Kobe Boussauw
email: kobe.boussauw@ugent.be

Tijs Neutens
email: tijs.neutens@ugent.be

Frank Witlox
email: frank.witlox@ugent.be

The Relationship Between Spatial Proximity and Travel-to-Work Distance: The Effect of the Compact City

Keywords: compact city, spatial proximity, commuting, sustainable spatial development, Flanders JEL index numbers R14, R23, R40

In this paper, an assessment is made of the relationship between selected aspects of spatial proximity (density, diversity, minimum commuting distance, jobs-housing balance and job accessibility) and reported commuting distances in Flanders (Belgium). Results show that correlations may depend on the considered trip end. For example, a high residential density, a high degree of spatial diversity and a high level of job accessibility are all associated with a short commute by residents, while a high job density is associated with a long commute by employees. A jobs-housing balance close to one is associated with a short commute, both by residents and by employees. In general, it appears that the alleged sustainability benefits of the compact city model are still valid in a context of continuously expanding commuting trip lengths.

Introduction

Although the spatial development model of the 'compact city' gained momentum in the planning literature particularly during the 1980s, there are still many prevailing spatial policy plans that draw from this concept. One of those is the Spatial Structure Plan for Flanders, that was adopted in 1997 (MINISTRY OF THE FLEMISH COMMUNITY, 1997COMMUNITY, /2004) and was inspired, embedded. However, this does not mean that mobility influencing characteristics that are attributed to the compact city are completely absent in suburbanized and even sprawled areas.

Sustainable urban development implies offering more opportunities for travel over short distances, and encouraging the use of alternative transport modes (instead of the private car). These two objectives are not independent. If the demand for long-distance travel is reduced, slower transport modes, that are usually less environmentally stressful, are likely to be chosen more often. [START_REF] Boussauw | Introducing a commute-energy performance index for Flanders[END_REF] show that at a regional scale the distance travelled per person can be considered a good approximation for the overall sustainability of the commute, since positive consequences of modal shifts (especially towards train) are often counterbalanced by increases in average trip length, while a reduction of trip lengths may result in a modal shift towards low-impact modes such as cycling and walking. These patterns result in a correlation between energy consumption (as a sustainability indicator) and distance travelled that is even stronger than intuitively expected. Furthermore, many recent policy plans (as in our study area: the Mobility Plan for Flanders and the Flemish Climate Policy Plan) overemphasize encouraging a modal shift, while research into the number of kilometres travelled has faded somewhat into the background. This justifies an approach in which the distance travelled is considered a sole sustainability indicator, although we are well aware that reality is significantly simplified by not taking into account modal split, congestion and other factors that influence the environmental impact of travel.

Within the scope of this paper we examine whether and to what extent there is a discernible link between the alleged qualities of the compact city and the travel patterns of its users on the basis of commuting data for Flanders and Brussels. To this end, we not only focus on cities, but on the presence of characteristics attributed to the compact city model throughout the suburbanised historically polycentric spatial structure that characterizes this region. More specifically, the present paper attempts to gain a deeper understanding of the observed spatial The restriction to home-to-work travel is motivated by the need for accurate data: in Belgium commuting is the only category of travel that is surveyed area-wide. Also, the study of the commute is particularly relevant from an environmental point of view, given that the longest average trip lengths are recorded in this travel category (see e.g. [START_REF] Zwerts | Onderzoek Verplaatsingsgedrag Vlaanderen 2000-2001[END_REF].

Although today a large body of literature describes aspects of the relationship between spatial structure and trip lengths, this paper adds considerably to the issue. One of the major difficulties regarding the realistic interpretation of previous studies is the uncertainty about the spatial scale at which the influence of certain spatial characteristics manifest. Much research has been done on monocentric urban structures, in a way neglecting the spatial characteristics that reflect the embeddedness in the larger region (e.g. [START_REF] Cervero R | Mixed land-uses and commuting: Evidence from the American housing survey[END_REF][START_REF] Peng | The jobs-housing balance and urban commuting[END_REF][START_REF] Wang | Explaining intraurban variations of commuting by job proximity and workers' characteristics[END_REF]SCHWANEN and MOKHTARIAN, 2005a). By studying a region that is characterized by a large spatial diversity, and by comparing a series of various spatial variables -which account for the characteristics of the surrounding area in different ways -we add to the general research framework on proximity and trip length and thus partly address the mentioned difficulty. In this way the validity of various computational methods for spatial proximity is examined explicitly. Moreover, the analysis is consistently applied to both origins of trips (in this case: residential locations) and destinations (in this case: work locations) in order to obtain more insight into the role played by the deviation in spatial distribution between both location patterns throughout the region. Although the approach adds to the complexity of the issue, it contributes to the practice of spatial planning by complementing the classical triad "density, diversity and design" that was introduced by CERVERO en [START_REF] Cervero | Travel demand and the 3Ds: Density, diversity, and design[END_REF].

