A pharmacovigilance framework for Finding the Optimal Regimen for Mycobacteroides abscessus Treatment (FORMaT), an investigator led, adaptive platform trial

Abstract

Background: Treatment for Mycobacteroides abscessus pulmonary disease (MABC-PD) is characterised by prolonged use of multiple antibiotics that are expensive, exhibit substantial toxicity and often poor effectiveness. Treatment guidelines are based upon consensus-derived expert opinion, rather than being evidence-based. The FORMaT adaptive platform trial attempts to address these limitations by assessing the efficacy and tolerance of current standard of care (SOC). The intervention program consists of an intensive phase with intravenous, inhaled, and oral antibiotics and a consolidation phase using oral and inhaled antibiotics, based on current SOC (13 drugs). The primary outcome is clearance of infection with tolerance (no adverse event (AE) related to trial drug Grade 3 or higher). Industry uses AE reporting systems that are out of financial reach for many investigator-led studies. We describe the implementation of a pharmacovigilance (PV) framework for safety reporting and coding in addition to findings from the safety database (SD). Methods: Trial sites report all AE/Serious AEs (SAEs) in the Research Electronic Data Capture (REDCap) trial database. Data capture includes AE/ SAE severity, relationship to study drug (assigned by trial site investigators using reference safety information) and any actions taken with study drugs (such as treatment interruption or withdrawal). These details are then ported to the SD for coding and grading according to the Common Terminology Criteria for Adverse Events (CTCAE). Each event is reviewed by two experienced clinicians and a senior pharmacist. Treatment emergent SAE reports are emailed from the SD to all Principal Investigators in a Council for International Organisations for Medical Sciences (CIOMS) report, providing real time safety updates. To highlight the utility of the SD, Treatment Emergent AE/SAEs (TEAEs) were analysed for whether treatment was interrupted and/or withdrawn and what drugs were implicated. Results: Thus far, 746 AEs and 73 SAEs including 24 CIOMS reports have been processed by the PV framework. Of 44 participants, 26 (59%) experienced 104 TEAEs that resulted in treatment interruption and/or withdrawal with nausea (n = 9), serum alanine aminotransferase increased (n = 7), serum aspartate aminotransferase increased (n = 7) and hearing impairment (n = 6) most frequently reported. Imipenem-cilastatin was reported as withdrawn in nine participants, with nausea being the most reported event associated with withdrawal (n = 4). Intravenous amikacin was reported as withdrawn from eight participants, with hearing impairment being the most associated with withdrawal (n = 6). Tigecycline was reported as withdrawn in six participants, with increased serum alanine transaminase levels implicated in two cases (refer to table 1 for further information). Conclusions: We have successfully implemented a PV framework and SD for an investigator-led complex adaptive platform trial that facilitates reporting and decisions on exclusion and/or substitution of treatments with unacceptable toxicities. This framework demonstrates the toxicity of current standard of care therapies, underscoring the need for safer, more effective therapeutic options, which future iterations of the trial will aim to address using the established platform. Acknowledgements: This work was supported by the United States Cystic Fibrosis Foundation; Medical Research Future Fund, University of Queensland and the Children's Health Foundation.