973, these promising results were confirmed by Truelove’s team, who found remission maintenance rates of 88 and 45% after 6  months of treatment in Salazopyrin- and placebo-treated UC patients, respectively.36 Remarkably, in the same year, another group reported only marginal effects of sulphasalazine as a maintenance drug.37 Truelove criticized this study by stating that the authors did not use objective criteria to define remission and relapse.36 Indeed, Riis et al.37 had only used clinical indices to measure disease activity, while Dissanayake and Truelove36 included endoscopic appearance in their evaluation. It is notable that these early clinical trial investigators from St Mark’s Hospital and Oxford had already stressed the importance of objective disease measures at that time. The next milestone in maintenance therapy for UC has to be attributed to Dameshek and Schwartz,38 who demonstrated in 1959 that certain antimetabolites were capable of inducing immunological tolerance, opening a window for their use in diseases that are characterized by immune-mediated responses. Following some

P. Hindryckx et al.

4 Table 2.  Definitions and frequency of relapse in the major ulcerative colitis maintenance trials in the pre-biological era. Author

Active compound

Year of publication

Study duration

Definition of relapse

Relapse rate (compound versus placebo)

Truelove and Witts33

Corticosteroids

1959

1 year

48.6 versus 41.9%

Lennard-Jones et al.34

Corticosteroids

1965

6 months

Misiewicz et al.35

Sulphasalazine

1965

1 year

Dissanayake and Truelove36

Sulphasalazine

1973

6 months

Jewell and Truelove42

Azathioprine

1974

1 year

(1) >4 stools/day for at least 1 week, OR (2) Macroscopic rectal bleeding for at least 1 week AND (3) sigmoidoscopic evidence of active disease Presence of diarrhoea (not further specified) or passage of blood or mucus in the stools Presence of diarrhoea (not further specified) or passage of blood or mucus in the stools Recurrence of colitic symptoms accompanied by sigmoidoscopic and histological evidence of inflammation Occurrence of diarrhoea with blood in motions and sigmoidoscopic evidence of inflammation

promising early reports on the use of 6-mercaptopurine and azathioprine in UC,39,40,41 the first controlled trial was performed in the early 1970s.42 Eighty patients with mild to severe UC received either azathioprin 2.5 mg/kg or placebo (n = 40 for both groups) in addition to conventional corticosteroid treatment. Interestingly, given the availability of sulphasalazine as an established effective maintenance drug, it was for the first time considered unethical to keep patients with three disease relapses during the study period in a placebo-controlled trial.42 The study showed a likely benefit from azathioprine in maintenance of remission after 1 year, although statistical significance was not provided. Almost 20 years later, Hawthorne et al.43 showed in a nicely conducted placebo-controlled double-blind trial that azathioprine effectively reduced the relapse rate in UC patients who had achieved remission after induction therapy. Nevertheless, in a recent Cochrane review the authors carefully concluded that thiopurines may be effective as maintenance therapy in UC, but that, in contrast to the situation in CD, the evidence is scarce and generally of poor quality.44 In parallel with the aforementioned METEOR trial of the GETAID group, the efficacy of methotrexate in UC for maintenance of steroid-free remission is currently under investigation in a controlled clinical trial (MERIT-UC) from the Crohn’s and Colitis Foundation of America; the results are eagerly awaited.

4.  Randomized Clinical Trials in the Biologicals Era (Table 3) The first experience with anti-TNF agents in UC was reported in 2001 by Sands et  al.45 Following this promising but prematurely ended pilot study with infliximab in severe, active, steroid-refractory UC and a conflicting negative but underpowered RCT by Probert et al., forces were joined to conduct two large-scale RCTs (ACT 1 and ACT 2) in order to definitively assess the therapeutic potential of infliximab in moderate to severe UC.45, 46, 47 The results were positive and infliximab was approved by the FDA for the treatment of UC in 2005. This promptly triggered the European Medicines Agency

