Effect of Hepatic Impairment on Trofinetide Exposures Using an In Silico Physiologically Based Pharmacokinetic Model.

INTRODUCTION: Trofinetide is the first drug to be approved for the treatment of Rett syndrome. Hepatic impairment is not expected to affect the pharmacokinetic (PK) profile of trofinetide because of predominant renal excretion. This study was conducted to help understand the potential impact of any hepatic impairment on trofinetide PK. METHODS: This study used physiologically based PK modeling to estimate trofinetide exposure (maximum drug concentration and area under the concentration-time curve from time zero to infinity) in virtual patients with mild, moderate, and severe hepatic impairment (per Child-Pugh classification) compared with virtual healthy subjects following a 12 g oral trofinetide dose. RESULTS: In individual deterministic simulations for matched individuals and stochastic simulations at the population level (100 virtual individuals simulated per population), as anticipated, predicted plasma exposures were similar for healthy subjects and for patients with mild, moderate, and severe hepatic impairment. However, predicted blood concentration exposures slightly increased with increasing severity of hepatic impairment because of change in hematocrit levels. CONCLUSION: This study indicates that hepatic impairment is not expected to have a clinically relevant effect on exposure to trofinetide.

Trofinetide is the first approved treatment for Rett syndrome, a rare genetic condition that affects brain development. When a person takes trofinetide, most is removed from the body via the urine in its unchanged form (no chemical alteration). Regulatory requirements mean researchers must confirm the safety of any pharmaceutical drug and evaluate whether changes in liver function lead to harmful levels of drug exposure. Researchers used a computer model to predict how much trofinetide would be present in the blood and plasma (the liquid portion of blood) over time in virtual healthy subjects and virtual patients with varying degrees of liver disease (mild, moderate, or severe). Computer simulations showed that predicted trofinetide levels in plasma were similar in virtual healthy subjects and each virtual patient group with liver disease. Predicted levels of trofinetide in blood were slightly elevated with increasing severity of liver disease. This is because people with liver disease have fewer red blood cells, so the cell portion of blood becomes smaller relative to the liquid portion (plasma), which leads to higher trofinetide concentrations in whole blood (trofinetide minimally enters the red blood cell). The small increase in trofinetide levels in blood and the absence of any change in trofinetide levels in plasma means that people with Rett syndrome and liver disease are unlikely to be exposed to harmful levels of trofinetide after a 12 g oral dose.

Trofinetide for the treatment of Rett syndrome: Results from the open-label extension LILAC study.

BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is a chronic disorder requiring long-term treatment. We report the efficacy and safety results of LILAC, a 40-week, open-label extension study of LAVENDER. METHODS: Females with Rett syndrome aged 5-21 years received open-label treatment with trofinetide for 40 weeks. The primary endpoint was long-term safety of trofinetide; secondary endpoints included the change from baseline at week 40 in the Rett Syndrome Behaviour Questionnaire score and the Clinical Global Impression-Improvement score at week 40. FINDINGS: Overall, 154 participants were enrolled and treated with trofinetide in LILAC. The most common adverse events in LILAC were diarrhea (74.7%), vomiting (28.6%), and COVID-19 (11.0%). Diarrhea was the most common adverse event leading to treatment withdrawal (21.4%). The Rett Syndrome Behaviour Questionnaire mean score (standard error) improvement from the LAVENDER baseline to week 40 in LILAC was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean Clinical Global Impression-Improvement scores (standard error) at week 40 rated from the LILAC baseline were 3.1 (0.11) and 3.2 (0.14) for participants treated with trofinetide and placebo in LAVENDER, respectively. CONCLUSIONS: Treatment with trofinetide for ≤40 weeks continued to improve symptoms of Rett syndrome. Trofinetide had a similar safety profile in LILAC as in LAVENDER. FUNDING: The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). This trial was registered at ClinicalTrials.gov (NCT04279314).

A Physiologically Based Pharmacokinetic Modeling Approach to Assess the Potential for Drug Interactions Between Trofinetide and CYP3A4-Metabolized Drugs.

