Michael Case

Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients

EXPEDITION and EXPEDITION2 were identically designed placebo‐controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid‐β peptide, on cognitive and functional decline over 80 weeks in patients with mild‐to‐moderate Alzheimers disease (AD). Primary findings for both studies have been published.

Comparison of neuroimaging modalities for the prediction of conversion from mild cognitive impairment to Alzheimer's dementia.

In this study we compared Pittsburgh compound-B (PIB) positron emission tomography (PET) amyloid imaging, fluorodeoxyglucose PET for metabolism, and magnetic resonance imaging (MRI) for structure to predict conversion from amnestic mild cognitive impairment (MCI) to Alzheimers dementia using data from the Alzheimers Disease Neuroimaging Initiative cohort. Numeric neuroimaging variables generated by the Alzheimers Disease Neuroimaging Initiative-funded laboratories for each neuroimaging modality along with apolipoprotein-E genotype (n = 29) were analyzed. Performance of these biomarkers for predicting conversion from MCI to Alzheimers dementia at 2 years was evaluated in 50 late amnestic MCI subjects, 20 of whom converted. Multivariate modeling found that among individual modalities, MRI had the highest predictive accuracy (67%) which increased by 9% to 76% when combined with PIB-PET, producing the highest accuracy among any biomarker combination. Individually, PIB-PET generated the best sensitivity, and fluorodeoxyglucose PET had the lowest. Among individual brain regions, the temporal cortex was found to be most predictive for MRI and PIB-PET.

Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression

BACKGROUND Atypical antipsychotics are widely used in bipolar mania. However, the efficacy of atypical antipsychotics in bipolar depression has not been comprehensively explored. AIMS To evaluate olanzapine monotherapy in patients with bipolar depression. METHOD Patients with bipolar depression received olanzapine (5-20 mg/day, n = 343) or placebo (n = 171) for 6 weeks. The primary outcome was change from baseline to end-point in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary outcomes included: Clinical Global Impression - Bipolar Version (CGI-BP) scale, 17-item Hamilton Rating Scale for Depression (HRSD-17) and Young Mania Rating Scale (YMRS) scores, and the rate of response (≥50% reduction in MADRS at end-point), recovery (MADRS ≤12 for ≥4 weeks plus treatment completion) and remission (MADRS ≤8). The trial was registered with ClinicalTrials.gov (NCT00510146). RESULTS Olanzapine demonstrated: significantly greater (P<0.04) improvements on MADRS (least-squares mean change -13.82 v. -11.67), HRSD-17 and YMRS total scores and all CGI-BP subscale scores v. placebo; significantly (P≤0.05) more response and remission, but not recovery; significantly (P<0.01) greater mean increases in weight, fasting cholesterol and triglycerides; and significantly more (P<0.001) patients gained ≥7% body weight. CONCLUSIONS Olanzapine monotherapy appears to be efficacious in bipolar depression. Additional long-term studies are warranted to confirm these results. Safety findings were consistent with the known safety profile of olanzapine.

Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

BACKGROUND Alzheimers disease is characterized by amyloid‐beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double‐blind, placebo‐controlled, phase 3 trial involving patients with mild dementia due to Alzheimers disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron‐emission tomography or Aβ1‐42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14‐item cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS‐cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS‐cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between‐group difference at week 80 (difference, ‐0.80; 95% confidence interval, ‐1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was ‐3.17 in the solanezumab group and ‐3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimers disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665.)

Early response to antipsychotic therapy as a clinical marker of subsequent response in the treatment of patients with first-episode psychosis.

Early response to antipsychotic medication has been shown to accurately predict later response to continued use of the same treatment in patients with chronic schizophrenia. This study examines whether this predictive pattern exists for patients with first-episode psychosis. We used a data-driven threshold for early response of ≥ 26.2% improvement from baseline on the Positive and Negative Syndrome Scale (PANSS(0-6)) Total score to determine whether response at Week 2 of treatment may predict response at Week 12 in a randomized, double-blind trial of olanzapine versus haloperidol for treatment of patients with first-episode psychosis (N=225). Later response was defined as a ≥ 40% and ≥ 50% improvement in PANSS Total(0-6) score and as remission. At Week 2, 43% (97/225) of patients were identified as early responders. At a threshold for later response of ≥ 50% improvement in PANSS(0-6) Total score, early non-response most strongly predicted later non-response, demonstrating high specificity (74%) and high negative predictive value (80%). As had been seen in the treatment of patients with chronic schizophrenia, early non-response was a robust predictor of subsequent non-response in the treatment of patients with first-episode psychosis.

