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

David B Henley,Sherie A Dowsett,David S Miller,Ann M Hake,Jeffrey Cummings,Joshua D Grill,Yun-Fei Chen,Rachelle S Doody,Paul Aisen,Hong Liu-Seifert,Rema Raman

doi:10.1186/s13195-015-0127-0

Abstract

IntroductionTo 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.MethodsFour 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).ResultsRegions 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.ConclusionsThese 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 registrationsClinicalTrials.gov NCT00594568 – IDENTITY. Registered 11 January 2008.ClinicalTrials.gov NCT00762411 – IDENTITY2. Registered 26 September 2008ClinicalTrials.gov NCT00905372 – EXPEDITION. Registered 18 May 2009ClinicalTrials.gov NCT00904683 – EXPEDITION2. Registered 18 May 2009

Highlights

To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer’s disease (AD) studies
IDENTITY and IDENTITY2 were 76week trials designed to study the effect of semagacestat, a γ-secretase inhibitor no longer in development, on the progression of AD; EXPEDITION and EXPEDITION2 were 80-week trials designed to study the effect of solanezumab, a humanized anti-Aβ peptide antibody currently in development, on the progression of AD
Efficacy measures in the four studies included the 11-item Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog11; range 0 to 70, higher scores worse) [17], the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Scale (ADCS-ADL; range 0 to 78, lower scores worse) [18], the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB; range 0 to 18, higher scores worse) [19,20], the Mini-Mental State Examination (MMSE) [21], and the Neuropsychiatric Inventory (NPI; range 0 to 144, higher scores worse) [22,23]

Summary

Introduction

To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer’s disease (AD) studies. Researchers have studied treatments that target the underlying pathophysiology of AD, as yet without approval of any diseasemodifying drug entity. Development of such diseasemodifying therapies is made challenging by the length and size of studies required to demonstrate positive effects on co-primary outcome measures of cognition and function. In order to enroll patients in a reasonable time period and meet regulatory requirements for local registration, sponsors have increasingly implemented more multinational AD studies [2] that cover multiple geographic regions and encompass many cultures, languages, and healthcare delivery systems. Multinational AD studies may be helpful in furthering our understanding of the effects of a therapy across various standards of care, family structures, and societal views on outcomes [3]

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Results

Discussion

Conclusion