PURPOSE: Trofinetide is the first drug to be approved by the US Food and Drug Administration for use in the treatment of patients with Rett syndrome, a multisystem disorder requiring multimodal therapies. Cytochrome P450 (CYP) 3A4 metabolizes >50% of therapeutic drugs and is the CYP isozyme most commonly expressed in the liver and intestines. In vitro studies suggest the concentration of trofinetide producing 50% inhibition (IC50) of CYP3A4 is >15 mmol/L; that concentration was much greater than the target clinical concentration associated with the maximal intended therapeutic dose (12 g). Thus, trofinetide has a low potential for drug-drug interactions in the liver. However, there is potential for drug-drug interactions in the intestines given the oral route of administration and expected relatively high concentration in the gastrointestinal tract after dose administration. METHODS: Using a validated physiologically based pharmacokinetic (PBPK) model, deterministic and stochastic simulations were used for assessing the PK properties related to exposure and bioavailability of midazolam (sensitive index substrate for CYP3A4) following an oral (15 mg) or intravenous (2 mg) dose, with and without single-dose and steady-state (12 g) coadministration of oral trofinetide. FINDINGS: Following coadministration of intravenous midazolam and oral trofinetide, the PK properties of midazolam were unchanged. The trofinetide concentration in the gut wall was >15 mmol/L during the first 1.5 hours after dosing. With the coadministration of oral midazolam and trofinetide, the model predicted increases in fraction of dose reaching the portal vein, bioavailability, Cmax, and AUCinf of 30%, 30%, 18%, and 30%, respectively. IMPLICATIONS: In this study that used a PBPK modeling approach, it was shown that CYP3A4 enzyme activity in the liver was not affected by trofinetide coadministration, but trofinetide was predicted to be a weak inhibitor of intestinal CYP3A4 metabolism after oral administration at therapeutic doses.

Exposure-Response Efficacy Modeling to Support Trofinetide Dosing in Individuals with Rett Syndrome.

INTRODUCTION: Trofinetide was recently approved for the treatment of Rett syndrome (RTT) on the basis of the efficacy and safety findings of the phase 3 LAVENDER study, which used a body weight-based dosing regimen. Exposure-response (E-R) efficacy modeling was used to characterize relationships between trofinetide exposure measures (maximum drug concentration and area under the concentration-time curve for the dosing interval of 0-12 h [AUC0-12]) and efficacy endpoints in RTT clinical studies to support the trofinetide dosing regimen. METHODS: Efficacy endpoints were modeled using trofinetide exposure measures predicted from the population pharmacokinetic model and Bayesian estimates. The analysis population for each E-R model comprised individuals receiving placebo or trofinetide who had available trofinetide exposure measures. Efficacy endpoints were scores from the Rett Syndrome Behaviour Questionnaire (RSBQ), the Clinical Global Impression-Improvement, the Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite, and the Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC). RESULTS: Higher trofinetide exposure was associated with improvements in RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Assuming target trofinetide AUC0-12 values of 800-1200 µg·h/mL, the reductions in RSBQ total scores at week 12 were approximately five- to seven-fold greater with trofinetide (range 3.55-4.94) versus placebo (0.76). Significant E-R relationships were also found for the CSBS-DP-IT Social Composite and RTT-COMC scores. CONCLUSION: E-R efficacy modeling demonstrated significant relationships between trofinetide exposure and RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Trofinetide is efficacious within the target exposure range, supporting the approved dosing regimen for trofinetide. TRIAL REGISTRATION: NCT01703533, NCT02715115, NCT04181723.

Trofinetide is the first approved treatment for people living with Rett syndrome, a rare genetic condition affecting brain development. This approval was based on the findings of clinical studies in which trofinetide showed significant improvements in the symptoms of Rett syndrome. In this study researchers were looking to see if the level of trofinetide in the blood was related to the level of improvement in symptoms observed in clinical studies. Information on the effectiveness of trofinetide was obtained from the phase 3 LAVENDER study which used doses of trofinetide according to body weight. Trofinetide's effectiveness was assessed on the basis of clinical measurements of key Rett syndrome symptoms. All the information on trofinetide dose, blood levels, and how much symptoms changed (i.e., effectiveness of trofinetide) was then used to develop models to predict symptom responses in the observed population. Researchers found that as the blood levels of trofinetide increased the symptom improvement also increased. When the blood levels were at the recommended level that was achieved in the LAVENDER study, the model predicted that symptom improvement was up to seven times greater with trofinetide than having no treatment (i.e., placebo). This study shows a positive relationship between trofinetide blood levels and improvement in the symptoms of Rett syndrome. Trofinetide was effective within the recommended blood level range in the LAVENDER study using the approved weight-based dosing.

