Initiation of symptomatic medication in Alzheimer's disease clinical trials: Hypothetical versus treatment policy approach.

In clinical trials in populations with mild cognitive impairment, it is common for participants to initiate concurrent symptomatic medications for Alzheimer's disease after randomization to the experimental therapy. One strategy for addressing this occurrence is to exclude any observations that occur after the concurrent medication is initiated. The rationale for this approach is that these observations might reflect a symptomatic benefit of the concurrent medication that would adversely bias efficacy estimates for an effective experimental therapy.

Disease Modification in Alzheimer's Disease: Current Thinking.

Alzheimer's disease (AD) has increasingly been recognized as a huge unmet medical need. Currently, there is no approved drug to cure, prevent, or even slow down the disease. It is imperative to develop disease-modifying treatments for AD to alter the underlying disease progression.

A head-to-head comparison of the efficacy and safety of ixekizumab and adalimumab in biological-naïve patients with active psoriatic arthritis: 24-week results of a randomised, open-label, blinded-assessor trial.

Objectives: To compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological disease-modifying antirheumatic drug-naïve patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARDs).

Methods: Patients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI100).

Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease.

Background: Alzheimer's 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 Alzheimer's 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.

Statistical properties of continuous composite scales and implications for drug development.

Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite.

Assessing quality of life in Alzheimer's disease: Implications for clinical trials.

Introduction: Characterization of the quality of life (QOL) in Alzheimer's disease (AD) scale within the context of a clinical trial may inform its applicability in future trials.

Methods: Using data from 1322 patients enrolled in two phase-III studies (EXPEDITION 1 [NCT00905372] and 2 [NCT00904683]) of intravenous solanezumab in outpatients with mild AD dementia, correlations between patient- and caregiver-assessed QOL and between QOL and clinical outcome measures were examined. Longitudinal effects of solanezumab over 80 weeks were explored, controlling for patient and caregiver baseline characteristics.

Function and clinical meaningfulness of treatments for mild Alzheimer's disease.

Introduction: Effectiveness of Alzheimer's disease (AD) treatments is commonly evaluated with coprimary outcomes; cognition with function to ensure clinical meaningfulness of a cognitive effect.

Methods: We reviewed the literature for functional outcomes in mild AD or mild cognitive impairment (MCI) patients (distinct from combined mild-moderate/severe AD) treated with approved AD drugs. Cognitive and functional treatment differences in mild AD patients in solanezumab EXPEDITION/EXPEDITION2 studies were compared across time.

Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer's Disease.

Background: The temporal relationship of cognitive deficit and functional impairment in Alzheimer's disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression.

Objective: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials.

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

Introduction: 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 Alzheimer's disease (AD). Primary findings for both studies have been published.

Methods: Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed.

Delayed-start analysis: Mild Alzheimer's disease patients in solanezumab trials, 3.5 years.

Introduction: Solanezumab is an anti-amyloid monoclonal antibody in clinical testing for treatment of Alzheimer's disease (AD). Its mechanism suggests the possibility of slowing the progression of AD.

Methods: A possible disease-modifying effect of solanezumab was assessed using a new statistical method including noninferiority testing.

Alzheimer's disease progression by geographical region in a clinical trial setting.

Introduction: To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer's disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology.

Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer's disease clinical trials.

Introduction: Most Alzheimer's disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region.

Methods: We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI).

A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease.

One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period.

Cognitive and functional decline and their relationship in patients with mild Alzheimer's dementia.

Background: In patients with Alzheimer's disease (AD), the relationship between cognitive and functional progression is not fully understood; however, functional decline has been postulated to follow cognitive decline.

Objective: To assess the relationship between cognitive and functional treatment effects in mild AD dementia patients.

Methods: Data of patients with mild AD were pooled from two multicenter, double-blind, Phase 3 studies.

Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.

Background: Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain.

Methods: In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months.

Bone loss associated with hyperprolactinemia in patients with schizophrenia.

Background: Elevated prolactin (hyperprolactinemia) has been commonly reported during treatment with some antipsychotic drugs. A decrease in bone mineral density (BMD) may be related to elevated prolactin. The objective of this study was to determine the prevalence of low BMD in patients with schizophrenia treated with conventional antipsychotics or risperidone and to evaluate any potential relationship with treatment.

Change in level of productivity in the treatment of schizophrenia with olanzapine or other antipsychotics.

Background: When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia.

Factors associated with adherence to treatment with olanzapine and other atypical antipsychotic medications in patients with schizophrenia.

Objectives: Poor treatment response is an important factor contributing to lack of treatment adherence. The goals of this research were to determine whether improvements in Positive and Negative Syndrome Scale (PANSS) symptom domains predict the likelihood of staying on treatment and whether differential responses to treatment with various atypical antipsychotics in specific symptom domains account for differences in discontinuation rates or treatment adherence.

Methods: We conducted a post-hoc analysis of pooled data from 5 randomized, double-blind, 24- to 28-week clinical trials in 1103 olanzapine-treated and 1090 risperidone-, quetiapine-, ziprasidone-, or aripiprazole-treated adult patients with schizophrenia.

Patient perspectives on antipsychotic treatments and their association with clinical outcomes.

This analysis examined patient-reported attitudes toward antipsychotic medication and the relationship of these attitudes with clinical outcomes and pharmacotherapy adherence. The analysis included three randomized, double-blind studies in patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition and randomly assigned to treatment with olanzapine 5-20 mg/day or another antipsychotic (haloperidol 2-20 mg/day, risperidone 2-10 mg/day, or ziprasidone 80-160 mg/day). Patient-reported improvements were significantly greater for olanzapine (n = 488) versus other treatments (haloperidol n = 145, risperidone n = 158, or ziprasidone n = 271) on multiple Drug Attitude Inventory items.

A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee.

Objective: To evaluate the efficacy and safety of duloxetine in the treatment of chronic pain due to osteoarthritis of the knee.

Methods: This was a 13-week, randomized, double-blind, placebo-controlled trial in patients meeting American College of Rheumatology clinical and radiographic criteria for osteoarthritis of the knee. At baseline, patients were required to have a ≥ 4 weekly mean of the 24-hour average pain ratings.

Efficacy and safety of duloxetine in patients with chronic low back pain.

Study Design: This was a randomized, double-blind, placebo-controlled clinical trial.

Objective: To assess the efficacy and safety of duloxetine in the treatment of chronic low back pain (CLBP).

Summary Of Background Data: Imbalance of serotonin and norepinephrine within modulatory pain pathways has been implicated in the development and maintenance of chronic pain.

A closer look at the baseline-observation-carried-forward (BOCF).

Purpose: The baseline-observation-carried-forward (BOCF) approach is one method to handle missing data from early treatment discontinuation. We examined modifications of this approach, taking into consideration treatment-related and nontreatment-related reasons for discontinuation.

Methods: Two duloxetine chronic pain trials (placebo-controlled) were used to examine the impact of different analytical methods on study outcome.

Predictors of premature discontinuation of treatment in multiple disease states.

Background: Premature discontinuation of treatment impacts outcomes of clinical practice. The traditional perception has been patient discontinuation is mainly driven by unwanted side effects. Systematic analysis of data from clinical trials across several disease states was performed to identify predictors of premature discontinuation during clinical interventions.

Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial.

Pain is a common cause of disability in osteoarthritis. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has demonstrated analgesic effects in diabetic peripheral neuropathy and fibromyalgia. Considering its central mechanism of action, duloxetine may be effective in other pain states with evidence of central sensitization.