A phase 2 randomized controlled trial using biologics to improve multi OIT outcomes (COMBINE): Design, rationale, and methods

Sayantani B Sindher^1*Andrew John Long¹Kristine Martinez¹Ji Hyun Choi¹Marleni Albarran¹Jackson Schuetz¹Alyssa Parry²Julia Tang²Maria Ines Garcia Lloret²Stacey Skura Zedeck²Amy Grissinger³Elizabeth Kiernan³Stephanie Leonard³Olivia Raeber¹Catherine Feight¹Brent Anderson¹Reyna Sharma¹Dinara Bogetic¹Andrew Ryan Chin¹Margaret Woch¹Julian Poyser⁴Joy Laurienzo Panza⁴Alkis Togias⁴Lisa Wheatley⁴Scott Dexter Boyd¹Stephen J Galli¹Kari Nadeau⁵R. Sharon Chinthrajah¹

• ¹Stanford University, Stanford, United States
• ²University of California Los Angeles, Los Angeles, United States
• ³University of California San Diego, La Jolla, United States
• ⁴National Institute of Allergy and Infectious Diseases, Bethesda, United States
• ⁵Harvard University, Cambridge, United States

Background: Food allergy remains a serious public health concern associated with significantly lowered quality of life and the risk of potentially life-threatening allergic reactions. While oral immunotherapy (OIT) has consistently demonstrated efficacy in the desensitization of multi-food allergic patients, many patients undergoing such treatment are burdened by dose-related side effects that can hinder their compliance and the overall efficacy of OIT. Recent efforts to improve upon OIT have begun to evaluate the concomitant use of biologics such as omalizumab and dupilumab with OIT for their ability to selectively inhibit pathways involved in the underlying pathology of food allergy. Methods: Herein, we detail the clinical trial design, rationale, and methods for a Phase 2 randomized, double-blind, placebo-controlled, multi-center study evaluating the safety and efficacy of omalizumab and/or dupilumab therapy in combination with participant-specific multi-food (mOIT) in patients aged 4 to 55 years, with multi-food allergy that includes peanut. In this two-arm superiority trial, participants will be randomized (5:5:1) to (1) omalizumab/placebo-dupilumab with mOIT (n=50), (2) omalizumab/dupilumab with mOIT (n=50), or (3) a mechanistic-only arm of placebo-omalizumab/dupilumab with mOIT (n=10). Double-blind placebo-controlled food challenges (DBPCFCs) will be used to assess desensitization to ≥1043 mg cumulative protein at Week 32, after which all treatment is to be discontinued. A follow-up assessment of sustained unresponsiveness via DBPCFCs will be conducted at Week 44. Conclusion: This trial tests the hypothesis that adding dupilumab to omalizumab-facilitated mOIT will increase the likelihood of inducing sustained unresponsiveness and decrease mOIT-related adverse events.