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Informal Care Time and Cost in a Large Clinical Trial Sample of Patients with Mild to Moderate Alzheimer’s Disease: Determinants and Level of Change Observed

Introduction We evaluate the association between caregiver (informal) time/cost and illness severity from two recently completed clinical trials of an investigational drug for Alzheimer’s disease (AD). Methods Changes from baseline caregiver time were calculated and treatment effects analyzed using a restricted maximum likelihood-based mixed model for repeated measures. Four separate models were then estimated to examine the association between caregiver time costs and the clinical endpoints measured during the trials, including cognition (MMSE), function (DAD), behavior (NPI), global disability (CDR) and dependence (DS). Results Caregiver time cost was significantly associated with all clinical measures of illness severity with a 1-unit change in MMSE, DAD, NPI, CDR and DS associated with a 11.57%, 4.81–4.97%, 3.58–3.67%, 42.52% and 71.05% change, respectively, in primary caregiver time cost. The association between caregiver time cost and DS was the strongest of all the associations examined. Conclusion Caregiver time costs increase with increasing AD severity in all key domains of AD (cognition, function, behavior, global disability and dependence on others). Our analysis demonstrated that patient dependence is a particularly important predictor of caregiver time costs and should be considered as a potential outcome measure in intervention clinical trials in AD. Funding Pfizer Inc. and Janssen Alzheimer Immunotherapy Research and Development.


INTRODUCTION
Alzheimer's disease is a progressive dementia characterized by cognitive deficits, altered behavior and inability to care for oneself. Sixty to seventy percent of persons with AD live in the community, with much of the care provided by family or other unpaid persons [1]. These unpaid caregivers provide an estimated 17.4 billion hours of unpaid care per year, constituting an estimated value of $210 billion [1]. The value placed on caregiver time, informal care cost, represents the largest component of the total cost of care for AD [2][3][4][5][6][7]. Estimates range from 37% of total care costs in community dwelling patients participating in a study in Scandinavia [3] to 86% of the total cost of care in a clinical trial sample of mild to moderate AD from multiple countries [4]. A study of cost of illness in dementia reported that 56% of total costs in the EU27 in 2008 were contributed by informal care costs [2]. In the US, Zhu et al. reported that when patients with AD are not institutionalized, informal care-giving cost represents 70% of the total cost of care [7].
Given the important role of care-giving time in the management of person with AD, informal care time/cost has been included as an outcome measure in evaluations of AD treatments [8][9][10][11][12]. Some of these studies reported significant reductions in caregiver time with galantamine [8] and donepezil treatment in patients with AD [8][9][10][11] and others did not [12]. More recently, care-giving time was included as an outcome measure in two RCTs examining the efficacy of bapineuzumab in mild to moderate AD, and is the focus of this analysis [13].
In the economic evaluation of interventions in AD, it is frequently necessary to model the economic implications of changes in clinical progression (e.g., MMSE), in order to determine cost-effectiveness. Having robust estimates of the associations between clinical progression measures and economic outcomes, like informal caregiver time, is very important for such models. Many studies have reported a significant association between informal care-time (and -cost) and disease severity measures of cognition [3][4][5], function [4,5,14] and behavior [4,5]. In Mauskopf et al.'s review of the literature, they concluded that functional and behavioral measures were consistently associated with caregiver time [15]. Two recent studies conducted comprehensive evaluations of associations in AD [4,5]. Gustavsson [23], functional ability with the disability assessment for dementia (DAD; range 0-100%) [24] and neuropsychiatric symptoms with the neuropsychiatric Inventory (NPI; range 0-144) [25]. Patient dependence on others was assessed using the dependence scale (DS; range 0-15) [26]. Global disability was assessed using the clinical dementia rating scale (CDR) [27]. In addition, the age and gender of patients and caregivers, their relationship, and marital status was recorded.

Analysis
Total Cost Analysis Using Merged 301 and 302

Dataset
The resource use and estimated costs at each visit corresponded to the 6-month period preceding the visit (i.e. -26 to 0, 1-26, 27-52, and 53-78 weeks). Unit costs ($US inflated to 2012) were applied to the resource use data collected in the study. Table 1 provides details of the component costs contributing to total costs and the sources used.

Merged 301 and 302 Dataset
The mean changes in primary caregiver and secondary caregiver time at week 78 were determined for three sub-groups of patients with the following baseline severity: (1) very To understand the relative distribution of time across different caring tasks, the mean times primary caregivers allocated to IADLs, ADLs and supervision at baseline and week 78 were estimated using the merged dataset.

Caregiver and Patient Demography and Characteristics
Baseline patient demographics are presented in Table 2 and caregiver demographics in Table 3 Fig. 2. In general, both the baseline and week 78 mean caregiver time tended to increase with increasing severity of the sub-groups. In addition, the mean change in caregiver time at week 78 tended to increase with increasing severity.
The mean primary caregiver time over each time point is presented in Fig. 3. The mean primary caregiver time allocated to IADLs, ADLs and supervision at baseline and week 78 is presented in Fig. 4. At baseline and week 78, primary caregiver time allocated to IADLs tended to be greater than time allocated to supervision, which tended to be greater than the time allocated to ADLs. An examination of   The trend towards increasing caregiver time with increasing cognitive decline, as measured by the MMSE, observed in our cross-sectional analysis, was consistent with previous reports [4]. The trend towards greater changes in caregiver time for the more severe sub-groups, was a new observation but still consistent with the above trend. The larger proportion of care-giving time dedicated to IADLs than supervision and ADLs at baseline in our sample is consistent with the functional and behavioral deficits experienced by patients with mild to moderate AD. Interestingly, the greatest changes over the 78 week period were related to supervision. Typically, in AD, supervision is required to prevent wandering, falls, and other accidents.
The significant associations between clinical severity measures and informal care time are consistent with other reports [3-5, 15, 16]. The proportional change in primary caregiver (11%) and total caregiver time cost (12%) with a unit change in MMSE is higher than the 4.7 estimate reported by Rapp et al. [5].  [28].
The levels of change were much higher than that reported by Zhu et al. in their analysis of Predictor study dataset [29]. They reported that a one point increase in DS was associated with a $1690 increase in informal cost. As the baseline mean informal cost was $12,808 in their study, the proportional change is considerably lower than our analysis showed. Our