A second important contribution is to be found in the specific attention that is paid to methodological problems such as MAUP, spatial autocorrelation, non-linearity and Although this paper does not aim to solve these issues directly, it does provide additional insight into the influence of the analytical methods used on obtained correlations and significances. For example, it is not inconceivable that in previous studies the apparent non-significance of assumed relationships between spatial phenomena was related to a non deliberate choice of the geographical scale.

While our approach disregards personal variations in travel behaviour that are not inherently spatial -which is indeed a major simplification -a purely geographical approach to the concept of proximity remains of major importance. Our argument for this is grounded in peak oil theory, which dictates that limited oil production will in the long run lead to an important increase in the mileage-related costs of mobility and give rise to the importance of spatial proximity [START_REF] Dodson | Shocking the suburbs: urban location, homeownership and oil vulnerability in the Australian city[END_REF].

The paper is structured as follows. In section 2, a summary of the literature on compact city characteristics and commuting trip length is presented. In section 3, a research methodology is developed, taking into account statistical issues and data limitations. In section 4, the results are analysed and confronted with our knowledge of the spatial structure of the study area, while section 5 discusses theoretical issues of scale level and origin versus destination.

Finally, section 6 provides concluding remarks and outlines possible improvements by further research.

2.

Relevant literature

Characteristics of the compact city

According to [START_REF] Neuman | The compact city fallacy[END_REF], the most important mobility-influencing characteristics of the compact city consist of a high density, a high degree of functional mix and a fine-grained land use pattern. (1989; 1999), who pointed out that global cities with more inhabitants per square kilometre consume less fuel per capita for transportation needs. A higher density ensures a critical mass of public transport patronage, but also enhances the potential for spatial interaction between humans based on short distances. While NEWMAN and KENWORTHY'S work has been criticized on many occasions (see for example, [START_REF] Mindali | Urban density and energy consumption: a new look at old statistics[END_REF], their thesis is still widely supported in spatial planning practice.

A sound spatial mix of functions is another important, yet often equivocal feature of the compact city. In particular, it is unclear at which geographical scale this mixture can play its full role. In the most extreme case, a high degree of spatial mix boils down to self-sufficiency of jobs, shops, schools and other services per neighbourhood. While several authors have studied the influence of spatial characteristics on travel behaviour of residents at this district level (among them: FRANK and PIVO, 1994;[START_REF] Cervero | Travel demand and the 3Ds: Density, diversity, and design[END_REF][START_REF] Crane | Does neighborhood design influence travel? A behavioral analysis of travel diary and GIS data[END_REF]SCHWANEN and MOKHTARIAN, 2005a, b), it may also be apposite to observe this kind of spatial mix at the level of a city or a region, at least with regard to the more specialized functions. That is because a small grain size may neglect economic agglomeration benefits at larger scales. Moreover, some activities (e.g. heavy industry) obviously need a lot of space, especially if desired or legally enforced environmental buffering is to be taken into account.

Although by the end of the nineties the debate on the compact city was transformed into a discourse on sustainable urban development [START_REF] Burton | Achieving sustainable urban form: an introduction[END_REF], density and diversity were retained as important elements. [START_REF] Cervero | Travel demand and the 3Ds: Density, diversity, and design[END_REF] argue that density, diversity and design are important spatial factors underlying travel behaviour, and focus on the scale of the neighbourhood, attributing an important role to the design of public space. [START_REF] Stead | Land use, transport and people: identifying the connections[END_REF] found that the size of the city and the proximity to key infrastructure are 8 additional factors that determine the relationship between spatial structure and travel, while [START_REF] Van Acker | The effects of the land use system on travel behavior: A structural equation modeling approach[END_REF] focus on the explanatory power of a range of social characteristics.

Based on these findings, we argue that high density, a sound land use mix and a small grain size are all spatial elements, amenable to modification by policy, that are part of an overarching spatial quality that we would like to call "spatial proximity".

A less frequently discussed, but nevertheless important aspect is the spatial scale at which the influence of certain spatial characteristics is at its maximum. In the literature on the compact city often no distinction is made between small towns and metropolises. In Flanders, the distance covered by an average trip (all purposes combined) amounts to 12.5 kilometres (one way). The average commuter even covers a distance of about 19 kilometres per ride between home and work [START_REF] Zwerts | Onderzoek Verplaatsingsgedrag Vlaanderen 2000-2001[END_REF]. For the UK, [START_REF] Lyons | A human perspective on the daily commute: costs, benefits and trade-offs[END_REF] found an average commuter trip length of 13.7 kilometres in 2002[START_REF] Wang F | Job proximity and accessibility for workers of various wage groups[END_REF]. According to BANISTER et al. (1997), commuter trip lengths increase year after year in European and North American metropolitan areas. It is patent that the average trip length does no longer correspond with the scale of a compact city, at least in a Belgian context.

