Validating Clinical Trial Endpoints in Ulcerative Colitis

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Authors examine the current challenges in endpoints of randomized controlled trials and summarize the validity of current endpoints used in patients with ulcerative colitis.

Despite recent advances in treatment, one-quarter of patients with ulcerative colitis (UC) are refractory to medical therapies.1 Current therapeutic options for moderate to severe UC include corticosteroids, tumor necrosis factor-α antagonists, vedolizumab, and tofacitinib1; however, these treatments are not uniformly effective and can be associated with an increased risk for serious infection. As a result, multiple randomized controlled trials (RCTs) are currently underway to try to identify better treatment alternatives.

In a review published in Current Treatment Options in Gastroenterology,1 authors reviewed the current challenges in RCT endpoints and outlined the validity of current endpoints used in populations of patients with UC.

The Problem With Patient-Reported Outcomes

“Historically, RCTs have used symptom-based indices to define treatment response,” wrote Reena Khanna, MD, of the department of medicine and the division of gastroenterology at the University of Ontario in Oshawa, Ontario, Canada, and colleagues, despite that these symptoms (eg, rectal bleeding and stool frequency) are “not reliable surrogates of mucosal inflammation.”

Furthermore, these types of clinical trials also reported high placebo rates1; however, despite these limitations, patient-reported outcomes (PROs) remain “essential” for drug approval: First, they are directly relevant to patient’s lives, and second, endoscopy and histopathology are not currently validated surrogate measures in the context of the drug approval paradigm.1 As a result, composite remission definitions — according to the Mayo Clinic Score (MCS) — incorporate both endoscopy and PROs together. Other limitations of endoscopic and histologic endpoint use include cost, patient acceptance, and access issues.1

Evaluating Clinical Endpoints

Currently, both the MCS and the Ulcerative Colitis Disease Activity Index (UCDAI) are most commonly used to define clinical remission in RCTs.1 Four items complete the MCS: stool frequency, rectal bleeding, physician’s global assessment, and endoscopic disease activity. 1 Each item is graded and yields a total compiled score of 0 to 12: no disease activity to severe disease activity. The partial MCS, which excludes the endoscopic subscore, can be useful to evaluate disease activity absent an endoscopic evaluation.1

The UCDAI is like the MCS but employs different terminology for each item and defines each grade differently. Scores range from 0 to 12, with higher scores correlating with more severe disease. Although the UCDAI is used interchangeably with the MCS, the UCDAI has not been formally validated and is not frequently used.1

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Dr Khanna and colleagues noted that although both the MCS and the UCDAI have been used as endpoints in RCTs, “they are not valid for use as PROs… because their development did not adhere to the rigorous criteria for PRO development required for regulatory approval.”1

Currently, no PRO has been developed and validated for use in trials of patients with UC.

Despite this, PROs remain a critical component required by regulatory authorities to support the approval of new therapies. In 2015, Dr Khanna and colleagues developed and partially validated an interim 2-item patient-reported outcome (PRO2).2 Researchers from this study indicated that PRO2 had acceptable diagnostic accuracy for both cohorts (area under the curve, 0.74-0.9) across cohorts; however, the investigators noted, results also indicated that PRO2 has “limited value” when used in isolation, and further study must be conducted.2

Current developments in endpoint validation have influenced recommendations made across expert bodies in terms of treatment targets. For example, the Selecting Therapeutic Targets in Inflammatory Bowel Disease group recommended as a remission target the resolution of both diarrhea and bleeding plus an MCS endoscopic subscore ≤1,3 which is compatible with US Food and Drug Administration guidance.4

Evaluating Endoscopic Endpoints

To be considered useful, endoscopic disease activity indices must be both reliable and responsive and must accurately measure the inflammatory process.1 More than 20 scoring systems have been developed to assess endoscopic disease, although a majority of these have not been validated appropriately.5 Currently, the most frequently used assessment for endoscopic disease activity in RCTs is the partially validated MCS.1

The MCS endoscopic subscore includes a 4-point scale ranging from 0 to 3,1 incorporating findings of the mucosal erythema, vascular pattern, friability, erosions, spontaneous bleeding, and ulceration,1 with recent modifications to eliminate the ambiguity of the finding of “mild friability.”1

This subscore serves as the current basis for the endoscopic component of the clinical remission definition that is used as the primary endpoint across RCTs. In 2012, investigators proposed an alternative to the MCS endoscopic subscore: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS).6 This scale, developed using a linear mixed regression model, includes 3 items: vascular pattern, bleeding, and erosions/ulcerations. A 2013 study that assessed 57 sigmoidoscopic videos scored by 25 gastroenterologists7 evaluated the reliability of the UCEIS. Moderate and substantial inter-rater reliability were demonstrated, as well as a “significant degree of correlation” between UCEIS and endoscopic disease activity. Researchers then confirmed UCEIS reliability in a subsequent clinical trial conducted with 7 experienced central readers.8

Recently, the blinded central reading of endoscopic videos has become a mainstay for assessing the eligibility for and determination of remission status across UC-focused clinical trials.1 The use of expert central reading, noted Dr Khanna and colleagues, rather than reading by site investigators, “minimizes observation bias and enables regulatory audit of trial results.”1 That is, central reading conducted by an endoscopist who is blinded to patient history is likely to ensure that the “minimum criterion for endoscopic disease activity is met.”1 As such, central reading has become a regulatory requirement for trials involving a population of patients with UC.

