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 18 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 in the United States (US) with moderate- to-severe PDP. Subjects were randomly assigned to pimavanserin or placebo in a 1:1 ratio for four weeks, showing the drug to be well-tolerated and effective in some, but not all, efficacy measures. 22,23 Pimavanserin tartrate was initiated at 20mg with optional titration to 40mg or 60mg based on clinical response (mean dose standard deviation [SD]=44.8±16mg). Instead of worsening motor symptoms, a nonsignificant improvement was observed with both pimavanserin (-3.05, 95% confidence interval [CI]=-6.56-0.46) and placebo (-3.86, 95% CI= -7.20-0.53) in UPDRS II and III, with no difference between groups (p=0.74). The primary efficacy measure was the Scale for the Assessment of Positive Symptoms (SAPS) total score, which trended toward greater improvement with pimavanserin, though statistical significance was not reached (p=0.09). However, pimavanserin did produce significant improvement in the SAPS global ratings of hallucinations (p=0.02, effect size=0.58) and delusions (p=0.03, effect size=0.53), with trends toward improvement in SAPS total hallucination (p=0.16) and total delusion (p=0.06) domain scores. Additional measures of psychosis, including the Parkinson's Psychosis Rating Scale (PPRS), Clinical Global Impression (CGI), and Epworth Daytime Sleepiness Scale, also displayed nonsignificant trends toward improvement in the pimavanserin group. ACP-103-012, a randomized, double-blind, placebo-controlled trial (N=298) investigated pimavanserin tartrate at doses of 10mg and 40mg and enrolled subjects from the US, five European countries, and India. 22,25,26 Efficacy was not statistically different between the placebo and pimavanserin arms (SAP- hallucinations + delusions [H+D] least- squares [LS] mean difference from baseline versus placebo for 10mg [-0.07, 95% CI -1.7-1.59] and 40mg [-1.16, 95% CI -2.83- 0.51]), which the investigators attributed to an enhanced placebo response. 22 ACP-103-014 was conducted concurrently in the US, eight European countries, and India, but used lower doses (10mg and 20mg). This study was terminated early, as investigators deemed the trial unlikely to display efficacy due to lack of significant improvement in ACP-103-012. Several design changes were incorporated to improve the ability to detect a treatment difference in the pivotal Phase III trial (ACP- 103-020). 24,28 ACP-103-020 was developed by identifying factors in ACP-103-012 and ACP-103-014 that positively correlated with effect size and applying those factors to the study design of ACP-103-020. 22 Thus, the investigators altered their methods, performing the study only in the US and Canada, incorporating centralized raters to reduce inter-rater variability, exclusively using the 40mg dose, employing a two-week lead-in period of psychosocial therapy to blunt the placebo response, and measuring a different primary outcome. 24 Whereas the three previous trials had used the SAPS total score as the primary outcome, ACP-103-020 employed a novel scale, the nine-item subset SAPS- PD. 23–25 While SAPS was originally developed for schizophrenia, SAPS-PD represents a more tailored scale, measuring only the symptoms of SAPS most relevant to PDP, based on symptom frequency from previous PDP studies. 21 In a study conducted to validate the SAPS-PD measure, a clinically significant change was defined as 2.33 points equivalent to a one-point change in the CGI-improvement scale (CGI-I). 29 ACP-103-020, a six-week, double-blind, placebo-controlled trial, randomized 199 patients to placebo or pimavanserin tartrate 40mg. 24 Inclusion criteria included being at least 40 years old with psychotic symptoms that occurred at least weekly, were severe enough to warrant treatment, and were present for at least one month prior to enrollment. Those treated with pimavanserin exhibited significant improvement in SAPS-PD compared to placebo (-5.79 [37% improvement] vs. -2.73 [14% improvement], respectively, p=0.0006). Pimavanserin-treated patients also displayed significantly greater improvement in other measures of psychosis, including the full 20-item SAPS-H+D score (pimavanserin [-6.51] vs. placebo [-3.14], p=0.0012), CGI-I (effect size 0.51, p=0.0011), and CGI-Severity (CGI-S, effect size=0.52, p=0.0007) scores. Thus, this trial showed a statistically significant decrease in SAPS-H+D, which was measured as the primary outcome in previous trials, indicating that the positive results from this trial were not simply a result of using the new SAPS-PD measurement as the primary outcome. Exploratory analyses displayed significant improvement versus placebo in caregiver burden (effect size=0.50, p=0.0016), as well as nighttime sleep (effect size=0.31, p=0.0446) and daytime wakefulness (effect size 0.39, p=0.0120) according to the Scale for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep). Both groups demonstrated nonsignificant motor symptom improvements, with no between-group difference (95% CI -2.14-2.72). Currently completed studies assessed six weeks of pimavanserin treatment. 24 To evaluate long-term safety and efficacy in larger patient populations, two ongoing open-label extension studies are underway. 25 While one extension trial is studying the currently approved dose of 34mg, the other incorporates flexible dosing up to 51mg. Preliminary data continue to demonstrate efficacy and safety of pimavanserin, providing early support for the long-term and early use of pimavanserin in PDP. 22,27 Additional studies to ascertain the effects of hepatic and renal failure on pimavanserin's tolerability and pharmacokinetics are also being conducted, as is a Phase II study of pimavanserin for the treatment of Alzheimer's disease psychosis. 22 A completed analysis of pimavanserin for schizophrenia showed safety and efficacy when used with risperidone. 30 Trial designs are summarized in Table 1 and results in Table 2. Dosing . Pimavanserin is available as 17mg tablets. 12 FDA-approved dosing for PDP-associated hallucinations and delusions is 34mg once daily (equivalent to 40mg pimavanserin tartrate used in ACP-103-020), administered orally as two 17mg tablets with no dose titration. It can be taken with or without food. Manufacturer labeling recommends considering dose adjustments when prescribed concomitantly with CYP3A4 inhibitors or inducers. 12 When co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole), the recommended dose is 17mg daily. Patients taking strong 3A4 inducers (e.g., rifampin) should be monitored for reduced efficacy. A dose increase might be necessary in such cases, though specific recommendations are not provided. Adverse effects . Pimavanserin appeared relatively safe and well-tolerated in pre-

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