3 results
152 Pimavanserin for the Treatment of Parkinson’s Disease Psychosis: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed
- Leslie Citrome, James Norton, Kathy Chi-Burris, George Demos
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, pp. 94-95
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Study Objective
Psychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A receptor antagonist/inverse agonist indicated for the treatment of hallucinations and delusions associated with PD psychosis (PDP). The study aim is to review theevidence-base for PIM for the treatment of PDP using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), andlikelihood to be helped or harmed (LHH), in order to better place this intervention into clinical perspective.
MethodsNNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. Categorical efficacy and tolerability data was extracted from the clinical trial databases of the double-blind placebo-controlled studies of PIM in persons with PDP. The studies were 6 weeks in duration and fixed dose with the exception of study ACP-103-006 which was 4-weeks in duration. NNT and NNH values were calculated with their respective 95% confidence intervals. Efficacy endpoints were defined based on 2 definitions: a) Scale for the Assessment ofPositive Symptoms in Parkinson’s Disease (SAPS-PD) total score decrease ≥3 points from baseline and b) Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). Tolerability outcomes of clinical interest, occurring at any time in available studies were assessed, including discontinuation due toan adverse event (AE). Likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response vs. discontinuation because of an AE.
ResultsNNT values for PIM 34 mg/d vs. placebo for several definitions of clinical response are <10, and as robust as 4, denoting that PIM is a potentially efficacious intervention. NNH values for tolerability outcomes for PIM 34 mg/d (as well as for doses that range from 8.5 mg/d to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for PIM over placebo (such as for postural hypotension), denoting that PIM is a potentially tolerable intervention. In terms of LHH, PIM 34 mg/d is about 5 times more likely to result in clinical response (as measured by ≥3 point decrease from baseline on the SAPS-PD) vs. discontinuation due to an adverse event.
ConclusionsUsing the metrics of NNT, NNH, and LHH, PIM 34 mg/d for the treatment of PDP appears to have a compelling benefit-risk profile.
Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.
135 Use of Pimavanserin in Combination With Selective Serotonin Reuptake Inhibitors (SSRIs)
- James Norton, Doral Fredericks, Kathy Chi-Burris, Randy Owen
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, pp. 84-85
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Study Objective
Psychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated withincreased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved in the U.S. for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Depression affects up to 60% ofPD patients and is frequently treated with SSRIs/SNRIs. Data suggest the potential for a synergistic effect between 5 HT2A receptor inverse agonist/antagonists and SSRIs insubjects with neuropsychiatric disease. This post-hoc analysis evaluated a subgroup of subjects from the pimavanserin clinical program to determine if there was any difference in antipsychotic response between the subjects receiving pimavanserin in combination with an SSRI versus those without.
MethodA pooled analysis of two 6-week randomized, double-blind, placebo-controlled Phase 3 studies was conducted to assess the overall treatment effect of pimavanserin34 mg. The outside-North America region in Study 012 was not included due to a difference in methodology in the assessment of the primary endpoint. Subjects in both the 020 and 012 studies received 42 days of treatment. The mITT population included 268 subjects; with 135 in the pimavanserin group. The full safety dataset included 433 subjects; with 202 in the pimavanserin group. Of the 268 subjects in the mITT population, a total of 77 received concomitant therapy with SSRIs. A subgroup analysis was conducted to determine if there was any difference in response among the subjects receiving concomitant SSRIs.
ResultsOverall, pimavanserin demonstrated a -6.21-point improvement in psychosis at Week 6 as measured by the PD-adapted Scale for Assessment of Positive Symptoms (primary change from baseline analysis [MMRM]). The treatment difference was 2.87 points over placebo (p<0.001) and was clinically meaningful. Both subgroups (pimavanserin +/- SSRI) demonstrated a statistically significant improvement over placebo. Among subjects taking concomitant SSRIs, the decrease in psychosis symptoms was more prominent for both pimavanserin and placebo-treated subjects (-8.33 points and -4.01 points, respectively) compared to the 189 subjects not taking SSRIs (-5.36 points and -3.01 points, respectively); the treatment difference was of greater magnitude in the concomitant SSRI treated group (-4.32 vs. -2.34). A total of 10% (4/40) and 7.4% (12/162) of pimavanserin treated subjects, with and without SSRIs, respectively, discontinued because of adverse reactions.
ConclusionsThe results of this analysis further support findings that the combination of selective 5-HT2A agonist/antagonists and SSRIs may have additive beneficial effects, suggesting a possible enhancement of antipsychotic effect in subjects treated with concomitant SSRIs.
Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.
Pimavanserin for the treatment of Parkinson’s disease psychosis: number needed to treat, number needed to harm, and likelihood to be helped or harmed
- Leslie Citrome, James C. Norton, Kathy Chi-Burris, George Demos
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- Journal:
- CNS Spectrums / Volume 23 / Issue 3 / June 2018
- Published online by Cambridge University Press:
- 03 November 2017, pp. 228-238
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Objective
Our aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH).
MethodsCategorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event.
ResultsNNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are <10, and as robust as 4. NNH values for tolerability outcomes for pimavanserin 34 mg/d (as well as for doses that range from 8.5 to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson’s disease) versus discontinuation due to an adverse event.
ConclusionsUsing the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.