Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer's disease.

INTRODUCTION: Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid ß and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI). METHODS: In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants. RESULTS: Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3-6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously. DISCUSSION: In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.

Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: findings from the phase 3 trials (SAMURAI and SPARTAN).

BACKGROUND: We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. METHODS: SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan. RESULTS: The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo. CONCLUSIONS: A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo. TRIAL REGISTRATION: SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].

Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine.

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia.

INTRODUCTION: Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid ß (Aß)1-40 and Aß1-42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aß isoforms and their relationship with solanezumab exposure. METHODS: CSF Aß isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3. RESULTS: Solanezumab produced statistically significant increases in CSF total Aß isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free Aß isoforms were observed. Solanezumab penetration into the central nervous system was low. DISCUSSION: Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aß concentrations.

Florbetapir F18 PET Amyloid Neuroimaging and Characteristics in Patients With Mild and Moderate Alzheimer Dementia.

BACKGROUND: Clinical diagnosis of Alzheimer disease (AD) is challenging, with a 70.9%-87.3% sensitivity and 44.3%-70.8% specificity, compared with autopsy diagnosis. Florbetapir F18 positron emission tomography (FBP-PET) estimates beta-amyloid plaque density antemortem. METHODS: Of 2052 patients (≥55 years old) clinically diagnosed with mild or moderate AD dementia from 2 solanezumab clinical trials, 390 opted to participate in a FBP-PET study addendum. We analyzed baseline prerandomization characteristics. RESULTS: A total of 22.4% had negative FBP-PET scans, whereas 72.5% of mild and 86.9% of moderate AD patients had positive results. No baseline clinical variable reliably differentiated negative from positive FBP-PET scan groups. CONCLUSIONS: These data confirm the challenges of correctly diagnosing AD without using biomarkers. FBP-PET can aid AD dementia differential diagnosis by detecting amyloid pathology antemortem, even when the diagnosis of AD is made by expert clinicians.

A pooled analysis of injection site-related adverse events in patients with schizophrenia treated with olanzapine long-acting injection.

BACKGROUND: Depot antipsychotic injections are an important tool for the management of patients with schizophrenia who have difficulty with adherence to oral medication. However, pain and discomfort at the injection site can be a potential impediment to the use of these long-acting formulations. We report here the results of a pooled analysis of injection site-related adverse events (AEs) collected during treatment with the olanzapine long-acting injection (olanzapine LAI). METHODS: Unsolicited injection site-related AEs were pooled from 7 olanzapine LAI clinical trials conducted in patients between March 2001 and December 2010. All patients had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of schizophrenia or schizoaffective disorder and were between the ages of 18 and 75. Doses ranged from 45 to 405 mg olanzapine LAI, and injection intervals were 2, 3, or 4 weeks. Events were evaluated for severity, timing, possible risk factors, and outcome. A criterion of p < .05 for statistical significance was used for all tests. RESULTS: A total of 1752 patients received at least 1 olanzapine LAI injection. Of these, 92 patients (5.3%) reported at least 1 injection site-related AE, with "pain" being the most common type (2.9%). Most events were mild (81.4%) and the median duration was 3 days. Four patients (0.2%) discontinued due to injection site-related AEs. Dose volume and body mass index did not appear to affect the probability of injection site-related AEs. However, patients who experienced a post-injection delirium/sedation syndrome event (n = 37) were more likely to have or have had an injection site-related AE at some time during the study. Incidence of injection site-related AEs appeared to decrease over time. In 94.2% of the injection site-related AEs, no specific treatment or concomitant medication was reported; in 9 cases, patients received pharmacologic treatment for reaction, mass, abscess, rash, or pain. CONCLUSIONS: Injection site-related AEs with olanzapine LAI were generally mild. The incidence and nature of these injection site-related AEs were generally similar to those occurring during treatment with other injectable antipsychotics. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Real-world use patterns of olanzapine long-acting injection in the United States: comparison to the recommended dosing strategy.

OBJECTIVE: Recommended doses for olanzapine long-acting injection (olanzapine LAI) are 150 mg/2 weeks, 210 mg/2 weeks, 300 mg/2 or 4 weeks, and 405 mg/4 weeks. This analysis evaluated the dosing and interval patterns to compare the actual dosing patterns with the recommended dosing strategy. RESEARCH DESIGN AND METHODS: These data, from March 2010 through September 2011, were collected as part of a Risk Evaluation and Mitigation Strategy mandatory patient registry that captures all post-approval olanzapine injections in the US. This registry includes both active and inactive (60 + days since last injection) patients. RESULTS: All patients with at least one olanzapine injection were included (n = 1694). The mean number of injections received was 6.6 (range of 1-40). The most frequent numbers of injections were one (26.3%) and two (12.9%). For the 11,228 olanzapine injections, the most common doses were 300 mg and 405 mg, accounting for 92.9% of injections. Although the most common time intervals between injections was about 14 days for 150 mg, 210 mg, and 300 mg, and about 28 days for 405 mg, the intervals ranged from less than 10 to more than 60 days for all doses. Among active patients (48.2% of registry), 68.2% had >120 days of treatment with any dose, and the number of days since the last injection was around 2 weeks or less for 61.2% of patients, around 3 weeks for 16.5% of patients, and around 4 weeks for 7.1% of patients. Among inactive patients (51.8% of registry), 48.6% had <30 days of treatment. For the pattern of the first five injections, most patients (70.9%) received four subsequent injections of the same dose as their initial injection. CONCLUSIONS: This registry will continue to change. There is a broad range in time between injections. Most patients continue to receive the same initial dose instead of switching to a maintenance dose. This may suggest that some clinicians are not reassessing the dose after the initial starting dose because the patient was stabilized on olanzapine oral before beginning olanzapine long-acting injection. The study is limited by a database that does not include reasons for dose and dosing interval decisions or reasons for delaying or discontinuing treatment.

