Do we need head-to-head trials to make treatment decisions in ulcerative colitis?

Wednesday, 20 Mar 2019

There are an increasing number of advanced therapies for ulcerative colitis on the market and in the development pipeline. But with the notable exception of results from the VARSITY trial comparing vedolizumab and adalimumab, there are no direct head-to-head randomised controlled trials of the efficacy and safety of the newer therapies.

Can clinicians therefore look to meta-analyses and real-world studies for comparative data on which to base their treatment decisions? At a Takeda sponsored symposium during ECCO 2019 in Copenhagen, leading IBD clinicians discussed the pros and cons of the different sources of comparative data.

The pros and cons of meta-analyses

Speaking during the satellite symposium, Treatment decisions with advanced therapies: comparative evidence in ulcerative colitis, Professor William Sandborn, Chief, Division of Gastroenterology, UC San Diego Health System, La Jolla, California, said meta-analyses were accepted as being in the top hierarchy of evidence and were an important source of information for indirect comparisons of advanced therapies in ulcerative colitis (UC).

He told delegates that meta-analyses also had the advantage of providing context that individual studies could not provide, and their outcomes could provide more precise estimates of treatment effects than individual studies. As long as they were comparing like with like, meta-analyses could reduce the need for long, repeated and expensive clinical studies, he said.

However meta-analyses were only as good as the studies they included, and had drawbacks such as publication and research bias, and the potential for their findings to be ‘tainted’ by inclusion of poorly conducted studies. In order to provide useful comparative information, the quality of a meta-analyses depended on careful selection of studies to ensure that they were using similar study methodologies in similar patient groups and with similar endpoints, Prof. Sandborn noted.

In ulcerative colitis, for example, there was only limited value in comparing studies of induction treatment with maintenance treatment, or studies of anti-TNF agent naïve patients with those exposed to anti-TNF treatment. Trials might also differ in terms of outcomes such as complete remission and mucosal healing, or in methodologies such as dose optimisation, he noted.

“What’s most important I think is really comparing like with like, so for the induction trials splitting out biologic failed patients from naïve patients and looking at them separately [is important] because they’re really not the same in terms of their response,” he said.

According to Prof. Sandborn, one of the most recent and relevant meta-analyses on UC published by Singh et al1 in 2018 included 14 RCTs of induction and maintenance treatment. This showed that based on trials such as OCTAVE, GEMINI and ULTRA, the biologics had higher rates of inducing clinical remission than placebo. In biologic naïve patients, infliximab and vedolizumab had the highest remission rates (0.85 and 0.82 surface under the cumulative ranking curve (SUCRA), respectively, compared to 0.43 for tofacitinib and 0.31 for adalimumab).

With second line therapy in patients with prior exposure to anti-TNF agents, the rates of clinical remission were highest for tofacitinib and vedolizumab (SUCRA 0.96 and 0.62).

“In analyses of biologic-naïve patients, avoid extrapolating to experienced patients,” Prof. Sandborn advised.

For maintenance therapy, all treatments appeared effective in maintaining remission and mucosal healing compared to placebo, but differences in study design limited the ability to make comparisons between therapies, said Prof. Sandborn.

Hence, Prof Sandborn said he agreed with the conclusion of Singh et al. that “head-to-head trials are needed to inform clinical decision-making with greater confidence.”

Real world evidence also has a place

Taking to the podium, Prof. Sandborn’s colleague at UC San Diego Health System, Dr Parambir Dulai, said there was also value in using data from real world settings such as claims/billing data and electronic health records.

“About four years ago a group of us in North America got together and said we needed to start bridging the gaps between clinical trial data and real-world evidence, because as the UC drug pipeline grows, it becomes more and more difficult to wait for phase 3 head to head trials to inform our decision making. In the interim we need to use the best available evidence,” he said.

The challenges of having unselected patients in observational trials could be addressed by propensity score matching to minimise or eliminate confounding, he said. Real world studies could also provide useful data on longer-term outcomes, given that UC was a lifelong disease and RCTs rarely went beyond one year of treatment, he added.

Dr Dulai said the North American VICTORY consortium now had retrospective data from more than 2500 UC patients, and one of the analyses2 showed that vedolizumab was associated with consistently higher rates of clinical remission (Hazard Ratio 1.54) and mucosal healing (HR 1.73) compared to anti-TNF agents. Similarly, for safety data3, the real-world data showed a significantly lower rate of serious adverse events for vedolizumab than with anti-TNF therapy, he noted.

“The data we have from this large consortium … shows that vedolizumab appears to be potentially superior to anti-TNF therapy and potentially safer, but again real-world data isn’t a clinical trial and we still need head-to-head trials to inform decision making,” he concluded.

What’s after VARSITY?4

Professor Jean-Frederic Clombel, director of the IBD services at the Mount Sinai Hospital, New York told the meeting that there were several head-to-head studies of biologics with different modes of action in UC underway, such as HIBISCUS (etrolizumab vs adalimumab, induction), EXPEDITION (vedolizumab vs brazikumab, maintenance) and GARDENIA (etrolizumab vs infliximab, maintenance), and their results would be published over the next three to four years.

However, he said that even head-to-head studies had their drawbacks, such as defining the non-inferiority margin in non-inferiority trials, or having underpowered placebo reference arms.

“Multiple drugs with differing mechanisms of action are now becoming available, both in UC and Crohn’s. Determining which to use is becoming a major issue and will be based on efficacy and safety.

Comparative data are needed to form well designed prospective trials to help us and patients to make choices and to select the best treatment options,” he concluded.

Professor Sandborn added that he believed cost was also becoming a major issue for which agent was used in UC, posing the question of whether it was ethical and appropriate to recommend a drug that was 10% more effective but ten times more expensive than an alternative treatment option.

With downward pressure on the costs of UC drugs from payers and funding groups in the US, Prof. Sandborn predicted that superiority studies would become preferable to non-inferiority trials and placebo controlled studies to show clear advantages for a particular agent to gain funding.



  1. Singh S et al, Aliment Pharmacol Ther 2018 Jan;47(2):162-175.
  2. Faleck D et al , J Crohns and Colitis 2018 12: Supp 1 S019 (abstr OP036)
  3. Lukin DJ et al, J Crohns and Colitis 2018 12: S036, (abstr DOP009)
  4. Journal of Crohn’s and Colitis,2019; 13, Supplement 1, S612–S613, (OP34)

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