Limitations of endoscopic endpoint evaluation include the difficulty of performing repeated endoscopies, as well as the lack of a clear definition of endoscopic remission. Future studies must determine the optimal cut points for endoscopic remission.1

Evaluating Histologic Endpoints

Histologic outcomes are frequently included in UC clinical trials as secondary endpoints.1 Researchers of one systematic review and meta-analysis of 74 studies found that histologic remission rates ranged from 15% to 44.9%,9 with strong correlations observed for histologic and endoscopic endpoints based on paired remission data.9

Despite this promising data, unanswered questions and challenges remain regarding the use of histology as a RCT endpoint. Dr Khanna and colleagues noted that standardized biopsy collection protocols are neither clearly delineated nor validated,1 and systematic random sampling of multiple locations or targeted sampling may result in better outcomes. Clarification, they also noted, is required regarding the optimal number of biopsies required to assess disease activity.1

“This increased emphasis on assessment of histologic disease activity underscores the need for valid measurement tools,” Dr Khanna and colleagues wrote.1

The most well-validated and commonly used indices include the Geboes score, the Robarts Histopathology Index, and the Nancy Histological Index.1

Evaluating Biomarker Endpoints

The most used biomarker in UC is fecal calprotectin because of the ‘relative ease of collection as a stool test”1 and a biologic plausibility as a measure of intestinal neutrophil degranulation. One recent meta-analysis, published in 2015, estimated that the measurement properties of fecal calprotectin for the assessment of endoscopically defined active disease had a sensitivity of 0.88 and a specificity of 0.79 — notably more sensitive than C-reactive protein, with a sensitivity of 0.49.10

Post hoc analyses of data from both phase 2 and 3 clinical trials have demonstrated that fecal calprotectin generally correlates with “meaningful” changes in disease activity. One such example is in the GEMINI 1 clinical trial, wherein patients with UC who achieved clinical, endoscopic, and deep remission experienced greater decreases in fecal calprotectin (FC) from baseline compared with patients with persistent disease activity11; however, it was noted that the overall performance of FC as a surrogate biomarker of disease activity could only be categorized as fair (area under the curve, 0.7 to 0.77).11

These studies, among others, “illustrate the potential application of FC and other biomarkers in treatment algorithm trials,” Dr Khanna and colleagues wrote. “The relative ease of collection, ability to centralize and standardize testing, and high sensitivity and specificity of FC suggest that it may be useful as a treatment target in individual patients,”1 as well as a guide for treatment intensification across management algorithm studies.

The exploration of biomarkers as a secondary endpoint in clinical trials, the authors noted, is likely to continue.1

Looking Forward

UC-100, a composite endpoint, has recently been developed using a combination of patient symptoms, stool, and serum measurements in addition to both endoscopic and histologic scores.12 The goal of the UC-100 is to increase the efficiency of signal detection for therapeutic efficacy. Investigators used an RCT of ozanimod to derive the score whereas they used a different RCT of vedolizumab for validation.12

Internal validation demonstrated good to excellent discrimination in both the derivation and validation cohorts. UC-100 scores range from 1 to 100, with higher values indicative of more severe disease activity. Investigators found that a UC-100 score <25 was associated with “a 95% probability of absence of [rectal bleeding].”1,12

This score, Dr Khanna and colleagues noted, fulfills the current need to identify therapeutic futility early on in clinical trials, as well as to detect efficacy with reduced sample size requirements.1 Before the UC-100 is widely adopted, though, further validation across varied patient populations is required.

“A need… exists for fully validated instruments that assess the impact of new treatment from the patients’ perspective,” Dr Khanna and colleagues wrote. “The concept of biomarkers as noninvasive surrogates for endoscopic or histology is attractive.”1

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

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1. Battat R, Dulai PS, Ma C, et al. Current endpoints of clinical trials in ulcerative colitis: are they valid? [published online January 4, 2020]. Curr Treat Opinions Gastroenterol. doi:10.1007/s11928-019-00259-w

2. Jairath V, Khanna R, Zou GY, et al. Development of interim patient-reported outcome measures for the assessment of ulcerative colitis disease activity in clinical trials. Ailment Pharmacol Ther. 2015;42(10):1200-1210.

3. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324-1338.

4. US Food and Drug Administration (FDA). Ulcerative colitis: clinical trial endpoints guidance for industry. Rockville, MD: US Food and Drug Administration; 2016.

5. Samaan MA, Mosli MH, Sandborn WJ, et al. A systematic review of the measurement of endoscopic healing in ulcerative colitis clinical trials: recommendations and implications for future research. Inflamm Bowel Dis. 2014;20(8):1465-1471.

6. Travis SP, Schnell D, Krzeski P, et al. Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut. 2012;61(4)535-542.

7. Travis SP, Schnell D, Krezeski P, et al. Reliability and initial validation of ulcerative colitis endoscopic index of severity. Gastroenterology. 2013;145(5):987-995.

8. Feagan BG, Sandborn WJ, D’Haens G, et al. The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis. Gastroenterology. 2013;145(1):149-157.

9. Battat R, Duijvestein M, Guizzetti L, et al. Histologic healing rates of medical therapies for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials. Am J Gastroenterol. 2019;114(5):733-745.

10. Mosli MH, Zou G, Garg SK, et al. C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis. Am J Gastroenterol. 2015;110(6):802-819.

11. Reinisch W, Bressler B, Curtis R, et al. Fecal calprotectin response following induction therapy with vedolizumab in moderate to severe ulcerative colitis: a post hoc analysis of GEMINI 1. Inflamm Bowel Dis. 2019;25(4):803-810.

12. Jairath V, Jeyarajah J, Zou G, et al. A composite disease activity index for early drug development in ulcerative colitis: development and validation of the UC-100 score. Lancet Gastroenterol Hepatol. 2019;4(1):63-70.