The scale problem is acknowledged by many authors. [START_REF] Van Wee | Land use and transport: research and policy challenges[END_REF], for example, suggests that the findings of [START_REF] Newman | Cities and Automobile Dependence. A sourcebook[END_REF][START_REF] Alberti | Urban patterns and environmental performance: what do we know?[END_REF], which are based on demarcated cities, cannot be applied to the Dutch Randstad conurbation, as this urban system is operating at a higher, regional scale level. ALBERTI (1999), on the other hand, refers to several possible approaches to a sustainable spatial structure, stating that at the regional level the settlement pattern is of interest while at the local level neighbourhood design is paramount. In short, the scale problem is well recognized, but not explicitly addressed yet. As will be shown in this paper, this is partly due to the fact that the quantitative analysis of scale effects is hampered by substantial methodological issues. Based on these arguments, we hypothesize that the main compact city variables (density and land use mix) are insufficient to represent the differences in the spatial distribution of residential locations and job locations at the scale of the region, or the embeddedness in the surrounding area. Therefore in section 3.2 we introduce three additional variables that should grasp the issue in a more comprehensive way.

Commuting trip length

Although it may be intuitively understood that spatial proximity is a predominant determinant for commuting trip lengths, many studies indicate that personal, economic and behavioural factors play an important role too, making aggregate non-spatial variables even prevalent in explaining commuting trip lengths. Both [START_REF] Cervero R | Mixed land-uses and commuting: Evidence from the American housing survey[END_REF], [START_REF] Peng | The jobs-housing balance and urban commuting[END_REF] and [START_REF] Van Acker | Commuting trips within tours: how is commuting related to land use? Transportation[END_REF] testing the applicability of several possible indicators on a regional scale.

Methodology

Research design

The aim is to examine relationships between commuting trip lengths and a number of spatial characteristics of the zones where the surveyed trips have their origin and their destination.

Since the analysis focuses on regional variations, we first explore possible relationships visually by confronting maps with our knowledge of the study area. Then, a quantitative analysis is conducted by calculating correlations between the average trip length and each of the other selected variables. The variables are aggregated within geographic zones, introducing effects of spatial autocorrelation and MAUP. To address this problem, the choice of an aggregation level that is adapted to the analysis is paramount.

The two most obvious variables that we include in this research are directly obtained from the compact city literature. These are density and spatial diversity. However, we want to add three additional spatial parameters: the theoretical minimum commuting distance (as a more sophisticated measure of proximity), the jobs-housing balance (as a measure of selfsufficiency of a zone regarding job supply) and the number of accessible jobs (as a measure of accessibility). In the next section we will explain how these three additional variables have been calculated. In our analysis, the dependent variable is trip length both for trips that depart from and arrive in each considered zone.

Relationships are deduced in two steps. First, we visualize all variables at an intermediate aggregation level to get an overview. This map allows for an initial impression of possibly present links. Subsequently, we apply an exploratory spatial correlation analysis at several Based on the initial results, we then select the most appropriate aggregation level for our analysis. Finally, we assess expected multicollinearity in variables and assumed linearity of relationships, aiming to detect redundancies and thus improve the interpretation of the results.

Used data and variable construction

In what follows, we discuss the origin and composition of the six used variables: distance per trip, density, diversity, minimum distance per trip, jobs-housing balance and number of potentially accessible jobs.

Distance per trip (dpt)

To determine the distance travelled per trip, the origin-destination (OD) matrices of the Flanders Multimodal Model (MMM) are used. The MMM is a macro traffic model that is developed since 1998 and is commissioned by the Flemish government. The matrices provided for this study simulate traffic on an average weekday between 4 am and 11 am (morning traffic). The zones, corresponding with the matrix, are in most places in line with census wards. The matrices are built on the basis of the 2001 census, which is an exhaustive survey of the Belgian population (excluding children under six years), assessing the address of residence and the address of the workplace [START_REF] Verhetsel | Pendel in België. Deel I: de Woon-Werkverplaatsingen[END_REF]. The processed data are aggregated by ward and present a picture of the daily travelled distances to and from each neighbourhood.

To obtain trip lengths, the shortest distance over the road network is calculated between the centroids of the connecting zones. Note that the distances calculated in this way are a slight , 2007). Since the fastest route depends on varying congestion levels, we aim to avoid added complexity and thus stick to calculating the shortest path. We calculate the average distance travelled per trip ) (obs h to and from each traffic analysis zone i as follows:

∑ ∑ = i O i O i O H obs h ) (
(1) and

∑ ∑ = i D i D i D H obs h ) ( (2),
where O and D, respectively, are the number of departing and arriving trips, and H is the distance covered by each trip.

