Stephen Kaplita

Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials

Aripiprazole is a novel antipsychotic with a unique mechanism of action. Presented here is a pooled analysis of safety and tolerability data from all completed short-term, placebo-controlled trials in schizophrenia from the aripiprazole clinical development program. Data were analyzed from five 4- to 6-week double-blind multicenter studies of patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder randomized to aripiprazole (n=932), placebo (n=416), or haloperidol (n=201). Daily aripiprazole doses ranged from 2 to 30 mg. Safety assessments included adverse event (AE) reports, EPS scales, ECGs, weight, and prolactin, glucose and cholesterol levels. Aripiprazole was well tolerated, with similar AE incidence rates to placebo, and lower rates than haloperidol for akathisia, extrapyramidal syndrome and somnolence. Objective EPS assessments demonstrated no significant differences between aripiprazole and placebo on Simpson-Angus Scale (SAS) scores, no dose-dependent effects on Barnes Akathisia scores, and significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores from baseline vs. placebo (p</=0.01). Haloperidol showed increased SAS and Barnes Akathisia scores over placebo (p</=0.01). There was minimal mean weight change with aripiprazole (+0.71 kg) and haloperidol (+0.56 kg), and a lack of QT(c) prolongation. Serum prolactin increased with haloperidol, but not aripiprazole. In conclusion, aripiprazole shows a favorable safety and tolerability profile with low potential for EPS, weight gain, prolactin elevation, QT(c) prolongation, and sedation. Aripiprazoles safety profile may offer benefits in schizophrenia treatment.

Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study.

This study compares the efficacy, safety, and tolerability of a partial dopamine agonist, aripiprazole, with placebo in the treatment of patients with bipolar I disorder experiencing an acute manic or mixed episode. In total, 272 hospitalized patients were randomized to aripiprazole 30mg/day or placebo in this 3-week, double-blind, placebo-controlled trial. Dosing could be reduced to 15mg/day for tolerability and, subsequently, increased to 30mg/day based on clinical response. Primary efficacy measure was mean change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score; response was defined as 50% decrease from baseline YMRS score. Aripiprazole-treated patients demonstrated significantly greater improvement from baseline to endpoint in mean YMRS total scores compared with placebo-treated patients as early as Day 4 and sustained through Week 3. A significantly higher response rate was observed in aripiprazole-treated patients (53% vs. 32% at endpoint). Aripiprazole produced significantly greater improvements from baseline on other efficacy assessments compared with placebo, including Clinical Global Impression – Bipolar Version Severity and Improvement scores. The 30mg/day dose was maintained by 85% of aripiprazole-treated patients. Incidence of discontinuations due to adverse events was similar for aripiprazole (8.8%) and placebo (7.5%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight and was not associated with elevated serum prolactin or QTc prolongation. In conclusion, aripiprazole demonstrated superior efficacy to placebo in the treatment of patients with bipolar I disorder presenting with acute manic or mixed episodes, and exhibited a favourable safety and tolerability profile.

Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder

BACKGROUND Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep. METHODS This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone (n = 64) with fluoxetine (n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1-4, 6, and 8. RESULTS Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine. CONCLUSIONS Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

Double-blind, placebo-substitution study of nefazodone in the prevention of relapse during continuation treatment of outpatients with major depression.

The efficacy of nefazodone in prevention of relapse of depression was evaluated in a 36-week double-blind, placebo-substitution, continuation treatment trial. After 16 weeks of acute, single-blind treatment with nefazodone, 131 patients responding to treatment and in stable remission were randomized in a 36-week double-blind trial to either nefazodone (n = 65) or placebo (n = 66). Patients were defined as having relapsed if they had a total score > or = 18 on the 17-item Hamilton Depression Scale on two consecutive visits or if they discontinued treatment for lack of efficacy. Relapse rates were significantly lower for patients randomized to continued nefazodone treatment than for patients switched to placebo. Kaplan-Meier estimates of relapse rates 9 months (36 weeks) after the end of acute treatment were 1.8% for nefazodone versus 18.3% for placebo (P = 0.009) by the Hamilton Depression Scale and 17.3% versus 32.8% (P = 0.028) by discontinuation for lack of efficacy. The mean modal dose of nefazodone was 412 mg/day at study endpoint. These results demonstrate the clinical effectiveness of up to 1 years treatment (16 weeks acute and 36 weeks continuation) with nefazodone in depressed patients. Long-term efficacy of nefazodone was accompanied by a good safety profile without any weight gain and with minimal symptoms of withdrawal upon abrupt discontinuation of treatment.

