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. We interrogate the assumptions underlying such an approach by estimating the effect of newly prescribed concurrent medications in an observational study, the Alzheimer's Disease Neuroimaging Initiative.

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. This paper reviews the most up-to-date regulatory guidance on how to demonstrate disease modification and provides an overview of available methodologies and applications to clinical trials. The intent is to assist the field with future clinical trials designed to demonstrate disease-modifying effect in AD. The methodologies may be generalizable to broader neurodegenerative diseases.

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). Major secondary objectives, also at week 24, were to evaluate whether IXE was: (1) non-inferior to ADA for achievement of ACR50 and (2) superior to ADA for PASI100 response. Additional PsA, skin, treat-to-target and quality-of-life outcome measures were assessed at week 24. RESULTS: The primary efficacy endpoint was met (IXE: 36%, ADA: 28%; p=0.036). IXE was non-inferior for ACR50 response (IXE: 51%, ADA: 47%; treatment difference: 3.9%) and superior for PASI100 response (IXE: 60%, ADA: 47%; p=0.001). IXE had greater response versus ADA in additional PsA, skin, nail, treat-to-target and quality-of-life outcomes. Serious adverse events were reported in 8.5% (ADA) and 3.5% (IXE) of patients. CONCLUSIONS: IXE was superior to ADA in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to csDMARDs. Safety and tolerability for both biologicals were aligned with established safety profiles.

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

BACKGROUND: Alzheimer's disease is characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aß, 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 Aß1-42 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 Alzheimer's 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 Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).

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. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer's disease (AD) clinical studies of solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.

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. RESULTS: Caregivers rated patients' QOL worse than did patients themselves. Patients' QOL was correlated, albeit modestly, with clinical/health measures. Patients' QOL changed minimally over 80 weeks, although a treatment effect of solanezumab on QOL was detected. DISCUSSION: Further investigations are needed to determine the optimal measures with which to quantify and qualify QOL of patients with mild AD.

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. RESULTS: Seven publications provided MCI/mild AD functional outcomes, one of which reported a significant functional treatment effect. Secondary analyses of EXPEDITION studies suggested a smaller functional effect of solanezumab relative to cognition. An increasing effect of solanezumab over 18 months was shown for cognition and function. DISCUSSION: Function as the sole measure to demonstrate clinical meaningfulness of cognitive effects in mild AD may have limitations. For disease-modifying treatments, point differences on cognitive and functional scales should be qualified with duration of treatment.

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-ß 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. RESULTS: In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. DISCUSSION: These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population.

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. METHODS: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. RESULTS: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. CONCLUSIONS: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process.

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. METHODS: Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI). RESULTS: Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline. CONCLUSIONS: These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00594568 - IDENTITY. Registered 11 January 2008. ClinicalTrials.gov NCT00762411 - IDENTITY2. Registered 26 September 2008 ClinicalTrials.gov NCT00905372 - EXPEDITION. Registered 18 May 2009 ClinicalTrials.gov NCT00904683 - EXPEDITION2. Registered 18 May 2009.