Phase 0 Experimental Medicine Study of Direct Intratarget Pulmonary Microdosing of nlrp3/1 Inflammasome Inhibitor ads032: the Micro Study. A Protocol Paper

Abstract

Introduction High attrition in drug development remains a significant challenge for research and development organisations worldwide. Most novel drug compounds fail at an early stage, often without knowledge of target engagement or molecular efficacy at diseased tissue level. Phase 0 trials provide an opportunity to provide mechanistic data in a small number of patients at the earliest stage of clinical development. The Micro study protocol is designed to deliver a microdose (100µg) of a novel inflammasome inhibitor ADS032 directly into the distal lung of patients with inflammatory and fibrotic interstitial lung disease and bronchiectasis with the aims of assessing feasibility, molecular efficacy and pharmacokinetics. Methods and analysis ADS032 (100µg) and vehicle will be delivered directly to the distal lung (intratarget microdosing) via a flexible catheter in patients undergoing bronchoscopy. Lung samples will be collected in the form of bronchoalveolar lavage, micro-alveolar lavage, and distal airway brushings Up to 12 patients will be recruited. The study is not randomised. The primary endpoint will be measurement of the inflammasome-pathway mediators IL-1β, TNF-α, LDH, ATP, IL-6 and IL-18 in BAL macrophages in the presence of ADS032. A secondary aim is to determine pharmacokinetic (PK) data for the microdosed drug in blood. Exploratory endpoints will include evaluation of a range of potential inflammasome mediators in other lung samples and PK data in urine and respiratory samples. Ethics approval, data management and dissemination The Micro study has received a favourable ethical opinion from South Central Oxford B Research Ethics Committee (REC) and approval from the National Health Service (NHS) Lothian Research and Development (R&D) department. The Medicines and Healthcare Products Regulatory Agency (MHRA) determined that the study is not a Clinical Trial of an Investigational Medicinal Product (CTIMP) and therefore does not require MHRA regulatory oversight. Clinical data management (CDM) will be in accordance with standard National Health Service (NHS) Lothian Research and Development (R&D) regulatory requirements. The results will be submitted for publication in a peer-reviewed journal as soon as possible after recruitment and data analysis is complete. Registration details The Micro study is registered with the primary clinical trial register ISRCTN. The record number is ISRCTN35867933.