Density (dens)

As an approximation for the density we calculate the number of departing commuting trips, as well as the number of arriving trips per square kilometre, based on the MMM. Residential density is approximated by counting the number of outbound trips per square kilometre in the morning traffic. Job density is approximated by the density of inbound trips. We calculate the densities C based on the number of outbound trips O and the number inbound trips D belonging to traffic analysis zone i with area A as follows: To calculate the spatial-functional diversity per zone, we apply the Shannon index. This index is used in landscape ecology as a measure of morphological diversity [START_REF] Nagendra | Opposite trends in response for the Shannon and Simpson indices of landscape diversity[END_REF], and is in this case also called spatial entropy [START_REF] Batty | Spatial entropy[END_REF]). An extension to urban diversity is obvious. The Shannon index is calculated as follows:

C O i = O i /A i (3) and C D i = D i /A i (4)

Diversity (div)

∑ = ⋅ - = N n n n i p p S 1 ln (5),
in which N is the number of features included within the considered aggregation zone i, and p n the proportion of each function that occurs within this zone.

Minimum distance per trip (mdpt)

We introduce the theoretical minimum commuting distance as a proxy for spatial proximity.

The minimum commuting distance stems from the research on excess commuting [START_REF] Hamilton | Wasteful commuting[END_REF][START_REF] Ma | Excess commuting: a critical review[END_REF][START_REF] Ma | Urban spatial change and excess commuting[END_REF][START_REF] Charron | From excess commuting to commuting possibilities: more extension to the concept of excess commuting[END_REF] [START_REF] Niedzielski | A spatially disaggregated approach to commuting efficiency[END_REF][START_REF] Boussauw | Minimum commuting distance as a spatial characteristic in a non-monocentric urban system: the case of Flanders[END_REF].

The principle of the method implies linking any observed departure (in this case in the morning traffic) to the nearest observed arrival, also in the morning traffic. Per traffic analysis zone the number of departures, as well as the number of arrivals, is retained, but the existing relationship between origins and destinations is cut with the aim of minimizing the total travelled distance within the system. This theoretical exercise deliberately disregards nonspatial factors that determine the real world match between origin and destination. When commuting trips are considered, this means that everyone who is part of the active population is considered suitable to perform any job.

In We calculate the average minimum distance to be covered (min) h per trip from and to a traffic analysis zone i as follows:

( ) ∑ ∑ = i O i O i O H h min (min) (6) and
( ) ∑ ∑ = i D i D i D H h min (min) (7),

Jobs-housing balance (jhb)

The jobs-housing balance is the ratio between the number of jobs localized in a zone and the number of working people who live in the same zone. Because of its simplicity, this indicator is often used as a spatial characteristic in commuting research [START_REF] Cervero R | The jobs-housing balance and regional mobility[END_REF][START_REF] Peng | The jobs-housing balance and urban commuting[END_REF]HORNER and MURRAY, 2003;see HORNER (2004) for an overview).

We calculate the jobs-housing balance for every traffic analysis zone i, based on the MMM, by dividing the number of arrivals in the morning traffic by the number of departures:

B i = D i /O i (8)

Number of potentially accessible jobs (potjob)

The accessibility of the job market is also included in the analysis, and is expressed as the number of jobs, located in Belgium, that can be reached from every zone. Accessibility, departing from a particular zone, is determined by combining a probability curve with the travel time between the considered zone and all other zones in Belgium, after which the values for all these other zones are summed. The probability distribution was deducted from empirical data, while the travel time was calculated on the basis of a network with attributed impedances. The basic data on the location of jobs was provided by the FEDERAL PUBLIC SERVICE OF ECONOMY (2001) and is aggregated by borough (i.e. a municipality in the former administrative system).

The number of jobs accessible from a borough i is defined as follows:

( ) ∑ = ⋅ = n j ij j i c F J A 1 (9),
where A i is the number of jobs accessible from the considered borough i, J j the number of jobs located in each borough j, and F(c ij ) the impedance function, based on the modelled probability curve.

We adopt the calculated results from [START_REF] Vandenbulcke | Accessibility Indicators to Places and Transports -Final Report, Federal Public Service Mobility / Federal Science Policy[END_REF]2009), and refer to these two papers for the exact calculation method. This accessibility index is related to the jobshousing balance, but also takes into account the travel time needed to reach the core of the labour market.