56.3 versus 56.7%

13.7 versus 51.1%

12.1 versus 54.8%

60 versus 77.5%

(EMA) to publish the first European regulatory position on clinical trials with new medicinal products for UC patients.48 In 2007, GETAID set up an open-label RCT to compare the efficacy of infliximab with that of ciclosporin in patients with severe, steroid-refractory UC. They found that ciclosporin was not more effective than infliximab in this setting.49 With the advent of the anti-TNF agents, a completely new era in clinical trial research in UC (and IBD in general) was introduced. For more than 5 years, infliximab remained the only biological for the treatment of UC. Following the successful use of adalimumab in CD, the ULTRA1 trial was set up to test its potential in UC.50 The results were published in 2011 and were not impressive. With a remission rate of 18.5% at week 8, the results were clearly weaker compared with the remission rates in the ACT trials. In addition, there was an unexpected high placebo response for secondary endpoints, which for some reason turned out to be geographically dependent.50 The high expectations and high number of study visits (five within an 8-week timeframe) contributed to the high placebo effect, although the rate of mucosal healing at 8 weeks in the placebo group (41.5%) remains impressive.50 The subsequent ULTRA 2 trial confirmed the efficacy of adalimumab (induction dose 160  mg/80  mg at week 0 and week 2, followed by 40 mg every other week) both for induction and maintenance of remission.51 The treatment effect in this trial remained lower than that observed in ACT 1 and ACT 2, but important differences in trial design (exclusion of patients with disease limited to the rectum, allowance of previous anti-TNF exposure and inclusion of open-label treatment in ULTRA 2) limit comparison between the trials. The PURSUIT-SC and PURSUIT-maintenance trials introduced a third anti-TNF agent exclusively for the treatment of UC: golimumab.52,53 Surprisingly, in the post-biological era, both studies had a weak primary endpoint (clinical response and maintenance of clinical response, respectively). In the light of the results of the SONIC trial in CD, which demonstrated the superiority of azathioprine + infliximab compared with

211

251

2005

2005

2011

2012

2013

ACT 147

ACT 247

ULTRA 150

ULTRA 251

GEMINI 156

PURSUIT-SC (phase 2014 3)52

103

94

55

62

Total Mayo score

Total Mayo score

Total Mayo score

Total Mayo score

UCSS Baron score

Main outcome parameter

774

Total Mayo score

374 (cohort Total Mayo score 1) + 521 (cohort 2)

494

576

364

364

43

2003

Probert et al.46 4

Year of Number of Number of publication study sites patients

Trial name

Oral CSs Azathioprine 5-ASA

Oral CSs Azathioprine 5-ASA

Oral CSs Azathioprine 5-ASA

Oral CSs Azathioprine 5-ASA

Oral CSs Azathioprine 5-ASA

Oral CSs Azathioprine 5-ASA

Azathioprine CSs 5-ASA

Concomitant drug exposure

No

Yes (60 days washout)

Yes (8 weeks washout)

No

No

No

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

52 weeks

8 weeks

54 weeks

6 weeks (+2 weeks follow-up if open-label infusion at 6 weeks) 30 weeks

Study duration

52 weeks Until week 6 (cohort 2) and after week 6 in case of lack of clinical response to vedolizumab induction therapy (cohorts 1 and 2) No 6 weeks

Yes (after 12 weeks)

No

No

No

Yes (1 infusion after 6 weeks)

Open-label? Previous anti- PlaceboTNF exposure controlled? allowed?