Effects of olanzapine long-acting injection on levels of functioning among acutely ill patients with schizophrenia.

OBJECTIVE: To assess the effects of olanzapine long-acting injection (olanzapine-LAI) on levels of functioning in acutely ill patients with schizophrenia. RESEARCH DESIGN AND METHODS: During this 8-week randomized, double-blind, placebo-controlled trial, 404 inpatients were randomized to four treatment arms (olanzapine-LAI 210 mg/2 weeks = 106; olanzapine-LAI 300 mg/2 weeks = 100; olanzapine-LAI 405 mg/4 weeks = 100; placebo = 98). Also, data from the three active dosing arms were combined and compared to placebo data. CLINICAL TRIAL REGISTRATION: NCT00088478. MAIN OUTCOME MEASURES: The treatment group comparison of mean change from baseline to endpoint in the total score and four subdomains of the Heinrichs-Carpenter Quality of Life Scale (QLS) and in the 2 summary scores and 8 subscale scores of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were assessed using an ANOVA model. RESULTS: All three olanzapine-LAI treatment groups and the combined olanzapine-LAI group were superior to placebo on the QLS total score (all p-values < 0.01) and the Intrapsychic Foundations subdomain (all p-values < 0.02). Olanzapine-LAI 210 mg/2 weeks (p < 0.001), 300 mg/2 weeks (p = 0.006), and the combined olanzapine-LAI group (p = 0.003) were superior to placebo on the Interpersonal Relations subdomain. The 300 mg/2 weeks group (p = 0.027) and the combined olanzapine-LAI group (p = 0.014) were also superior to placebo on the Instrumental Role subdomain. For the SF-36, the 300 mg/2 weeks and 405 mg/4 weeks olanzapine-LAI groups and the combined olanzapine-LAI group were superior to placebo on the Mental component score (all p-values < 0.05). Each olanzapine-LAI group and the combined group were superior on the Mental Health scale (all p-values < 0.05). Significant negative correlations between PANSS scores and measures of functioning indicate that as symptoms decreased, functioning increased. CONCLUSION: These results suggest that olanzapine-LAI may improve level of functioning in acutely ill patients with schizophrenia within 8 weeks of initiating treatment.

Reasons for continuing or discontinuing olanzapine in the treatment of schizophrenia from the perspectives of patients and clinicians.

BACKGROUND: The aim of this study was to assess the reasons for discontinuing or continuing olanzapine in patients with schizophrenia, from the perspectives of the patients and their clinicians. METHODS: The Reasons for Antipsychotic Discontinuation/Continuation (RAD) is a pair of questionnaires assessing these reasons from the perspectives of patients and their clinicians. Outpatients with schizophrenia (n = 199) who were not acutely ill participated in a 22-week open-label study of olanzapine from November 2006 to September 2008. Reasons for continuing or discontinuing olanzapine (on a five-point scale), along with the single most important reason and the top primary reasons, were identified. Concordance between reasons given by patients and clinicians was assessed. RESULTS: The top primary reasons for continuing olanzapine were patients' perceptions of improvement, improvement of positive symptoms, and improved functioning. The study discontinuation rate was low (30.2%), and only a subset of patients who discontinued reported reasons for medication discontinuation. The top primary reasons for discontinuing olanzapine were insufficient improvement or worsening of positive symptoms, adverse events, and insufficient improvement or worsening of negative symptoms. Ratings given by patients and clinicians were highly concordant. CONCLUSION: The main reason for continuing or discontinuing olanzapine appears to be medication efficacy, especially for positive symptoms. Reasons for medication discontinuation differ somewhat from reasons for continuation, with a high level of concordance between patient and clinician responses.

A 24-week open-label extension study of olanzapine-fluoxetine combination and olanzapine monotherapy in the treatment of bipolar depression.

OBJECTIVE: Olanzapine-fluoxetine combination has shown efficacy in the acute treatment of depressive episodes in patients with bipolar I disorder. The present analyses examined the efficacy and safety of longer term treatment with olanzapine-fluoxetine combination or olanzapine monotherapy in a 6-month open-label extension study. METHOD: 376 patients with DSM-IV bipolar I disorder, depressed, who completed an acute trial entered the open-label study and received 1 week of olanzapine monotherapy (5-20 mg/day). At all subsequent visits, patients could choose between olanzapine monotherapy or olanzapine-fluoxetine combination (6/25, 6/50, or 12/50 mg/day). Three treatment groups were defined retrospectively according to the medication course taken from week 1: olanzapine, olanzapine-fluoxetine combination, or switched. The efficacy measures were the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Bipolar Version, and Young Mania Rating Scale. The study was conducted from July 2000 to May 2002. RESULTS: Among patients who started in remission, MADRS total scores did not change significantly from baseline to endpoint in the olanzapine-fluoxetine combination (0.8) or olanzapine (0.3) groups, but increased slightly in the switched (2.3, p = .02) group. For patients who started in nonremission, MADRS total scores decreased significantly in all groups (olanzapine-fluoxetine combination: -5.7, p = .001; olanzapine: -11.6, p = .004; switched: -6.4, p = .015). The majority of patients who entered the study in nonremission achieved remission (MADRS total score < or = 12) during the trial (olanzapine-fluoxetine combination: 66.7%, olanzapine: 64.7%, switched: 62.5%). The overall rate of depressive relapse was 27.4%, and the overall incidence of mania emergence was 5.9%. CONCLUSIONS: The present findings suggest that long-term treatment with olanzapine-fluoxetine combination may be a useful option for the management of depressive symptoms and carries a low risk of mania emergence.