Trofinetide Treatment Demonstrates a Benefit Over Placebo for the Ability to Communicate in Rett Syndrome.

BACKGROUND: Trofinetide was approved by the US Food and Drug Administration for the treatment of Rett syndrome (RTT) in March 2023. Benefiting the ability to communicate in RTT is often identified as the most important caregiver goal for new therapies. This analysis reports the communication-related end points from the phase 3 LAVENDER study of trofinetide in RTT. METHODS: Females with RTT, aged five to 20 years, were randomized 1:1 to trofinetide or placebo for 12 weeks. Secondary efficacy end points related to communication were based on change from baseline to week 12 and included the caregiver-rated Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite score (key secondary end point; scores ranged from 0 to 26 [higher scores indicated better communication]) and novel clinician rating scales (0 [normal] to 7 [severe impairment]) measuring the ability to communicate choices nonverbally (RTT-COMC) and verbally (RTT-VCOM). RESULTS: Trofinetide demonstrated a statistically significant difference versus placebo for the CSBS-DP-IT Social Composite score (least squares mean [LSM] difference = 1.0; 95% confidence interval [CI], 0.3 to 1.7; P = 0.0064; Cohen's d effect size = 0.43) and a nominally significant difference for the RTT-COMC (LSM difference: -0.3; 95% CI, -0.6 to -0.0; P = 0.0257; Cohen's d effect size = 0.36). As expected, there was no difference for the RTT-VCOM. CONCLUSIONS: Significant treatment benefit for trofinetide versus placebo was observed in scales measuring the ability to communicate. These scales may be appropriate for future clinical studies in RTT and other neurodevelopmental disorders.

Gastrointestinal manifestations in pediatric and adult patients with Rett syndrome: an analysis of US claims and physician survey data.

Aim: Patients with Rett syndrome (RTT) experience gastrointestinal (GI) manifestations. This study aimed to describe the prevalence of GI manifestations and the associated medical costs in patients with RTT in the USA. Patients & Methods: The study combined an insurance claims database analysis with a survey of 100 physicians experienced in RTT management. Results: GI manifestations affected 43.0% of 5940 patients, with increased prevalence in pediatric patients (45.6%) relative to adult patients (40.2%). Annualized mean medical cost of managing GI manifestations was $4473. Only 5.9-8.2% of neurologists and pediatricians ranked GI symptom management among the five most important treatment goals. Conclusion: Patients with RTT experience a high burden of GI manifestations, which translate to considerable medical costs. Importantly, the prevalence of GI manifestations was likely underestimated in this study, as only those symptoms which resulted in a healthcare encounter were captured.

Characterization of the Pharmacokinetics and Mass Balance of a Single Oral Dose of Trofinetide in Healthy Male Subjects.