Table 3.  Main study design characteristics and primary endpoint data of the major ulcerative colitis trials with biologicals

Clinical response at week 6

51.0% (200 mg/100 mg) and 54.9% (400 mg/200 mg) versus 30.3%

69.4% (5 mg/ kg) and 61.5% (10 mg/kg) versus 37.2% Clinical response 64.5% (5 mg/ at week 8 kg) and 69.2% (10 mg/kg) versus 29.3% 18.5% Remission at (160 mg/80 mg) week 8 (total and 10.0% Mayo score ≤2 (80 mg/40 mg) and no subscore versus 9.2% >1) (1) Remission at (1) 16.5 versus 9.3% week 8 (2) Remission at (2) 17.3 versus 8.5% week 52 (1) 47.1 versus (1) Clinical response at week 25.5% (2) 41.8% (every 6(2) Clinical remission at week 8 weeks) and 44.8% (every 4 52 weeks) versus 15.9%

(1) 13 versus 5% (NS) (2) 39 versus 30% (NS)

(1) UCSS < 2 (2), Baron score = 0

Clinical response at week 8

Active compound versus placebo response (for primary endpoint)

Primary endpoint(s)

Clinical Trials in Ulcerative Colitis 5

P. Hindryckx et al.

No analysis Corticosteroidpossible free clinical remission at week 16 16 weeks

47.0% (50 mg) and 49.7% (100 mg) versus 31.2% Maintenance of clinical response to week 54 54 weeks

either therapy alone, the SUCCESS trial was initiated. Remarkably, the SUCCESS trial is the first trial with a primary efficacy endpoint in line with the latest EMA recommendations, namely steroid-free remission.54 All previous trials with biologicals allowed continuous concomitant use of corticosteroids at a stable dose. Although the study had to be ended prematurely due to slow patient recruitment, the chance of achieving the primary endpoint was twice as high with combination therapy as with azathioprine or infliximab in monotherapy, a finding in line with the similarly designed SONIC trial in CD.55 The GEMINI 1 study evaluated the efficacy of vedolizumab, a humanized monoclonal antibody directed against the α4β7 integrin, for induction and maintenance of remission in active UC.56 Tapering of steroids was forced in the maintenance phase. The results of the trial were impressively positive, even in the anti-TNF-experienced subgroup. Hence vedolizumab has recently entered the market as the second biological for the treatment of UC.

5.  Challenges and Perspectives (Table 4)

Total Mayo score

Oral CSs Oral mesalamine

No

Yes

5.1. The war against the placebo effect

NS, not significant; CSs, corticosteroids.

239 62 2014 SUCCESS54

251 PURSUIT2014 MAINTENANCE53

464

Total Mayo score

Oral CSs Azathioprine 5-ASA

No

Yes

Yes (for placebo/ golimumab induction nonresponders, at week 6) No

Primary endpoint(s) Trial name

Table 3.  Continued

Year of Number of Number of publication study sites patients

Main outcome parameter

Concomitant drug exposure

Open-label? Previous anti- PlaceboTNF exposure controlled? allowed?

Study duration

Active compound versus placebo response (for primary endpoint)

6

In a paper published in Gastroenterology in 2007, Su and co-workers reviewed all placebo-controlled RCTs for active UC from 1966 to 2005 and found placebo remission rates from 0 to 40% and placebo response rates from 0 to 67%.57 Factors associated with a lower placebo effect were a short duration of study, a low number of study visits, severe disease at inclusion and a stringent definition of outcome parameters, preferably including endoscopic mucosal healing in the definition of remission.57 The last of these factors is especially interesting, as the inclusion of objective disease measures like endoscopic assessment in the primary endpoint seems to be an effective intervention to reduce the placebo effect in clinical trials for CD as well.58,59 At first sight, this issue may be less relevant for UC, as the distal nature of the disease presumes an easy inclusion of sigmoidoscopy in the initial disease assessment and during follow-up. However, many of the major trials in UC have not included endoscopic remission in their primary efficacy endpoint.47,52,53,54,56 Exceptions are the ULTRA trials, which included the criterion of an endoscopic Mayo score of ≤1 in their primary endpoint.50, 51 Indeed, the placebo effect (for the primary endpoint) in these trials was much lower compared with studies that only included clinical parameters. On the other hand, data from both ULTRA and ACT show a much higher rate of spontaneous endoscopic remission in the placebo group compared with what is seen in CD clinical trials, and therefore macroscopic mucosal healing alone as a primary endpoint (as in the EXTEND trial in CD) is probably not the best way to avoid a high placebo effect in UC.47,50,51,60 The combination of clinical and endoscopic remission and/or histological healing is probably a better choice. Indeed, the concept paper on the upcoming revision of the EMA guidelines states that ‘a thorough evaluation of the available data on validity and feasibility of mucosal healing (alone or in combination with clinical remission and/or biomarkers) as a primary measure of efficacy has to be made’.61 Table 4.  Major challenges for future clinical trials in ulcerative colitis. Objective outcome measures Mucosal/histological healing as the ultimate therapeutic goal Central reading of endoscopic images Comparative effectiveness design Use of patient-reported outcomes as secondary or primary endpoints