Targeting prodromal Alzheimer disease with avagacestat: A randomized clinical trial

IMPORTANCE Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms. OBJECTIVES To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia. DESIGN, SETTING, AND PARTICIPANTS A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity. INTERVENTIONS Oral avagacestat or placebo daily. MAIN OUTCOMES AND MEASURE Safety and tolerability of avagacestat. RESULTS Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures. CONCLUSIONS AND RELEVANCE Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00890890.

Baseline clinical scores and volumetric MRI parameters across subjects randomized in mild-to-moderate (BMS CN156-013) and predementia (BMS CN156-018) Alzheimer's disease clinical trials of avagacestat

the safety and tolerability of avagacestat in patients with PDAD. Key entry criteria for subjects included: memory complaints documented by subject or study partner, objective memory loss on the Wechsler Memory Scale Logical Memory II or the Free & Cued Selective Reminding Test, a CDR-global score of 0.5 with a memory box score of 0.5, and a MMSE of 24-30. Entry criteria required that subjects not meet DSM-IV criteria for dementia, and their MRI findings show no alternative cause for cognitive impairment. After meeting all key criteria, subjects underwent lumbar puncture and were included if their CSF amyloid-beta42 levels < 200pg/mL or total tau/amyloid-beta42 ratio of 0.39. Co-medication with a stable dose of a marketed cholinesterase inhibitor or memantine was permitted. Results: Randomization completed in September 2011, approximately 24 months after first patient visit. Of 1350 subjects enrolled at 72 centers in North America and Europe; 263 (19%) were randomized. Nearly 800 enrolled subjects (approximately 60%) were excluded prior to CSF testing due to clinical criteria. Of nearly 550 subjects whomet the clinical inclusion criteria and completed the lumbar puncture, approximately one-half met the CSF biomarker criteria for study entry. There were 104 subjects who met entry requirements except the CSF criteria, whowere enrolled into a nonrandomized observational cohort. The major reasons for exclusion were cognitive criteria, abnormal laboratory tests, meeting dementia criteria, compliance to protocol issues, MRI findings, or concurrent medications. Conclusions: The recruitment of this study population of subjects with PDAD demonstrates both the feasibility and challenges of trials, which require both clinical phenotypic features as well as CSF criteria. Efforts are warranted to refine entry criteria and decrease screen failures.

Cerebral microbleeds in a phase 2 clinical trial of mild-to-moderate Alzheimer's disease with the gamma secretase inhibitor BMS-708163

three cohorts (equal sample size) according to their rates of change in ADAS-Cog total scores. Patients with most positive rates of change in ADAS-cog total scores (i.e., worsening) showed significantly more rapid hippocampal atrophy as compared with to patients that showed the most negative rates of change in ADAS-Cog total scores (i.e., improving), and patients with intermediate, near-zero, rates of change in ADAS-cog total scores (i.e., stable) (trend). Conclusions: The rate of hippocampal degeneration may be altered in DAT patients who respond to treatment with memantine or donepezil as compared to patients who are treated with these drugs but who do not respond. However, we were not able to detect drug-specific changes in hippocampal degeneration. Cognitive improvement and slowing of disease progression in AD as a result of drug treatment may be dependent upon neuroanatomical factors that influence who will respond to treatment. Improving our understanding of these factors way lead to the development of more effective therapies.