Innovations In Clinical Neuroscience

JAN-FEB 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 19 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 marketing clinical trials, with adverse events (AEs) occurring at rates similar to placebo. 23–25 In both the pivotal study (ACP-103-020) and the pooled clinical trial data presented in the pimavanserin prescribing information, peripheral edema (pooled data: 7% vs. 2%) and confusional state (pooled data: 6% vs. 3%) were the only AEs occurring in at least five percent of patients and at least twice the rate of placebo. 12,24 Importantly, worsening of motor symptoms has not been observed. An additional concern with pimavanserin therapy is possible QT prolongation, which occurred in 19.5 percent of patients. 25 ACP-103-020 displayed a mean 7.3ms QTcB (Bazett's corrected formula) interval increase with pimavanserin. 24 Sporadic QTcF (Frederica's corrected formula) values of 500ms or greater and changes from baseline 60ms or greater have been reported with 34mg pimavanserin. 25 Compared with placebo, increased rates of ventricular repolarization- related AEs, such as torsades de pointes, have not yet been reported. Precautions, contraindications, drug monitoring . As with all antipsychotic drugs, pimavanserin labeling includes a boxed warning for increased mortality in elderly patients with dementia-related psychosis, as previous studies of antipsychotic drugs have detected an increased risk of all-cause mortality in this population. 12 Preliminary data from ongoing extension studies revealed five deaths (pimavanserin [4] vs. placebo [1], estimated odds ratio [OR] 2.94, p=0.61) that were attributed to probable myocardial infarction, septic shock, septicemia, or respiratory distress among those in the pimavanserin group. 25 Clinicians should exercise caution before prescribing pimavanserin to patients at risk for QT prolongation, and should avoid prescribing pimavanserin altogether to patients with known QT prolongation. 16 Drug interactions . As pimavanserin is metabolized by CYP3A4, healthcare providers should be aware of potential drug interactions. 12 Concomitant use of TABLE 1. Summary of pimavanserin safety and efficacy trials CHARACTERISTICS ACP-103-00629 ACP-103-02030 ACP-103-01231 ACP-103-01431 Participants 60 men and women who met criteria for PDP 199 men and women (>40 years) meeting diagnostic criteria for PDP 298 subjects with PDP with MMSE scores >21 and with 30 days of stable PD medications prior to study start 123 subjects with PDP with MMSE scores >21 and with 30 days of stable PD medications prior to study start (planned sample size was 279) Design Four-week treatment with a four- week follow-up period Two-week lead in with BPST-PD, then six-week treatment period Multicenter, international, six-week, double-blind, randomized, placebo- controlled trial Multicenter, international, six-week, double-blind, randomized, placebo- controlled trial Doses Starting dose of 20mg daily; increased to 40 or 60mg daily after Weeks 1 and 2, depending on clinical response 40mg daily 8.5mg daily and 35mg daily 8.5mg daily and 17mg daily Primary endpoint Safety and tolerability, as measured by UPDRS Parts II and III Change in total SAPS-PD score from baseline to Day 43 Efficacy, as measured by decrease in SAPS-H+D scale Efficacy, as measured by decrease in SAPS-H+D scale Secondary endpoints SAPS individual items and global ratings scores; PPRS; CGI-S; Epworth Daytime Sleepiness Scale; UPDRS Parts I, IV, and VI Change in CGI-S and CGI-I scores CGI-S, CGI-I, SAPS-H,-D, CBS, SCOPA- sleep, NMSS, RUD-Lite, UPDRS II+III CGI-S, CGI-I, SAPS-H,-D, CBS, SCOPA- sleep, NMSS, RUD-Lite, UPDRS II+III Results No worsening of motor symptoms compared to placebo; SAPS global ratings total (H+D) score (95% CI -3.39, -0.39; p=0.02); global rating of hallucinations (95% CI -1.83, -0.16, p=0.02). SAPS-PD score: 37% vs. 14% improvement (p=0.0006); improvement in CGI-I (3.45 vs. 2.78; p=0.0011) and CGI-S (-0.44 vs. -1.02; p=0.0007) Neither pimavanserin treatment group showed statistically significant separation from placebo at Week 6. For US sites, 34mg dose showed trend (p<0.1) toward improvement compared to placebo (-6.9 vs. -4.4; 95% CI: -5.4 to 0.5; p=0.099) Premature termination precluded conclusions; some positive efficacy signals with 17mg dose but no significant difference (-6.9 vs -4.4; 95% CI: -4.9 to 0.8; p=0.159). Improvement for 17mg over placebo in CGI-I (treatment difference of -0.66; 95% CI: -1.21 to -0.11; p=0.020). Abbreviations—SAPS: Scale for Assessment of Positive Symptoms; PPRS: Parkinson Psychosis Rating Scale; CGI-S: Clinical Global Impression-Severity; UPDRS: Unified PD Rating Scale; BPST-PD: nonpharmacological brief psychosocial therapy adapted for PD; CGI-I: Clinical Global Impression-Improvement; SAPS-PD: SAPS-Parkinson's disease; MMSE: Mini Mental Status Exam; H+D: hallucinations and delusions; CBS: Caregiver Burden Scale; SCOPA-Sleep: Scales for Outcomes in PD-sleep; NMSS: Non-Motor Symptoms Score; RUD-Lite: Resource Utilization in Dementia Scale

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