RESUMO
Background: In patients with schizophrenia, study design to optimize adherence and objective measurement of adherence is critical for interpreting results. Two randomized, double-blind studies evaluating adjunctive pimavanserin in patients with schizophrenia who received stable antipsychotic treatment included measures to encourage and assess treatment adherence. Objective: This post hoc analysis evaluated adherence levels achieved in the Phase III ENHANCE study (NCT02970292) and the Phase II ADVANCE study (NCT02970305). Methods: Blood levels of participants receiving adjunctive treatment with pimavanserin or placebo added to their ongoing antipsychotic medication were tested and evaluated regularly throughout both studies. For both the background antipsychotic and pimavanserin, treatment adherence was defined as a blood sample test result above the lower limit of quantification. Results: Overall, 392 of 633 screened patients and 403 of 608 screened patients were in the safety populations in ENHANCE and ADVANCE, respectively. In ENHANCE, at weeks 1, 3, and 6/early termination (ET), the adherence rates remained ≥ 95.1% for the background antipsychotic in both pimavanserin and placebo treatment groups and ≥ 96.8% for pimavanserin. In ADVANCE, high adherence rates (≥90.6%) with the background antipsychotic (for both treatment groups) and pimavanserin (≥95.0%) were observed at weeks 2, 8, 14, and 26/ET. Conclusion: Rigorous screening was performed to exclude patients not adherent to their background antipsychotic before enrollment and to pimavanserin during study visits by using regular blood sampling. Mandatory caregiver participation further supported adherence to study treatment and procedures. These efforts may have contributed to the high levels of adherence to both background antipsychotic and pimavanserin reported in ENHANCE and ADVANCE.
RESUMO
Background: Pimavanserin prolongs the QT interval, with mean increases in corrected QT (QTc) of 5-8 ms, and is currently being investigated for the treatment of negative symptoms of schizophrenia. Objectives: To assess QT interval prolongation in 3 studies investigating once-daily pimavanserin as an adjunct to current antipsychotic treatment in patients with schizophrenia. Methods: Electrocardiograms were unblinded from trials in which pimavanserin or placebo was added to main antipsychotics over 6 weeks (ENHANCE), 26 weeks (ADVANCE), and up to 78 weeks (ongoing 52-week, open-label extension study [study 035]) of treatment. Antipsychotic treatment was permitted throughout these studies. The 3 most frequently used antipsychotic treatments were examined-aripiprazole (including long-acting injectable), risperidone (including long-acting injectable), and olanzapine. QT intervals were corrected (QTc) using Fridericia's method, with elevated risk defined as either postbaseline value maximum of >500 ms or change from baseline to postbaseline maximum of >60 ms. Results: Of patients treated with adjunctive pimavanserin in ENHANCE, there were no postbaseline QTc values >481 ms; one patient in each of the risperidone and aripiprazole groups had change from baseline to postbaseline maximum >60 ms. More patients had change from baseline to postbaseline maximum ranging from 31 to 60 ms in the risperidone plus adjunctive placebo group (n = 5; 6.6%) than those in the risperidone plus adjunctive pimavanserin group (n = 3, 4.1%). In the pimavanserin plus antipsychotic group of ADVANCE, one patient had postbaseline QTc value >481 ms, and one patient treated with aripiprazole had change from baseline to postbaseline maximum of >60 ms. In study 035, a change from double-blind baseline to overall postbaseline maximum >60 ms occurred in one patient treated with aripiprazole and pimavanserin and in one patient treated with risperidone and pimavanserin. Similar proportions of patients had changes from double-blind baseline to post double-blind baseline maximum between 31 and 60 ms across treatments. No adverse events associated with an increase in the QTc interval were reported. Conclusions: Adjunctive pimavanserin with background antipsychotic treatment showed no evidence of QTc prolongation >500 ms postbaseline, consistent with previously reports on QT prolongation with pimavanserin.
