In clinical trials, particularly those of medium or longer duration, such comorbidities may induce intercurrent events and influence trial outcomes. Ultimately, this may adversely affect the applicability of trial results to real-life settings. In this vein, effectively managing comorbidities before and during NASH trials is crucial to maximising their chances of success.
This proposal, elaborated by the Liver Forum, aims to provide guidance for the management of relevant comorbidities in both potential candidates and enrolled participants in NASH therapeutic trials.
Relevant comorbidities in patients with NASH include high blood pressure, overweight or obesity, type 2 diabetes (T2D), and impaired glucose homeostasis. NASH is also associated with increased risks of incident arterial hypertension, atrial fibrillation, early atherosclerosis, and clinical cardiovascular events. Strategies to stabilise and minimise the impact of comorbidities in NASH patients before their inclusion in therapeutic trials include restricting weight change to a maximum of 5% in 6 months. Similarly, it is recommended that metabolic stability be defined 3 months before the baseline liver biopsy and/or other baseline measures serving for efficacy assessment. Moreover, although they may be considered on a case-by-case basis (particularly in trials with ALT as the primary endpoint), general placebo run-ins prior to randomisation are not recommended in any NASH trial. In the context of ongoing NASH trials, changes in weight, glycaemic control, dyslipidaemia, and high blood pressure control are the most common non-liver-related intercurrent events. In longer trials, management of T2D in patients who do not present with it at baseline warrants pharmacological intervention with widely recommended and NASH-neutral medications, e.g. metformin, rather than glucagon-like protein 1 receptor agonists and sodium-glucose transporter 2 inhibitors. Importantly, these recommendations serve to guide clinicians and are open to further refinement once additional data emerges.