BACKGROUND AND OBJECTIVE: Trofinetide is the first drug to be approved for the treatment of Rett syndrome, a neurodevelopmental disorder. The purpose of the study is to fully characterize the metabolic and excretion profiles of trofinetide in humans. METHODS: This Phase 1, open-label, single-dose trial conducted in healthy male adults was designed to characterize the pharmacokinetics of trofinetide (absorption, metabolism, and excretion), mass balance of [14C]-trofinetide, and safety profile of trofinetide following administration of an oral 12-g dose administered as a mixture of trofinetide and [14C]-trofinetide. Blood, urine, and fecal samples were collected at prespecified timepoints. The pharmacokinetics of trofinetide were assessed in blood and urine samples using high-performance liquid chromatography (HPLC) with tandem mass spectrometric detection. Bioanalysis of radioactivity was conducted in blood, plasma, urine, and fecal samples using liquid scintillation counting. Metabolite profiling was conducted in blood, plasma, urine, and fecal samples using HPLC with liquid scintillation counting of chromatographic fractions. Safety and tolerability, including treatment-emergent adverse events (TEAEs), were assessed. RESULTS: Blood concentration-time profiles of trofinetide and total radioactivity were almost superimposable up to ~12 h after dosing. Urine concentration-time profiles of trofinetide and total radioactivity were similar. Trofinetide was rapidly absorbed into the circulation with an initial rapid decline (half-life [t½] alpha ~2.6 h), followed by a relatively slow terminal elimination phase (t½ beta ~20 h). The blood-to-plasma total radioactivity ratios were 0.529-0.592, indicating a lack of affinity for the cellular portion of blood. Renal excretion accounted for 83.8% of the administered radiochemical dose; 15.1% was recovered in feces. Urine and fecal recovery of radioactivity accounted for 99% of the administered dose at 168 h after dosing. Parent [14C]-trofinetide was the major radiolabeled entity in blood and plasma (88.4% and 93.1% in area under the concentration-time curves from 0 to 12 h [AUC0-12] in pooled blood and plasma samples, respectively) and the major entity excreted in urine (91.5% in 0-48-h pooled urine samples) and in feces (52.7% in 0-192-h pooled fecal samples). Only small levels of metabolites were present. In blood and plasma, only two minor metabolites were identified (each metabolite ≤ 2.24% of the AUC0-12 pool). These two metabolites were also observed in urine and fecal samples (≤ 2.41% of dose). In feces, one additional metabolite (0.84% of dose) was identified. Two mild TEAEs were reported in two participants and were not considered related to trofinetide. There were no clinically meaningful changes in individual laboratory parameters, vital signs, physical findings, or electrocardiogram results. CONCLUSIONS: Metabolic and excretion profiles confirm that trofinetide undergoes minimal hepatic or intestinal metabolism and is primarily excreted unchanged in the urine. Trofinetide containing radiolabeled [14C]-trofinetide was well tolerated.

Trofinetide is the first approved treatment for Rett syndrome, a rare genetic condition that affects brain development. Study aims were to look at how a single oral dose of trofinetide is absorbed into the bloodstream, to see whether trofinetide's chemical structure is changed once in the body, and to see how trofinetide and any metabolites (chemically altered trofinetide) are removed from the body. Safety and tolerability of trofinetide were also assessed. Eight healthy adult men took a single oral 12-g dose administered as a mixture of ¹⁴C-radiolabeled and nonlabeled trofinetide. Researchers collected blood, urine, and stool samples at regular intervals for up to 10 days postdose to measure levels of trofinetide and its metabolites. Trofinetide was rapidly absorbed (time to maximum concentration was 2 h postdose) and was primarily present in the blood as the unaltered compound. Concentrations decreased rapidly during the first 24 h postdose and more slowly thereafter. Most of the dose was recovered in urine with a lower amount in stool samples (83.8% and 15.1% of the radiochemical dose, respectively). Total recovery in urine and stool samples was 99%, primarily as the chemically unaltered compound. Only low levels of three trofinetide metabolites were detected. Two metabolites were found in blood, urine, and stool samples, while one metabolite was found in stool samples only. Two mild treatment-emergent adverse events, considered to be unrelated to trofinetide, were reported. In summary, trofinetide is rapidly absorbed, minimally metabolized, and mainly removed from the body in the urine as the unchanged drug.

Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study.

Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study ( https://clinicaltrials.gov identifier NCT04181723 ), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was -4.9 versus -1.7 (P = 0.0175; Cohen's d effect size, 0.37), and LSM Clinical Global Impression-Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite score was -0.1 versus -1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.

Development of trofinetide for the treatment of Rett syndrome: from bench to bedside.

Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the MECP2 gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with roles in epigenetic regulation of gene expression. Functional loss of MeCP2 results in abnormal neuronal maturation and plasticity, characterized by loss of verbal communication and loss of fine and gross motor function, among others. Trofinetide, a synthetic analog of glycine-proline-glutamate, was approved by the US Food and Drug Administration for the treatment of RTT in adult and pediatric patients aged 2 years and older. Here, we present the development of trofinetide from bench research to clinical studies and emphasize how the collaboration between academia, the pharmaceutical industry, and patient advocacy led to the recent approval. The bench-to-bedside development of trofinetide underscores the value of collaboration between these groups in the development and approval of treatments for rare diseases.

A Phase 1, Open-Label Study to Evaluate the Effects of Food and Evening Dosing on the Pharmacokinetics of Oral Trofinetide in Healthy Adult Subjects.