Level of aggregation and MAUP

In order to discover correlations, we need to aggregate the various parameters within the same zonal classification. The traffic analysis zones of the MMM are not suitable for this. These zones are small in high density regions and vice versa, which apparently results -among other objections -in a non-normal distribution of the variables linked to these zones. The large dispersion in area size makes the traffic analysis zones unsuited for the calculation of the Shannon index, which is area dependent, and also the calculation of the number of accessible jobs was initially based on another zoning (boroughs). For the sake of uniformity, we choose to aggregate all data into a grid of square cells.

However, the choice of the size of these cells is not evident. It is a well-known phenomenon that statistical correlations change whenever a different level of spatial aggregation is chosen, and that these become generally stronger when the aggregation level increases, even if accuracy of the data is in fact lost by increasing the aggregation level [START_REF] Amrhein | Searching for the elusive aggregation effect: evidence from statistical simulations[END_REF]. This OPENSHAW and TAYLOR (1979) argue that the choice of the aggregation level should depend on the expected significance for the studied variables. However, this suggestion does not solve the question. Our main variable, average trip length, shows important dispersion. Even if we choose the mesh size of the grid so that the average trip has its destination in a zone adjacent to the zone of origin, this will often not be the case for trip lengths deviant from this average. In this context, "mesh size" points to the length of a side of a cell in a uniform square grid. Regarding the independent variables it is even less clear what an appropriate level of aggregation would be.

To support the choice of a suitable aggregation level, in the exploratory stage we applied four different grids, with a mesh size of 1, 4, 8 and 16 kilometres. These options are illustrated in The highest level of aggregation (16x16 km) seems inappropriate because of the large number of non-significant relationships that are revealed by means of spatial regression, due to the reduced dataset size. The lowest level of aggregation (1x1 km) also seems inapplicable: the relatively high degree of discontinuity between adjacent cells makes it sometimes difficult to clearly distinguish local patterns, resulting in often very low coefficients. Therefore, for the current analysis we choose an intermediary level of aggregation with a mesh size of 4 km (Figure 2). If we take into account a general detour factor of 1.40 [START_REF] Rietveld | On the relationship between travel time and travel distance of commuters. Reported versus network travel data in the Netherlands[END_REF][START_REF] Witlox | Evaluating the reliability of reported distance data in urban travel behaviour analysis[END_REF], then this choice implies that about 70% of all commuters have their destination in another zone than the origin zone of their trip [START_REF] Zwerts | Onderzoek Verplaatsingsgedrag Vlaanderen 2000-2001[END_REF]. For the construction of the grid, the border zones of the study area are joined so that any cell size approaches the area of a square cell. The aggregation of those data that were originally available at the level of traffic analysis zones (i.e. travelled distance, density, minimum commuting distance and jobs-housing balance) or borough (access to jobs) is done proportionally to the geographical overlap between two geographical divisions. The Shannon index (diversity) is calculated once for the grid with a mesh size of 1 km, and then aggregated to the applied scale level.

Spatial regression

Given the nature of the examined spatial characteristics, an important degree of positive spatial autocorrelation between the zones themselves occurs. Spatial autocorrelation is the correlation between values of a variable that has its origin in the vicinity of the locations where these values are measured. Positive spatial autocorrelation, meaning that neighbouring areas are similar, is a phenomenon that is typically present in most empirical spatial datasets, and is explained by Tobler's first law of geography, in that "Everything is related to everything else, but near things are more related than distant things" [START_REF] Tobler | A computer movie simulating urban growth in the Detroit region[END_REF]. The [START_REF] Anselin | Do spatial effects really matter in regression analysis[END_REF].

Like the MAUP, spatial autocorrelation has often been ignored in past spatial planning studies. One of the reasons for the neglect of these issues in research applications is that the theoretical study of useful spatial alternatives to traditional statistical methods has been debated for a long time [START_REF] Ord | What were we thinking?[END_REF]). An alternative regression method that was adopted by many authors is the so-called "spatial regression" technique, developed by Anselin [START_REF] Anselin | Spatial dependence in linear regression models with an introduction to spatial econometrics[END_REF]. This method starts from a significance test for spatial autocorrelation based on the calculation of Moran's I, a measure of spatial autocorrelation. If this test is not significant, the application of an ordinary least squares (OLS) regression is suggested. If the Moran's I test is significant (this is usually the case), the occurring kind of spatial dependence ("spatial lag" or "spatial error") should be detected. The occurrence of spatial lag implies that the dependent variable in a cell is not only affected by the independent variables in the cell itself, but also by those of the neighbouring cells. In the case of spatial error, only the residuals in the regression analysis of neighbouring cells are correlated.

