Statistical analysis plan for “A randomised, controlled study to evaluate the effects of switching from cigarette smoking to using a tobacco heating product on health effect indicators in healthy subjects”

Tobacco harm reduction strategies aim to substitute smoking with potentially reduced risk products (PRRPs) such as e-cigarettes and tobacco-heating products (THPs). The health benefits of switching from smoking to PRRPs is unknown. A randomised controlled trial is being conducted to increase understanding of the health effects of switching from smoking to a THP in a 12-month long ambulatory study (ISRCTN81075760). Here we describe the study endpoints and the statistical analysis plan. Endpoints are divided into biomarkers of exposure (BoE) to tobacco smoke constituents and health effect indicators related to risk of lung cancer, cardiovascular and obstructive lung disease. These have been selected on the basis of extensive literature evidence. Three primary endpoints, augmentation index (risk factor for cardiovascular disease), total NNAL (linked to lung cancer) and 8-Epi-PGF2α type III (indicator of oxidative stress linked to various diseases), and multiple secondary endpoints will be analysed at 90, 180, and 360 days. Changes from baseline will be compared between study arms by specific contrasts in mixed models. Study wise multiple comparisons adjustments will be performed to account for multiplicity of timepoints and comparisons within timepoints. Generalisability of outcomes will be tested by a sensitivity analysis adjusting for age and gender. Importantly, an ancillary analysis will be performed to assess product compliance during the study based on plasma levels of CEVal, a surrogate marker for acrylonitrile exposure. The rationale underlying the selection of BoEs and health effect indicators, coupled with the statistical analysis plan will be central to understanding the potential health effects of replacing smoking with THP use for one year.