Although some factors associated with asthma symptom deterioration and risk of exacerbation have been identified, these are not yet fully characterised. We conducted a clinical modelling and simulation study to understand baseline factors affecting symptom control, reliever use and exacerbation risk in patients with moderate-severe asthma during follow-up on regularly dosed inhaled corticosteroid (ICS) monotherapy, or ICS/long-acting beta2-agonist (LABA) combination therapy.Individual patient data from randomised clinical trials (undertaken between 2001 and 2019) were used to model the time course of symptoms (n = 7593), patterns of reliever medication use (n = 3768) and time-to-first exacerbation (n = 6763), considering patient-specific and extrinsic factors, including treatment. Model validation used standard graphical and statistical criteria. Change in symptom control scores (Asthma Control Questionnaire 5 [ACQ-5]), reduction in reliever use and annualised exacerbation rate were then simulated in patient cohorts with different baseline characteristics and treatment settings.Being a smoker, having higher baseline ACQ-5 and body mass index affected symptom control scores, reliever use and exacerbation risk (p < 0.01). In addition, low forced expiratory volume in 1 s percent predicted, female sex, season and previous exacerbations were found to contribute to a further increase in exacerbation risk (p < 0.01), whereas long asthma history was associated with more frequent reliever use (p < 0.01). These effects were independent from the underlying maintenance therapy. In different scenarios, fluticasone furoate (FF)/vilanterol was associated with greater reductions in reliever use and exacerbation rates compared with FF or fluticasone propionate (FP) alone or budesonide/formoterol, independently from other factors (p < 0.01).This study provided further insight into the effects of individual baseline characteristics on treatment response and highlighted significant differences in the performance of ICS/LABA combination therapy on symptom control, reliever use and exacerbation risk. These factors should be incorporated into clinical practice as the basis for tailored management of patients with moderate-severe asthma.