Depending on the occurrence of spatial lag or spatial error, a regression model is selected that reduces the influence of these phenomena. In some cases, both the spatial lag and the spatial error model can be applied. Each of these calculations provides, inter alia, a regression coefficient, a significance test and a pseudo coefficient of determination (pseudo R²). The relative popularity of this method in the recent literature is probably due to the user-friendly implementation in the freely distributed software tool GeoDA [START_REF] Anselin | GeoDa: An introduction to spatial data analysis[END_REF]. In this study, models were estimated by means of GeoDa 0.9.5-i5, which is a public domain software package making spatial regression techniques available in a GIS environment.

Cartographic analysis

In order to gain a better understanding of the spatial variations of the variables, we make a cartographic representation in Figures 5 to 13, aggregated at an intermediate scale in a grid of 4 by 4 km. Figure 14 shows a schematic reference of the study area (Flanders and Brussels).

The variables distance per trip, minimum commuting distance and density are each shown twice: once the zones are regarded as origins and once the zones are regarded as destinations.

The variables diversity, jobs-housing balance and number of potentially accessible jobs are displayed once.

<insert Figures 5,6,7,8,9,10,11,12,13 and 14 about here -remark: figures should preferably be presented in small format and tabulated > Before using this data in a statistical spatial analysis, we can already note a number of interesting findings from the maps.

The most obvious relationships can be seen in the maps where the zones are considered origins, or residential zones (Figs. 5,7 and 9). The spatial variations of the distance travelled per trip (Fig. 5) is in most regions similar to the spatial pattern of the minimum commuting distance (Fig. 7), although values of the second variable are of course considerably lower. The map showing residential density (Fig. 9) is in many regions quasi the opposite of Figure 5 and On the maps where the zones are regarded as destination or labour zone (Figs. 6 and8), the patterns are less consistent. Here the thorough spatial concentration of jobs, in comparison with the more dispersed structure of housing, plays an important role. In areas with a low job density the value of the minimum commuting distance is of little significance.

A comparison of Figure 10 with Figures 6 and8 indicates that job density is correlated with commuting distance, as well as with the minimum commuting distance to the destination areas. For a better insight, also the jobs-housing balance (Fig. 12) should be taken into account. In theory, a jobs-housing balance fluctuating around 1 would be most likely to yield short commuting distances [START_REF] Peng | The jobs-housing balance and urban commuting[END_REF]. Because of the large differences in spatial concentration between housing and jobs, Fig. 12 does not seem to support this theory at the first sight. The jobs-housing balance therefore requires more specific attention in the following paragraphs. In the economic core of Flanders there also seems to be a correlation between the accessibility of the job market (Fig. 13) and the distance travelled, while this relationship is much less clear in the rest of Flanders.

Correlation analysis for the average distance travelled per trip

All the independent variables are considered approximations for spatial proximity, in this case between the housing market and the job market. A Pearson's correlation matrix shows that most coupled variables in the origin zones exhibit correlations in the range of 20 to 50%, amounting even to 72% (between job density and minimum commuting distance) in the destination zones. The couple job accessibility and jobs-housing balance is an exception, with a correlation coefficient of only 9,7%. We normalize all variables to z-scores and subsequently include them in a bivariate spatial regression using GeoDA. The average distance travelled is always regarded as the dependent variable. For the spatial lag and spatial error models, spatial weight matrices are constructed on the basis of the grids, according to the so-called "queen" method. This means taking into account the influence of all adjacent cells, including these cells that touch the studied cell with only one point, like the adjacent squares in chess that are covered by the queen.

First an OLS regression is done, as well as a test on spatial autocorrelation (through a significance test for Moran's I), and the presence of spatial lag and spatial error is detected. In case no significant spatial autocorrelation is found, the results of the OLS regression would be selected. In the other case, the spatial lag or spatial error model is applied, depending on which phenomenon is significant. If both phenomena appear significant, we apply both models. Each time we select the regression coefficient r, which can be considered as a spatial correlation coefficient, and the value of the significance test. We regard the zones firstly as origins and secondly as destinations. The results are presented in Table 1.

<insert Table 1 about here>

Interpretation regarding the origin zones

In this case, we consider each zone as a residential area, acting as a source of home-to-work trips in the morning traffic. For all variables, a significant amount of spatial autocorrelation was found, making the application of a simple linear regression (OLS) inappropriate. The applied spatial regression models were suggested by GeoDA. Except for the jobs-housing give an overview of our findings.

• A higher population density is associated with shorter commuting distances.

• A greater diversity is also associated with shorter commuting distances. The link with spatial diversity is much stronger than the relationship with population density.

• The minimum commuting distance shows a positive correlation with the observed commuting distance, the magnitude of r being similar as for the relationship with population density.

• There is no significant correlation between the observed commuting distance and the jobs-housing balance. Given the specific characteristics of the job-housing balance we will devote a separate section to this variable below.