Olanzapine/Fluoxetine Combination in Patients With Treatment-Resistant Depression: Rapid Onset of Therapeutic Response and Its Predictive Value for Subsequent Overall Response in a Pooled Analysis of 5 Studies

OBJECTIVE To characterize response profiles of olanzapine/fluoxetine combination therapy in treatment-resistant depression (TRD) and to investigate predictive relationships of early improvement with olanzapine/fluoxetine combination for subsequent response/remission during the acute phase of treatment. METHOD Results were pooled from 5 outpatient studies comparing oral olanzapine/fluoxetine combination, fluoxetine, or olanzapine for a maximum of 8 weeks in patients with TRD who had at least 1 historical antidepressant treatment failure during the current episode and who failed a prospective antidepressant therapy during the study lead-in period. Mean Montgomery-Asberg Depression Rating Scale (MADRS) total and core mood items scores from the 8-week evaluation period were compared across treatment groups. Positive and negative predictive values (PPVs, NPVs) were computed from olanzapine/fluoxetine combination-treated patients demonstrating response and remission based on whether they demonstrated early improvement. RESULTS Mean olanzapine/fluoxetine combination MADRS score reductions were significantly greater than fluoxetine by week 0.5 and olanzapine by week 1. Significantly more olanzapine/fluoxetine combination patients demonstrated MADRS onset of response compared with fluoxetine and olanzapine patients (P < .001 for both MADRS total and core mood items). In olanzapine/fluoxetine combination patients, 38.1% exhibited MADRS total score response versus 26.9% of fluoxetine patients (P < .001) and 22.2% of olanzapine patients (P < .001). NPVs for MADRS total and core mood items response and remission ranged from 85.7% to 92.1%; PPVs ranged from 29.9% to 45.1%. CONCLUSIONS Olanzapine/fluoxetine combination is superior to fluoxetine and olanzapine in producing early improvement in patients with TRD. The absence of early improvement is highly predictive for overall response failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00035321.

Trajectories of response to treatment with atypical antipsychotic medication in patients with schizophrenia pooled from 6 double-blind, randomized clinical trials

Research has identified distinct trajectories of antipsychotic response in patients with chronic schizophrenia in short-duration trials (~12 weeks). This post-hoc analysis identified trajectories in patients with chronic schizophrenia treated for ≤24 weeks. We pooled data from 1990 patients with chronic schizophrenia from 6 randomized, double-blind, olanzapine-comparator trials of atypical antipsychotics. Trajectory analysis identified homogeneous subpopulations within the larger heterogeneous population. Baseline demographics were compared between the identified latent classes. Five distinct response trajectories based on Positive and Negative Syndrome Scale (PANSS) Total score were identified: Dramatic Responders (n=47/1990, 2.4%), severely-ill patients (PANSS=124) with rapid and sustained improvement (51%) by Week 3; Partial Responders (n=1802/1990, 90.6%), moderately-ill (PANSS=90) with minimal improvement (21%) by Week 4, and little further improvement; Partial Responders-Unsustained (Late) (n=32/1990, 1.6%), markedly-ill (PANSS=95) with minimal initial improvement followed by worsening after Week 12; Partial Responders-Unsustained (Early) (n=28/1990, 1.4%), markedly-ill (PANSS=102) with minimal initial improvement followed by worsening after Week 8; and Delayed Responders (n=81/1990, 4.1%), markedly-to-severely-ill (PANSS=113) with minimal (11%) improvement at Week 8, but noticeable improvement thereafter (49%). Significant differences were noted for several baseline characteristics (p<.05) and discontinuation rates (46%-72%). Dramatic Responders were younger and more likely to be female and Hispanic with higher baseline illness severity. Analysis of antipsychotic response over 24 weeks in a large, pooled, heterogeneous population treated for schizophrenia revealed 5 distinct trajectories. Most patients had modest and sustained improvements during atypical antipsychotic treatment, regardless of their baseline illness severity, representing a partial response to currently available treatments.

Treatment response trajectories and their antecedents in recent-onset psychosis: a 2-year prospective study.

