LAUSR

Abstract Background Individuals with schizophrenia experience an inadequate response to antipsychotic (AP) treatment at a high rate, up to 70% in some cases (McEvoy et al. 2006). Possible reasons for this include subtherapeutic AP blood levels and medication ineffectiveness. Although patient self-report and clinician opinion are commonly used to identify non-adherence, they are unreliable. AP polypharmacy for inadequate response remains widespread despite a lack of supportive evidence. Few completed trials offer guidance on the optimal trial design and procedures to establish inadequate response at screening/baseline. Adequate treatment is defined as an AP taken at a therapeutic dose for a sufficient duration (Taylor et al. 2012). Confirming treatment stability and adherence, both prior to enrollment and during the trial, is necessary to ensure sufficient exposure to an AP prior to deeming a response inadequate and justifying augmentation. Measuring adherence during the trial is necessary to ensure correct interpretation of trial results. We present the trial design and adherence data from a recently completed Phase 3 clinical trial of an adjunctive therapy in inadequately responding patients with schizophrenia. The trial did not meet the primary endpoint (Bugarski-Kirola, et al. 2019). Methods ENHANCE was a 6-week, randomized, double-blind study of adjunctive pimavanserin (PIM; a 5-HT2A inverse agonist) versus placebo to evaluate the treatment of schizophrenia in patients with an inadequate response to their prescribed AP (aripiprazole, olanzapine, risperidone, and others). During screening, patients provided documentation showing treatment stability for at least 8 weeks prior to screening, a blood sample was tested for adherence, and a telemedicine interview was completed with an independent clinician. After randomization, blood sampling occurred at Baseline, Week 1, Week 3, and Week 6 for pharmacokinetic (PK) assessments of the AP and adjunctive PIM. Results ENHANCE screened 633 patients with 35 rescreens for a total of 668 screenings. Adherence to background AP was high for all patients screened as background AP levels were detected in 90.6% of patients. However, the most common reason for screen failure was still a failure to detect background AP (16.9% of all screen failures). Other common reasons for screen failure included lack of prescription stability/appropriate dosing, investigators determining the patient was inappropriate for the study, and withdrawal of consent, the latter of which often reflected the rigorous screening process required for the study. Proactively screen failing non-adherent patients led to higher levels of adherence at Baseline compared to screening with 94.9% of patients demonstrating adherence at Baseline. Moreover, this is a substantial improvement over the theoretical adherence rate of 84.5% had non-adherent patients been randomized. The high rate of adherence at Baseline for background AP was maintained at Weeks 1, 3 and 6. High adherence was also found for adjunctive PIM. 198 patients were randomized to the PIM treatment arm, 190 had a blood sample at Week 1 with 187 (98.4%) showing measurable levels of PIM, and 182 had a blood sample at Week 3 with 180 (98.9%) showing measurable levels of PIM. Patients leaving the study (either at Week 6 of treatment or as a result of early termination) showed a 96.8% adherence rate. Discussion By employing rigorous screening procedures, including testing for AP treatment adherence, the ENHANCE study enrolled a representative sample of patients with a confirmed inadequate response to their current AP and achieved a high level of treatment adherence (both to patient’s AP treatment and study drug).