A randomized, double-blind, placebo-controlled, Phase 1/2a trial protocol to assess the safety and efficacy of TAK-101 administered by microneedles in patients with celiac disease

Abstract

Introduction: Celiac disease (CD) affects 0.2 to 2.0% of the worldwide population, causing significant enteropathy and systemic symptoms. There is no effective treatment for CD, and patients must follow a strict gluten-free diet lifelong. Recent studies investigated the efficacy of the non-immunosuppressive agent TAK-101 delivered intravenously in reducing immunological response to gluten in CD patients. However, no study has evaluated transdermal delivery, which initiates different immunological pathways.

Objective: In a population of CD patients, we aim to assess the safety and pharmacokinetics of TAK-1 delivered by a Hollow Microstructured Transdermal microneedle (MN) (Phase 1) and the efficacy of MN-TAK-101 compared to placebo (Phase 2).

Methods: This will be a Phase 1/2a trial lasting 180 days for each phase. Phase 1 will be an open-label, 2-part multicenter study: 1A, a group of patients will be divided into escalating dose cohorts. While, in 1B, another group of patients will be divided into repeated ascending dose cohorts until the maximum tolerated dose is reached. Phase 2 will be a double-blind multicentered randomized (stratified, block) placebo-controlled trial comparing TAK-101 and placebo, using different subjects than those in Phase 1. The primary outcome is the change in Interferon-γ production from baseline after MN-TAK-101 or MN-placebo administration. Secondary outcomes will assess the changes in the ratio of villous height to crypt depth, in the number of intestinal intraepithelial lymphocytes, in CD4, CD8, and γδ cells frequency, in the Celiac symptom index-modified questionnaire and safety measurements. The sample size is between 27-49 patients for phases 1A and 1B; 76 patients in phase 2. For statistical analysis, only descriptive analysis will be done for phase 1, while for Phase 2, the choice of parametric vs. nonparametric tests will be considered according to the normality of the data. This is a first Phase 1/2a placebo control randomized trial to assess the safety and efficacy of TAK-101 applied transdermally for patients with celiac disease.

Keywords: Celiac Disease; TAK-101; Microneedle; Gluten intolerance; Gluten desensitization.