Background: The extent of heterogeneity in antipsychotic treatment response for over extended period is unclear. This study aimed to quantify treatment response trajectories and their characteristics up to 2 years in recent-onset psychosis. Method: Participants were from a double-blind randomized controlled trial of recent-episode psychosis (N = 263). Recurrent Positive and Negative Syndrome Scale (PANSS) administrations were used to index treatment response trajectories for up to 2 years. Trajectories were calculated with mixed-mode latent class regression modeling from which groups were derived. Group differences were examined on sex, age of first admission, duration of untreated psychosis, premorbid functioning, diagnoses of substance abuse and schizophrenia, and cognitive functioning. Results: Five trajectories based on PANSS total scores were identified at 2 years. In the trajectory group (23.1%) with the most improvement, approximately 62% met the PANSS 30% change criteria. Logistic regression modeling indicated that membership in the trajectory with the most improvement was significantly (P < 0.05) predicted by absence of a diagnosis of schizophrenia, better premorbid functioning, and higher cognitive scores. Membership in the trajectory with the least improvement was significantly predicted by higher PANSS baseline scores. Conclusions: Based on clinical trial data, treatment response in early episode psychosis seems to be characterized by amelioration and ongoing change. Premorbid functioning, cognitive functioning, and early symptom severity have prognostic value in predicting treatment response trajectories. Across trajectory studies, approximately 16% of patients experience a dramatic treatment response trajectory characterized by approximately a 60% to 80% symptom reduction.

Assessment of Treatment Algorithms Including Amantadine, Metformin, and Zonisamide for the Prevention of Weight Gain With Olanzapine: A Randomized Controlled Open-Label Study

OBJECTIVE This 22-week, open-label study, conducted between November 2006 and September 2008 in a community setting, was designed to determine if weight gain during olanzapine treatment can be prevented or mitigated with adjunctive treatment algorithms that include amantadine, metformin, and zonisamide. METHOD Outpatients with schizophrenia or schizoaffective disorder (DSM-IV-TR criteria) were randomly assigned to olanzapine alone (n = 50), olanzapine plus algorithm A (olanzapine + A [amantadine 200 mg/d with possible switches to metformin 1,000-1,500 mg/d and then to zonisamide 100-400 mg/d; n = 76]), or olanzapine plus algorithm B (olanzapine + B [metformin 1,000-1,500 mg/d with possible switches to amantadine 200 mg/d and then to zonisamide 100-400 mg/d; n = 73]). Brief weight management education was provided at baseline. The primary outcome measure was comparison of mean weight gain between olanzapine and pooled olanzapine + A and olanzapine + B results. RESULTS Least squares mean ± SE weight gain was 2.76 ± 0.75 kg for olanzapine, 2.40 ± 0.65 kg for olanzapine + A, and 0.65 ± 0.63 kg for olanzapine + B. Mean weight gain during olanzapine treatment did not differ significantly from pooled results for olanzapine + A and olanzapine + B (P = .065). Participants treated with olanzapine + B experienced significantly less mean weight gain than olanzapine-treated participants (P = .036). CONCLUSIONS Pooled treatment algorithm results were not significantly different from olanzapine monotherapy in mitigating weight gain. However, participants who received treatment with metformin with possible progression to amantadine and then zonisamide had significantly less mean weight gain than participants treated with olanzapine alone. Progression of some participants through the algorithm indicated that a single therapy solution may not be adequate for every patient. Patients treated with olanzapine should receive regular weight monitoring. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00401973.

Early symptom change and prediction of subsequent remission with olanzapine augmentation in divalproex-resistant bipolar mixed episodes

Potential predictors of remission in mixed bipolar I disorder were identified using early Clinical Global Impression-Severity (CGI-S) improvement criteria in divalproex-resistant patients randomized to olanzapine augmentation (olanzapine + divalproex; N = 101) in a 6-week, double-blind, placebo-controlled trial. In a post-hoc analysis, receiver operating characteristics of 1-point decreases in the CGI-S total score after 2, 4, 7, and 14 days were examined as predictors of endpoint (Week 6 or last observation) remission of depression and/or mania as defined by 21-item Hamilton Depression Rating Scale (HDRS-21) and Young Mania Rating Scale (YMRS) total score ≤8. Based on a 1-point improvement in CGI-S as a predictor of remission, all odds ratios (ORs) and 95% confidence intervals (CIs) were statistically significant for depression or mania remission criteria. ORs for mixed symptom remission with a decrease ≥1 in CGI-S scores at Day 2 for olanzapine augmentation were (6.727; CI: 2.382, 18.997; p < .001) with negative predictive value = 89.5% and positive predictive value = 44.2%. Changes in HDRS-21 and YMRS individual item scores after 2 days of augmentation as predictors of endpoint remission identified that decreases in HDRS-21 symptom item scores (early, middle, and/or late insomnia; paranoid; agitation; and somatic/gastrointestinal) predicted depressive symptom remission at endpoint, and decreases in YMRS item scores (language-thought disorder and irritability) were associated with manic symptom remission at endpoint. Because remission with augmentation therapy may occur in as few as one in ten individuals who lack very early symptom reduction, lack of early improvement may indicate a need to expediently reassess treatment strategy.