• Better access to the job market is associated with shorter commuting distances. In comparison with the other independent variables we can call this relationship strong.

Interpretation regarding the destination zones

Now, we consider each zone as a labour area, a destination of the commute during the morning. Again, we find significant spatial autocorrelation for all variables. The calculation of the spatial regression models suggested by GeoDA results in following findings:

• In contrast to the population density in the origin zones, a higher density of jobs in destination zones is associated with longer commuting distances. The relationship with job density is however less strong than the relationship with population density in the origin zones.

• There is no demonstrable correlation with spatial diversity.

• There is a relatively strong positive correlation between minimum commuting distance and observed commuting distance. • Even if jobs-housing balance appears not relevant in the origin zones, this variable provides a relatively strong correlation in the destination zones. The higher the jobshousing balance is, the larger the commuting distances. This finding should, however, be qualified (see next section).

• The interpretation of the influence of the number of potentially accessible jobs is not obvious, since this variable represents the number of jobs accessible departing from the considered zone, and not from the other zones. This parameter yields a positive r.

Better access to the job market seen from the considered zone is associated with a concentration of jobs, and thus with longer commuting distances to this zone.

Non-linearity in the jobs-housing balance

The use of spatial correlation analysis assumes a linear relationship between the corresponding variables. This was assessed by the estimation of a Lowess curve in a scatter plot, showing indeed linearity for most of the used datasets. Lowess or Loess (locally weighted/estimated scatterplot smoothing) is a regression technique that applies linear least squares regression on segments of the data, yielding a smoothly fitted curve. However, slopes tend to flatten in the border areas of the sample curve. This is particularly the case when dealing with extremely high densities or large minimum commuting distances, or extreme values (both high and low) of accessibility. Only with regard to the jobs-housing balance the relationship is clearly not linear, especially when considering origin zones.

At one hand, it seems logical that a higher jobs-housing balance leads to a larger share of nearby jobs, reducing average commuting distances. On the other hand, it is clear that a high jobs-housing balance in the destination zones is accompanied with an (over)concentration of jobs, leading to larger commuting distances. Thus, a high jobs-housing balance would be When we consider the total amount of travelled distances produced per zone, adding the distances covered by inbound trips to these covered by the outbound trips, and plot this summed variable against the jobs-housing balance, we should obtain a U-shaped curve (PENG, 1997) (Fig. 15). The minimum distance corresponds to an equilibrium point where the jobshousing balance is close to 1, representing a perfectly equal spatial distribution of housing and jobs.

To verify the validity of this hypothesis, we visualize the link between the total generated distance per zone (4x4 km) and the jobs-housing balance by means of a scatter plot for which we estimate a Lowess curve and a best-fit quadratic curve (Fig. 16).

<insert Figures 15 and 16 about here -remark: figures should preferably be presented in small format and tabulated >

The curves appear to correspond to our hypothesis: i.e. the total commuting distance associated with one zone reaches a minimum at an optimal jobs-housing balance, which is situated around 1. However, the fit is rather weak. This is partly due to the fact that there are many more zones with a low jobs-housing balance than with a high jobs-housing balance.

Though, a more important reason is that the natural relationship between spatial segregation and trip length is disturbed and smoothed by non-spatial influences, as discussed in the introduction. The same reason applies to the generally low values of r that were found in the previous section.

Discussion

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Regional

Origin versus destination zones

For most parameters, a positive correlation with the outbound trip length corresponds with a negative correlation with the inbound trip length. A higher population density in an origin zone means shorter trips. A higher job density, by contrast, just means longer trips. We observe a similar pattern when considering the number of accessible jobs. With respect to spatial diversity, there seems to be no discernible relationship in the destination zones, while we should approach the jobs-housing balance in a non-linear way.

These results derive from the unequal spatial distribution of housing and jobs. Jobs occur more often than housing in high concentrations in urban areas, where the density and the spatial diversity is generally high. In most zones the jobs-housing balance is lower than 1, making job supply in the other zones, which are much less numerous, overconcentrated.

Overconcentration means that employees more often come from very far away to take up available jobs. On the origin side, however, employees living in an area with urban characteristics (high density and spatial diversity) more often find a job close to home.

Therefore, [START_REF] Newman | Cities and Automobile Dependence. A sourcebook[END_REF][START_REF] Alberti | Urban patterns and environmental performance: what do we know?[END_REF] thesis that fuel consumption is negatively correlated with density, is only valid when we consider the residential zones. In the case of the labour zones, we find an inverse correlation. However, modal choice was not taken up in this study. We can assume that zones with a very high job concentration are accessed more than average by public transport. Consequently, energy consumption (and other undesired external effects of traffic) is expected to grow slower than the travelled distance itself. But because the highest job concentrations entail the most extreme forms of long-distance commuting, this mitigating effect on fuel consumption will be rather limited.

