Representativeness of European clinical trial populations in mild Alzheimer's disease dementia: a comparison of 18-month outcomes with real-world data from the GERAS observational study

Abstract

Background: Comparison of disease progression between placebo-group patients from randomised controlled trials (RCTs) and real-world patients can aid in assessing the generalisability of RCT outcomes. This analysis compared outcomes between community-dwelling patients with mild Alzheimer's disease (AD) dementia from two RCTs (pooled European (EU) data from EXPEDITION and EXPEDITION 2) and similar patients from the EU GERAS observational study.

Methods: Data from placebo-group patients with mild AD dementia from the RCTs (EU countries only) were compared with data from GERAS patients with mild AD dementia. Between-group differences for changes over 18 months were analysed for cognition, functioning, neuropsychiatric symptoms, health-related quality of life (HRQoL) and caregiver time using propensity score-adjusted models. A sensitivity analysis compared EU/North American (EU/NA) EXPEDITION patients with GERAS patients.

Results: EU EXPEDITION patients (n = 168) were younger than GERAS patients (n = 566) (mean (standard deviation, SD) age 71.9 (7.4) versus 77.3 (6.9) years; p < 0.001) and were more likely to use AD treatment (95% versus 84%; p < 0.001). Cognitive performance was similar at baseline in both populations, although GERAS patients showed greater functional impairment (p = 0.005) and lower HRQoL (p < 0.05). At 18 months, no statistically significant differences between EXPEDITION (n = 133) and GERAS (n = 417) patients were observed for changes in cognitive, functional, neuropsychiatric and HRQoL outcomes. Least squares mean (95% confidence interval) change in caregiver time (hours/month) spent on instrumental activities of daily living (iADL; 29.22 (19.16, 39.27) versus 3.20 (-11.89, 18.28), p = 0.001) and supervision (66.59 (47.49, 85.69) versus 3.04 (-25.39, 31.48), p < 0.001) showed greater increases in GERAS than EXPEDITION. In the sensitivity analysis, changes in neuropsychiatric and HRQoL scores and caregiver time spent on basic ADL were also significantly greater in GERAS than in EU/NA EXPEDITION patients.

Conclusions: Patients with mild AD dementia participating in the EU EXPEDITION RCTs and the GERAS observational study showed a similar decline in cognitive, functional and neuropsychiatric symptoms over 18 months, whereas changes in caregiver time measures were significantly greater in GERAS. Results indicate the importance of using similar regions when comparing real-world and RCT data.

Trial registration: ClinicalTrials.gov NCT00905372 EXPEDITION. Registered 18 May 2009. ClinicalTrials.gov NCT00904683 EXPEDITION 2. Registered 18 May 2009.

Keywords: Alzheimer’s disease; Observational studies; Randomised controlled trials; Real-world data; Regional differences.

Conflict of interest statement

Ethics approval and consent to participate

Ethical review board approval of the GERAS study was obtained in each country according to individual country regulations, as follows: France—Commission Nationale de l’Informatique et des Libertés (CNIL) (reference EGY/DP/AR104863); Germany—Philipps University, Marburg, Fachbereich Medizin, Dekanat/Ethikkommission (reference 105/10); UK—NHS National Research Ethics Service, South West 5 REC (reference 10/H0107/43) and Scotland A Research Ethics Committee (reference number 10/MRE00/63). The patient (or their legal representative) and caregiver were both required to provide written informed consent prior to enrolment.

For the EXPEDITION trials, the research protocol was approved by the ethical review board at each study site participating in that trial. Written informed consent for study participation was provided by the study subject or a legally authorised representative.

Consent for publication

Not applicable for EXPEDITION or GERAS studies.

Competing interests

All authors are employees of Eli Lilly and Company, except Dr David Henley and Dr Gopalan Sethuraman who were employees of Eli Lilly and Company at the time the study was conducted and when the paper was drafted and finalised. No non-financial conflicts of interest exist for any of the authors.

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Figures

Fig. 1

Standardised differences (between EU EXPEDITION and GERAS patients) for baseline characteristics before and after propensity score adjustment. AChEI acetylcholinesterase inhibitor, MMSE Mini-Mental State Examination

Fig. 2

Change in Mini-Mental State Examination score (propensity score-adjusted). p = 0.7912 for overall difference between study type; p = 0.1297 for study type × visit interaction. EU European

Fig. 3

Change in Neuropsychiatric Inventory-12 score (propensity score-adjusted). *p < 0.05 for difference between study type at 12 months; p = 0.1882 for overall difference between study type; p = 0.1580 for study type × visit interaction. EU European

Fig. 4

Change in caregiver time spent on instrumental activities of daily living (propensity score-adjusted). **p < 0.01; ***p < 0.001 for difference between study type at that time point; p = 0.0011 for overall difference between study type; p = 0.0023 for study type × visit interaction. EU European

Fig. 5

Change in supervision time (propensity score-adjusted). *p < 0.05; **p < 0.01; ****p < 0.0001 for difference between study type at that time point; p = 0.0001 for overall difference between study type; p = 0.0254 for study type × visit interaction. EU European

Fig. 6

Change in overall caregiver time (propensity score-adjusted). *p < 0.05; ***p < 0.001; ****p < 0.0001 for difference between study type at that time point; p < 0.0001 for overall difference between study type; p = 0.0074 for study type × visit interaction. EU European