Over 200 publications, including the composite endpoints regulators now recognize. We publish our methodology in the open so reviewers meet it before your submission does.
Alzheimer's Association International Conference (AAIC) · 2024:Poster Tue-17 · Hendrix, Dickson et al.
Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer's disease (AD) clinical trials. Successful trials are reliable…
When the sample size a conventional design demands is larger than the trial you can run, a Global Statistical Test lets the clinical-endpoint hypotheses be tested anyway. The paper sets out when GST applies, how it is pre-specified, and how it has been received in review.
12 publications
Sorted newest first
2013 · The American Journal of Geriatric Psychiatry
Introduction: In Alzheimer’s disease (AD), significant behavioral symptoms are associated with patient distress, caregiver burden, admission to long-term care facilities, and use of psychotropic medications. Because of safety risks involved with antipsychotic use in this patient population, evaluating the efficacy of antidementia drugs on behavioral symptoms is of great interest. A new, extended-release (ER) formulation of memantine (28 mg, once daily) has been approved in the US, based upon the results of a 24-week, multinational, randomized, placebo-controlled trial (MEM-MD-50, NCT00322153) in patients with moderate to severe AD concurrently taking a cholinesterase inhibitor (placebo, n¼335; memantine, n¼342). In that trial, memantine ER treatment was associated with significant benefits compared with placebo on multiple outcome measures, including the Neuropsychiatric Inventory (NPI), a scale designed to assess behavioral symptoms in AD. Here we report results from a post hoc analysis of that trial, in which we assessed the behavioral effects memantine ER as a function of patients’ disease severity at Baseline, as determined using the Mini Mental State Examination (MMSE). Methods: Patients (observed cases; N¼540) were divided into 14 subgroups, corresponding to Baseline MMSE scores (range: 4-17). Baseline-to-Endpoint (Week 24) changes for memantine ER and placebo groups were assessed for each subgroup using a mixed-effects model with repeated measures, with the Baseline MMSE score as a linear covariate; sensitivity analyses were conducted using a quadratic model and a separate means model. Due to the exploratory nature of this analysis, no corrections for multiple hypothesis testing were performed. Results: At Week 24, memantine ER was associated with mean improvement on the NPI over placebo for patients with Baseline MMSE values across the full range of 4-17, with mean between-group differences ranging from 2.7 to 3.0 points. The mean differences reached significance (p<0.05) in the range of 7-14, with the analysis of the outlying score ranges being limited by small n values and low statistical power. Sensitivity analyses yielded similar results. Conclusions: In this post hoc analysis, 6 months of treatment with memantine ER in patients with moderate to severe AD was associated with a significant mean improvement in behavioral symptoms across a wide range of Baseline severities.
2013 · Journal of International Medical Research
Objective: To model the estimated disease-modifying effect of etanercept over sulphasalazine in patients with ankylosing spondylitis. Methods: A post hoc analysis of data from the Ankylosing Spondylitis Study Comparing ENbrel and Sulfasalazine Dosed Weekly (ASCEND) study was performed using the Natural History Staggered Start (NHSS) method. A mixed model with a linear effect over time was fitted to the ASCEND data and resampling was performed to generate confidence intervals. Results: At week 16, the total additional improvement in Bath Ankylosing Spondylitis Metrology Index of the etanercept arm over the sulphasalazine arm was 0.62 points, of which 31% (0.19 points) was estimated to be due to disease-modifying effect. Conclusions: The analysis of ASCEND data suggests that etanercept may have a larger disease-modifying effect than sulphasalazine. Further research is needed with more objective measures such as magnetic resonance imaging or X-radiography to confirm these results.
2013 · Alzheimer's & Dementia
An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer's disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit.