BACKGROUND AND OBJECTIVE: Trofinetide, a synthetic analog of tripeptide glycine-proline-glutamate, is an investigational agent for the treatment of Rett syndrome, a neurodevelopmental disorder with affected individuals requiring lifelong support. Food can affect the pharmacokinetic profile of a drug, and this phase 1 study assessed the potential effect of food on the pharmacokinetics of trofinetide. The study also evaluated the potential effect of evening dosing on trofinetide bioavailability and characterized the pharmacokinetic profile of trofinetide in urine. METHODS: A 60 mL oral solution of trofinetide (12 g) was administered in three dosing periods: morning fasted (A; reference), morning fed (B), and evening fasted (C). Healthy adult subjects (18-45 years) were randomized to sequence ABC (n = 19) or BAC (n = 22). Blood and urine samples were collected at scheduled timepoints for trofinetide pharmacokinetic analysis. Bioequivalence was confirmed if 90% confidence intervals for geometric mean ratio between B/A or C/A fell within 80-125% equivalence limits for area under the concentration-time curve (AUC) and maximum concentration (Cmax) in whole blood. RESULTS: Bioequivalence criteria were met for all conditions (i.e., morning fed vs. morning fasted and evening fasted vs. morning fasted) except Cmax in the fed versus fasted condition, which was just below the bioequivalence limit (75.49%), suggesting a negligible food effect and lack of diurnal variation on bioavailability. Trofinetide was primarily excreted unchanged in urine. Trofinetide was well tolerated, and there were no significant changes in vital signs or laboratory parameters. CONCLUSION: This study supports dosing of trofinetide without regard to food.

Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome.

INTRODUCTION: Rett syndrome (RTT) is a debilitating neurodevelopmental disorder with no approved treatments. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor 1. In a phase 2, placebo-controlled trial in 82 females with RTT aged 5-15 years, a significant (p ≤ 0.042) improvement over placebo was observed with the highest trofinetide dose (200 mg/kg twice daily [BID]) on three measures: Rett Syndrome Behaviour Questionnaire (RSBQ), Clinical Global Impression-Improvement (CGI-I), and RTT-Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC-VAS). Trofinetide was well tolerated at all doses (50, 100, and 200 mg/kg BID). A phase 3 trial utilizing disease-specific and novel scales was designed to investigate the efficacy and safety of trofinetide in girls and women with RTT. METHODS: This 12-week, double-blind, randomized, placebo-controlled study (LAVENDER; NCT04181723) will evaluate trofinetide in 187 females, aged 5-20 years, with RTT. Co-primary endpoints are the RSBQ and CGI-I scales. Clinical domains of the CGI-I include communication, ambulation, hand use, seizures, attentiveness, and social (eye contact) and autonomic (breathing) aspects. Secondary endpoints will leverage four novel RTT-specific clinician ratings (derived from the RTT-DSC-VAS) of hand function, ambulation, ability to communicate, and verbal communication, and existing scales, to evaluate other core symptoms of RTT, quality of life and caregiver burden. A 40-week, open-label extension study will follow. DISCUSSION: This study was designed using disease-specific scales optimized to demonstrate changes in core symptoms of RTT and may provide the first phase 3 data demonstrating drug efficacy in individuals with RTT. TRIAL REGISTRATION: Clinicaltrials.govNCT04181723.

Trial of Pimavanserin in Dementia-Related Psychosis.

BACKGROUND: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis. RESULTS: Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin. CONCLUSIONS: In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).

Revisiting Criteria for Psychosis in Alzheimer's Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research.

BACKGROUND: Psychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. OBJECTIVE: To establish research criteria for the diagnosis of psychosis in AD. METHODS: The International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. RESULTS: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. CONCLUSION: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study.