Clinical Trials in Ulcerative Colitis Numerous endoscopic scores for UC have been developed over time and they have recently been extensively reviewed elsewhere.62,63 The recently developed UC endoscopic index of severity (UCEIS) is the only validated index.63, 64 However, all scores are subject to substantial intra- and interobserver variability, which may have a considerable influence on the results of clinical trials in UC. The concept of centralized reading of endoscopy to verify patient eligibility was first introduced by Sandborn et al.65 in 2009 in a study of delayed-release mesalamine in moderately active UC. However, the importance of this practice was only assessed 4 years later by Feagan et al.,66 who clearly demonstrated that verification of patient eligibility by an expert central reader of endoscopy could greatly reduce the placebo response rate, thereby increasing the magnitude of the treatment effect and the efficiency of a clinical trial. It is expected that central review of endoscopic images will be a gold standard practice in every future induction trial. This will also shed light on the real (unbiased) endoscopic placebo response in UC and CD.

5.2.  Moving away from a MAYO endoscopic score of 0–1 as a primary endpoint 5.2.1.  Is a Mayo endoscopic subscore of 0 the therapeutic goal in UC? Mucosal healing in UC has traditionally been defined in most studies as a Mayo endoscopy subscore of 0 or 1.67 Whether a subscore of 0 is associated with better outcomes than a subscore of 1 requires further investigation.68 In a combined analysis of ACT 1 and ACT 2 and a post-study follow-up evaluation, Colombel et  al.69 found that early endoscopic remission (after 8 weeks of treatment) reduced the chance of colectomy by 10–15% after 1 year. The authors did not find a significant difference in outcome at 1  year between UC patients with a Mayo endoscopy subscore of 0 and those with a subscore of 1. The use of UCEIS with a wider range (3–11) to define mucosal healing and the recommended minimal therapeutic goal is still being investigated. Intervention trials are needed to determine whether a Mayo endoscopy subscore of 0 should be a primary endpoint in upcoming UC clinical trials. 5.2.2.  Is histological healing the ultimate treatment goal in UC? Although Truelove70 had already suggested in 1966 that histological healing was likely to be important in the prevention of UC relapses, it took until 1991 before Riley et al.71 demonstrated that remission at a histological level was associated with a lower risk of relapse in UC patients with complete clinical and endoscopic remission. In addition, accumulating evidence suggests that resolution of histological inflammation in UC is associated with a reduced risk of hospitalization, colectomy and colorectal cancer. Together, this provides a strong rationale for considering histological healing as a relevant treatment goal.72,73,74,75 Although different histological scoring systems for UC exist (with good correlation among them), none of them has been fully validated thus far.76 5.2.3.  UC clinical trials: where do we go from here? From a clinical point of view, the most relevant study endpoint is the risk of disability, hospitalization, cancer and colectomy which are known to be major long-term outcomes. The data from two step-up/ top-down trials in CD, published in 200877 and 201078 respectively, showed that early intensive treatment could result in better outcomes compared with a classical step-up approach. The results were confirmed in a recently completed large disease modification trial (REACT), again showing that, compared with an accelerated stepup treatment, the conventional treatment approach is likely to be

