Celiac disease’s only treatment is far from ideal. Not only is the gluten-free diet hard to follow, costly, and socially isolating, but even adherent patients can suffer persistent and disabling symptoms, Daniel A. Leffler, MD, MS, of Beth Israel Deaconess Medical Center in Boston, and his associates noted. This “high unmet medical need” inspired their discussion of clinical trials in celiac disease at the third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3). A summary appears as a Clinical Practice Update in Gastroenterology (2016 Jul 22. doi: 10.1053/j.gastro.2016.07.025).
Celiac is the “outlier among intestinal diseases,” the experts noted. Few randomized trials have assessed nondietary celiac disease therapies, drug developers lack a precedent approval to clarify a “guiding regulatory pathway.” The first step toward bridging these gaps is to better define target populations for clinical trials, meeting attendees agreed. Such groups might include patients with diet-refractory symptoms; newly diagnosed patients who need pharmacologic support for symptom resolution and duodenal healing; patients with asymptomatic mucosal damage, if such damage is shown to cause malignancy; and patients with neurobehavioral disorders that impede gluten avoidance. Medications that enable patients to safely consume gluten could benefit even more, including those who already face “arduous” dietary controls from comorbidities such as type 1 diabetes, the experts added.
Dr. Daniel A. Leffler
Defining “clinical benefit” in pivotal trials of celiac disease also poses a challenge. “While every patient might desire something slightly different, the overarching theme of clinical benefit from the patient’s perspective appears to be quality of life – free of symptoms and inflammation without worry about [gluten] contamination,” attendees emphasized. Indeed, one recent survey found that patients prioritized protection against cross-contamination over being able to consume gluten at will. But initial trials should focus on gastrointestinal symptoms, which are common, affect patients of all ages, and “can be measured in a reasonable time frame,” they concluded.
Unfortunately, defining and measuring atypical symptoms can be difficult, particularly in children and adolescents. In an unpublished study at the Nationwide Children’s Hospital, gastrointestinal symptoms affected 77% of celiac patients, while only about 5% experienced atypical or nongastrointestinal symptoms, the experts noted. Such low percentages could make it difficult to adequately power studies of these nongastrointestinal outcomes. Furthermore, measuring sequelae such as osteoporosis or anemia “would require longer studies, as these conditions do not resolve quickly.”
Phase II and III trials cannot secure marketing approvals without clearly defining and measuring “clinical benefit,” Food and Drug Administration representatives at the meeting noted. Accordingly, diarrhea and abdominal pain will be key patient-reported outcome measures, and pivotal trials of young children with celiac disease will require observer-reported outcomes, attendees agreed. Although both celiac disease and the gluten-free diet profoundly undercut health-related quality of life, this measure is too broad and easily confounded to be a good endpoint in pivotal trials of celiac therapies. Likewise, histology is valuable for relating symptoms to active disease, but mucosal healing is too variable and unpredictable to serve as a primary endpoint, experts noted.
In contrast, serologic tests could serve as enrollment criteria, stratification measures, and endpoints if these tests received the appropriate FDA approvals, experts asserted. The endomysial antibody, tissue transglutaminase antibody, and deamidated gliadin peptide tests are most often used in practice, but have only been approved for diagnosing celiac disease – not as a replacement for biopsy or as a measure of disease progression or therapeutic response, FDA representatives noted. Although drug developers need tools to measure therapeutic efficacy in celiac disease, FDA recommended soliciting advice from its Center for Drug Evaluation and Research before testing these tools or kicking off monitoring studies.
The meeting was supported by the Celiac Disease Foundation and Beyond Celiac, and was sponsored by the FDA Center for Drug Evaluation and Research; the American Gastroenterological Association; the American College of Gastroenterology; the American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; and the North American Society for the Study of Celiac Disease. Dr. Leffler disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, INOVA Diagnostics, Coronado Biosciences, Pfizer, and GI Supply. One coauthor and senior author, Dr. Sheila Crowe, disclosed ties to Alvine Pharmaceuticals, Ferring, and Celimmune.