BACKGROUND: Pimavanserin is a selective 5-HT2A receptor inverse agonist and antagonist approved in the USA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. No safe or effective pharmacological treatment is approved for psychosis in patients with Alzheimer's disease. Therefore, we aimed to evaluate the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis. METHODS: We did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer's disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (<6 or ≥6) and Neuropsychiatric Inventory-Nursing Home version (NPI-NH) psychosis score (<12 or ≥12). Participants, caregivers, the study sponsor, and study personnel at the clinic site were masked to treatment assignment. The primary endpoint was mean change from baseline to week 6 in the NPI-NH psychosis score for pimavanserin versus placebo in the modified intention-to-treat population. Sustained benefit and safety of pimavanserin were assessed through week 12. This study is registered at ClinicalTrials.gov, number NCT02035553. FINDINGS: Between Jan 16, 2014, and Oct 27, 2016, 345 participants across 133 nursing homes were screened, of whom 181 were randomly assigned treatment (n=90 pimavanserin and n=91 placebo). 178 participants were included in the modified intention-to-treat population. Mean total baseline NPI-NH psychosis scores were 9·5 (SD 4·8) for the pimavanserin group and 10·0 (5·6) for the placebo group. Mean change in the NPI-NH psychosis score at week 6 was -3·76 points (SE 0·65) for pimavanserin and -1·93 points (0·63) for placebo (mean difference -1·84 [95% CI -3·64 to -0·04], Cohen's d=-0·32; p=0·045). By week 12, no significant advantage for pimavanserin versus placebo was observed for the overall study population (treatment difference -0·51 [95% CI -2·23 to 1·21]; p=0·561). Common adverse events were falls (21 [23%] of 90 participants in the pimavanserin group vs 21 [23%] of 91 in the placebo group), urinary tract infections (20 [22%] vs 25 [28%]), and agitation (19 [21%] vs 13 [14%]). Eight (9%) participants on pimavanserin and 11 (12%) on placebo discontinued treatment because of adverse events. No detrimental effect was observed on cognition or motor function in either group. INTERPRETATION: Pimavanserin showed efficacy in patients with Alzheimer's disease psychosis at the primary endpoint (week 6) with an acceptable tolerability profile and without negative effect on cognition. Further follow-up to week 12 did not show significant advantage for pimavanserin versus placebo. FUNDING: ACADIA Pharmaceuticals.

Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants.

OBJECTIVE: To assess the efficacy, tolerability, and safety of brexpiprazole as adjunctive therapy to antidepressant treatments (ADTs) in adults with major depressive disorder (as defined by DSM-IV-TR criteria) and inadequate response to ADTs. METHOD: Patients with historical inadequate response to 1-3 ADTs were enrolled. All patients entered a prospective 8-week phase on physician-determined, open-label ADT. Those with inadequate response were randomized to ADT + brexpiprazole 2 mg/d or ADT + placebo for 6 weeks. The study was conducted between July 2011 and May 2013. The primary efficacy end point was change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The key secondary end point was change from baseline to week 6 in Sheehan Disability Scale (SDS) mean score. The efficacy population comprised all patients who had ≥ 1 dose of study drug in the double-blind phase and both baseline and ≥ 1 postrandomization MADRS scores. The efficacy population per final protocol included patients from the efficacy population who met amended randomization criteria of inadequate response throughout prospective treatment. RESULTS: Brexpiprazole (n = 175) reduced mean MADRS total score versus placebo (n = 178) at week 6 in the efficacy population per final protocol (-8.36 vs -5.15, P = .0002). Brexpiprazole improved SDS mean score versus placebo (-1.35 vs -0.89, P = .0349). The most common treatment-related adverse events were weight gain (brexpiprazole, 8.0%; placebo, 3.1%) and akathisia (7.4% vs 1.0%). CONCLUSIONS: Adjunctive brexpiprazole therapy demonstrated efficacy and was well tolerated in patients with major depressive disorder and inadequate response to ADTs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01360645.

Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study.