2013 · Alzheimer's & Dementia
Background: Memantine is an NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer’s disease (AD); donepezil is a cholinesterase inhibitor (ChEI), approved for mild to severe AD in the US. Treatment of AD typically involves initiation of donepezil therapy in early stages, with memantine added as the disease progresses to moderate and severe stages. Two large 24-week randomized trials and several observational studies suggest that this combined treatment is superior to monotherapy with either drug; while results of one small 52-week randomized trial generated debate. To further investigate the effects of combination therapy vs monotherapy, we pooled four similarly designed randomized, placebo-controlled trials of memantine inpatients with moderate to severe AD and compared Baseline-to-Endpoint changes in measures of cognition (SIB), function (ADCS-ADL 19), behavior (NPI), and global clinical status (CIBIC-Plus), stratified by treatment/concur-rent therapy regimen (placebo, memantine, placebo/donepezil, or memantine/donepezil). Methods: All patients from two memantine monotherapy trials (MRZ-9001-9605 and MEM-MD-01; N¼567) and donepezil-treated patients from two memantine add-on trials (MEM-MD-02 and MEM-MD-50; N¼841) were pooled and Endpoint changes from Baseline for the SIB, ADCS-ADL 19, NPI, and CIBIC-Plus were assessed using a mixed-effects model with repeated measures (observed cases). Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. Results: At study Endpoint, the memantine/donepezil treatment group was significantly superior to placebo (P<0.001) and both memantine and placebo/donepezil monotherapy groups (P<0.05) on all four efficacy measures. There were no statistically significant differences between memantine and placebo/donepezil monotherapy groups on the CIBIC-plus, ADCS-ADL 19, and NPI; however, the placebo/donepezil group performed significantly better than the memantine group on the SIB (P<0.001). Both memantine and placebo/donepezil treatment groups were significantly better than placebo on the SIB, ADCS-ADL 19, and CIBIC-plus (P<0.01), but no significant treatment differences were observed among these three treatment groups on the NPI. Conclusions: This pooled analysis is in agreement with evidence suggesting that adding memantine to stable donepezil treatment in patients with moderate to severe AD is associated with improvements across several clinical domains, compared with monotherapy using either drug. Appropriately powered, long-term, prospective studies of add-on therapy in AD are warranted.
2013 · PLoS Computational Biology
Although many methods are available to test sequence variants for association with complex diseases and traits, methods that specifically seek to identify causal variants are less developed. Here we develop and evaluate a Bayesian hierarchical regression method that incorporates prior information on the likelihood of variant causality through weighting of variant effects. By simulation studies using both simulated and real sequence variants, we compared a standard single variant test for analyzing variant-disease association with the proposed method using different weighting schemes. We found that by leveraging linkage disequilibrium of variants with known GWAS signals and sequence conservation (phastCons), the proposed method provides a powerful approach for detecting causal variants while controlling false positives.
2013 · Alzheimer's Research & Therapy
2013 · Neurology
OBJECTIVE: In this post hoc analysis of a 24-week, randomized, placebo-controlled trial (MEM-MD-50, NCT00322153) of extended-release (ER) memantine (28 mg, once daily) in patients with moderate to severe Alzheimer's disease (AD) concurrently taking a cholinesterase inhibitor (placebo, n=335; memantine, n=342), we assessed the behavioral effects memantine ER as a function of patients' disease severity at Baseline, as determined using the Mini-Mental State Examination (MMSE). BACKGROUND: Because of safety risks involved with antipsychotic use in patients with AD, the use of antidementia drugs to help manage behavioral symptoms is of great interest. A new memantine ER formulation has demonstrated significant benefits compared with placebo on multiple outcome measures, including the Neuropsychiatric Inventory (NPI), a scale designed to assess behavioral symptoms in AD. DESIGN/METHODS: Patients (observed cases; N=540) were divided into 14 subgroups, corresponding to Baseline MMSE scores (range: 4-17). Baseline-to-Endpoint (Week 24) changes for memantine ER and placebo groups were assessed for each subgroup using a mixed-effects model with repeated measures, with the Baseline MMSE score as a linear covariate; sensitivity analyses were conducted using a quadratic model and a separate means model. Due to the exploratory nature of this analysis, no corrections for multiple hypothesis testing were performed. RESULTS: At Week 24, memantine ER was associated with mean improvement on the NPI over placebo across the full Baseline MMSE range of 4-17, with statistically significant (p<0.05) differences observed in the range of 7-14; outlying score ranges were limited by small n values and low statistical power. Mean between-group differences ranged from 2.7 to 3.0 points. Sensitivity analyses yielded similar results. CONCLUSIONS: In this post hoc analysis, 6 months of treatment with memantine ER in patients with moderate to severe AD was associated with significant improvement in behavioral symptoms across a wide range of Baseline severities.
2013 · Alzheimer's & Dementia
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