7 suboptimal in terms of CD-related complications, hospitalizations and operations.79 As of today, no evidence is available that early intervention with a top-down approach would be beneficial in UC. It is unlikely that future trials will get ethics committee approval unless previous use of biologicals was unsuccessful. However, if only anti-TNF failures are to be included, the feasibility of classically designed placebo-controlled superiority studies becomes an important issue, which is the reason why many phase 3 programmes now move to Eastern Europe and Asia, where the penetration of biologicals is lower. The EMA and FDA suggest in their recommendations the inclusion of an active arm in upcoming trials, and hence switching to comparative effectiveness trials with a non-inferiority approach aiming to show that the new drug is not less effective than the current standard (in most cases a biological).48,80 However, non-inferiority trials require enormous patient numbers with a long follow-up time, triggering a debate on their feasibility. The introduction of a biological with a mechanism of action other than that of the classical anti-TNF compounds, vedolizumab, opens the door for more therapeutic strategy trials that will compare different treatment regimens with established therapies in different subsets of patients. In this regard, head-to-head trials comparing anti-TNF agents and vedolizumab, for instance, are eagerly awaited. Also, the relevance of immunogenicity and pharmacokinetics was recognized during the anti-TNF trials, and this knowledge is likely to be made use of in future trials with biological.81 More recently, the management of chronic medical disorders has undergone a paradigm shift from mainly disease-oriented care towards patient-centred care. In this regard, it is expected that patient-reported outcomes (PROs), which are psychometric instruments created and defined by patients to quantify symptoms, will become an important aspect of the evaluation of IBD, both in the clinical trial setting and in daily practice.82 Several instruments are available to assess PROs in IBD. For example, Khanna and co-workers83 have recently found that PROs could be derived from Crohn’s disease activity index (CDAI) diary items. However, it is important to state that if PROs are to be included in clinical trials, they will have to be developed according to the recently published FDA guidelines.84 Finally, another recent novelty that is changing the landscape of therapy in many fields in medicine is the introduction of biosimilar biologicals. The approval of biosimilars requires preclinical and pharmacokinetic/pharmacodynamic studies to confirm the biosimilarity and clinical efficacy trials. For the latter, two trials are required, one studying the pharmacology and pharmacokinetics using a single dose and a second pivotal study on efficacy and safety in one indication, with extrapolation to other indications. The EMA has recently issued its final guideline on biosimilar monoclonal antibodies in accordance with the guidelines of the Committee for Human Medicinal Products (CHMP).85

Acknowledgements No funding was obtained for drafting this manuscript. PH drafted the manuscript. FB, AH, FM and AA reviewed the manuscript for its intellectual content. LPB coordinated the writing process and reviewed the manuscript for its intellectual content. Competing interests: PH: Consulting fees from Abbvie. Lecture fees from Abbvie and Vifor. FB: Received research grants from Abbott and MSD and lecture and consulting fees from Abbott, MSD, Falk, Pfizer and Vifor. AH: Consulting fees from MSD, Abbott, Ferring, Tillots, Shire, Therakos, Pharmacosmos and BMS.

8 FM: Lecture fees from MSD, Abbott, Ferring, Vifor, Lab Vitoria, Dr Falk, Om Pharma and Hospira. AA: Consulting fees from Abbvie, Astra-Zeneca, Hospira, Lilly, MSD and Sofar, and lecture fees from Abbvie, Chiesi, Ferring, MSD, Nycomed, Otsuka, Takeda and Zambon. LPB: Consulting fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Takeda and Boerhinger-Ingelheim, and lecture fees from Merck, Abbott, Janssen, Ferring, Norgine, Tillots, Vifor and Therakos.

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Clinical trials in ulcerative colitis: a historical perspective.

The clinical trial landscape in ulcerative colitis has evolved significantly in recent decades. Study endpoints have been shifting from mere clinical ...
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