OBJECTIVE: To evaluate efficacy, safety, and tolerability of brexpiprazole adjunctive to antidepressant treatments (ADTs) in patients with major depressive disorder (as defined by DSM-IV-TR criteria) with inadequate response to ADTs. METHOD: Patients still depressed despite 1-3 prior ADTs followed by 8 weeks of prospective physician-determined, open-label ADT were randomized (1:1:1) to double-blind brexpiprazole 3 mg/d, brexpiprazole 1 mg/d, or placebo for 6 weeks. The primary efficacy end point was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 6. The key secondary efficacy end point was change in Sheehan Disability Scale mean score. The Hochberg procedure corrected for multiplicity. The efficacy population comprised all patients who had ≥ 1 dose of study drug with baseline and ≥ 1 postrandomization MADRS scores; the efficacy population per final protocol consisted of efficacy population patients meeting amended criteria for inadequate response throughout the 8-week prospective ADT. The study was conducted between June 2011 and September 2013. RESULTS: In the efficacy population per final protocol, brexpiprazole 3 mg (n = 213) showed a greater improvement in MADRS total score versus placebo (n = 203; -8.29 vs -6.33; P = .0079), whereas brexpiprazole 1 mg did not (n = 211; -7.64 vs -6.33; P = .0737). The brexpiprazole groups showed comparable improvement in SDS mean score versus placebo (least squares [LS] mean difference: [1 mg] -0.49, P = .0158; [3 mg] -0.48, P = .0191). The most frequent adverse events were akathisia (4.4%, 13.5%, 2.3%), headache (9.3%, 6.1%, 7.7%), and weight increase (6.6%, 5.7%, 0.9%) in brexpiprazole 1-mg, 3-mg, and placebo groups, respectively. Mean changes from baseline in Abnormal Involuntary Movement Scale (LS mean difference = 0.08, P = .0141) and Barnes Akathisia Rating Scale (LS mean difference = 0.17, P = .0001) total scores were significantly greater with brexpiprazole 3 mg versus placebo. CONCLUSIONS: Brexpiprazole 3 mg demonstrated efficacy versus placebo in the efficacy population per final protocol. Both doses of brexpiprazole were well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01360632.

Investigation of a possible interaction between quetiapine and armodafinil in patients with schizophrenia: an open-label, multiple-dose study.

The wakefulness-promoting medication armodafinil (R-modafinil) is being studied as an adjunctive treatment for patients with schizophrenia receiving antipsychotic therapy. This open-label study in 37 adults with schizophrenia evaluated whether a drug-drug interaction occurs between armodafinil (a moderate CYP3A4 inducer) and the atypical antipsychotic quetiapine (primarily metabolized by CYP3A4). Patients were required to be on a stable dose of quetiapine ≥300 mg once daily in the evening before enrollment. Steady-state quetiapine pharmacokinetics were determined following daily administration of quetiapine alone in the evening (day 5) and then following concomitant armodafinil administration (titrated to 250 mg) daily in the morning (day 38). In 25 evaluable patients, concomitant armodafinil resulted in a statistically significant decrease in mean AUC(0-24) and C(max) values of quetiapine by 42% and 45%, respectively, versus quetiapine alone. Adverse events occurred more frequently with combination therapy and were consistent with the known profiles of the 2 drugs. No significant changes in mean PANSS negative, positive, and total scores or SANS scores were observed. Although the data do not suggest that the observed decrease in systemic exposure to quetiapine was associated with a change in disease state, patients with schizophrenia should be monitored during combination therapy with quetiapine and armodafinil.

Adjunctive armodafinil for negative symptoms in adults with schizophrenia: a double-blind, placebo-controlled study.

OBJECTIVE: A prior 4-week, proof-of-concept study suggested that adjunctive therapy with armodafinil 200mg/day decreases negative symptoms in patients with clinically stable schizophrenia. This study investigated the efficacy and tolerability of adjunctive armodafinil for treatment of negative symptoms in adults with schizophrenia receiving antipsychotic medications. METHODS: This parallel-group, 24-week study enrolled adults with schizophrenia who were receiving oral olanzapine, risperidone, or paliperidone for ≥ 6 weeks, and had a Positive and Negative Syndrome Scale (PANSS) negative symptom subscale score of ≥ 15. Patients received one of 3 doses of once-daily armodafinil (150 mg, 200mg, or 250 mg) or placebo. The primary efficacy measure was the change from baseline to final visit in the PANSS negative symptom subscale score. Secondary measures included the PANSS total score, Clinical Global Impression of Severity, Personal and Social Performance Scale, and CNSVitalSigns cognitive battery. RESULTS: Of 285 randomized patients, 213 received armodafinil and 72 received placebo. The mean (SD) changes in PANSS negative symptom subscale score were -1.9 (3.8) for armodafinil 150 mg (n = 70), -2.3 (3.6) for armodafinil 200mg (n = 69), -2.0 (3.3) for armodafinil 250 mg (n = 71), and -2.2 (4.1) for placebo (n=70) (p ≥ 0.70 for each armodafinil group versus placebo). Secondary measures were generally not different between groups. Armodafinil was generally well tolerated, without worsening positive symptoms. CONCLUSIONS: This study found no benefit of adjunctive armodafinil versus placebo for negative symptoms in patients with schizophrenia receiving treatment with olanzapine, risperidone, or paliperidone. Armodafinil was generally well tolerated in these patients.

Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of armodafinil, the longer-lasting isomer of modafinil, as adjunctive therapy in patients with schizophrenia. METHOD: This 4-week, randomized, double-blind, placebo-controlled, proof-of-concept study was conducted between July and December 2007. Patients had a history of stable schizophrenia (DSM-IV-TR criteria) for ≥ 8 weeks and were treated with oral risperidone, olanzapine, or paliperidone for ≥ 6 weeks at stable doses for ≥ 4 weeks. Patients were randomly assigned to once-daily placebo or armodafinil 50, 100, or 200 mg. The primary efficacy measure was the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery. Secondary outcome measures included the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessment of Negative Symptoms (SANS). RESULTS: Sixty patients were randomly assigned (15 in each group). No apparent differences between groups in the MATRICS composite score were observed (mean ± SD change from baseline to final visit: armodafinil 50 mg, 1.9 ± 6.22; 100 mg, 2.8 ± 7.98; 200 mg, 2.9 ± 4.72; placebo, 2.2 ± 5.06). The mean ± SD changes in PANSS total scores were -6.3 ± 7.25 for armodafinil 200 mg and -1.7 ± 4.89 for placebo at final visit (effect size=0.73; 95% CI, -0.08 to 1.54) and PANSS negative symptoms scores were -3.4 ± 2.07 and 0.1 ± 1.93 (effect size=1.69; 95% CI, 0.78 to 2.60), respectively. Although reductions in SANS total score were observed with both armodafinil and placebo at final visit, no between-group difference was shown. Armodafinil was generally well tolerated, with diarrhea and headache the most commonly reported adverse events. There was no evidence of worsening of psychosis with adjunctive armodafinil. CONCLUSIONS: In this 4-week study, adjunctive armodafinil was not associated with an improvement in cognitive measures, but armodafinil 200 mg/d appeared to mitigate the negative symptoms of schizophrenia. Treatment was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00487942.

Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study.

OBJECTIVE: To evaluate the efficacy and safety of armodafinil, the longer-lasting isomer of modafinil, when used adjunctively in patients with bipolar depression. METHOD: In this 8-week, multicenter, randomized, double-blind, placebo-controlled study conducted between June 2007 and December 2008, patients who were experiencing a major depressive episode associated with bipolar I disorder (according to DSM-IV-TR criteria) despite treatment with lithium, olanzapine, or valproic acid were randomly assigned to adjunctive armodafinil 150 mg/d (n = 128) or placebo (n = 129) administered once daily in the morning. The primary outcome measure was change from baseline in the total 30-item Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C30) score. Secondary outcomes included changes from baseline in scores on the Montgomery-Åsberg Depression Rating Scale, among other psychological symptom scales. Statistical analyses were performed using analysis of covariance (ANCOVA), with study drug and concurrent mood stabilizer treatment for bipolar disorder as factors and the corresponding baseline value as a covariate. A prespecified sensitivity analysis was done using analysis of variance (ANOVA) if a statistically significant treatment-by-baseline interaction was found. Tolerability was also assessed. RESULTS: A significant baseline-by-treatment interaction in the total IDS-C30 score (P = .08) was found. Patients administered adjunctive armodafinil showed greater improvement in depressive symptoms as seen in the greater mean ± SD change on the total IDS-C30 score (-15.8 ± 11.57) compared with the placebo group (-12.8 ± 12.54) (ANOVA: P = .044; ANCOVA: P = .074). No differences between treatment groups were observed in secondary outcomes. Adverse events reported more frequently in patients receiving adjunctive armodafinil were headache, diarrhea, and insomnia. Armodafinil was not associated with an increased incidence and/or severity of suicidality, depression, or mania or with changes in metabolic profile measurements. CONCLUSIONS: In this proof-of-concept study, adjunctive armodafinil 150 mg/d appeared to improve depressive symptoms according to some, but not all, measures and was generally well tolerated in patients with bipolar depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00481195.