Spatial diversity does not explain commuting distance viewed from the labour zones. This can be explained by the large differences in types of labour areas: high job concentrations generating long trips occur both in urban centres with a high spatial diversity and in isolated where diversity is an explaining factor: a high residential density is usually associated with a large supply of jobs, and thus a sound spatial mix of both functions.

When considering the relationship between the observed commuting distance and the minimum commuting distance, values of r are significantly higher for labour areas compared to residential areas. However, the relationship with job density (in the labour areas) is weaker if we compare to the relationship with housing density (in residential areas).

When we examine the origin zones, we conclude that job accessibility and spatial diversity should be considered the most appropriate indicators influencing commuting trip length. In this case, residential density and minimum commuting distance have a relatively low predictive value, while jobs-housing balance is not a linear predictor at all. In the destination zones, however, the minimum commuting distance is a relatively good indicator, while the jobs-housing balance and job density have only conditional predictive value.

Relevant scale levels

We have to take into account that the relationships that we derive from an analysis at the level of zones of 4x4 km cannot necessarily be extended to processes that play at a different aggregation level. The importance of scale may mainly depend on the considered trip length classes.

Density, diversity and proximity are spatial characteristics that are important for traffic generation, but mainly on a scale level that can be associated with the considered distance class. Influencing travel behaviour of motorists should be done especially at higher scale levels. To influence trips of pedestrians, cyclists and users of local public transport, the lowest scale levels are perhaps the most relevant. The travel behaviour of the 21st century commuter deviates strongly from that of the historical inhabitants of a medieval or nineteenth-century compact city, so that only a limited overall environmental impact is to be expected of a policy that only focuses on strengthening these old structures. Potentially more impact could be expected from a policy that focuses on strengthening density, diversity, jobs-housing balance and proximity within the higher levels of aggregation, comprising also suburban areas. In addition, the quality of the urban structure on the lowest scale levels may still have an impact on the share of pedestrians, cyclists and users of public urban transport, and may in that sense have a positive impact on the urban environment.

Conclusions and pathways for further research

Daily trips on foot, by bike or public urban transport, but also short car trips, fit into the spatial model of the compact city. By strengthening the characteristics of the compact city, with the emphasis on residential density and proximity of functions, a spatial framework may be created that makes trips over long distances less necessary or even unnecessary. However, the category of short trips has become a niche market, especially within the commute. In Flanders, the average commuter covers a distance of about 19 kilometres per trip, a trip length that is well beyond the compact urban scale. However, a number of qualities that are attributed to the compact city are still valuable, even if they also influence spatial processes at the regional scale. Viewed from a sustainability perspective, an equal jobs-housing balance and a high residential density are paramount. A high degree of spatial diversity and accessibility of the labour market play also a positive role. By contrast, high concentrations of employment are not desirable. High job densities seem to give rise to overconcentration easily, so that workers should be recruited from a wide hinterland. These features are reflected in the minimum commuting distance, which is a good measure for the proximity of housing The outlined research design, however, also calls for further elaboration. The results for the commute cannot simply be extrapolated to other types of travel. Trips to school, shops or social activities usually are much shorter than home-to-work trips [START_REF] Zwerts | Onderzoek Verplaatsingsgedrag Vlaanderen 2000-2001[END_REF]. Therefore, it might be possible that the correlations for this type of travel are stronger at the lower scale levels, in comparison to home-to-work trips. Another extension concerns the feasibility of an equal jobs-housing balance: it has to be taken into account that neighbourhood's jobs-housing balances fluctuating area-wide around 1 may not be compatible with agglomeration trends that are important for many economic sectors.

Another improvement could be incorporating the modal split in the comparisons. Long commuting distances are often covered by train, which means that the negative impact of these trips increase at a slower rate than the number of kilometres travelled. Moreover, it may well be that increasing spatial proximity at the lowest scale levels will result in a larger share of pedestrians, cyclists and users of urban public transport in urban areas, strengthening the positive effect of shorter trips by a modal shift. We hope to address these and related issues in future research. http://mc.manuscriptcentral.com/cres Email: regional.studies@fm.ru.nl

Regional Studies

  lengths on the basis of commuting data available for Flanders and Brussels.

  with the intention to quantify a number of relationships and to test their significance.

  real distances travelled, since detour factors associated with faster routes or the public transport network are not included (WITLOX

  [START_REF] Boussauw | Minimum commuting distance as a spatial characteristic in a non-monocentric urban system: the case of Flanders[END_REF] an algorithm was developed to calculate the local values of minimum commuting distance, based on the MMM, for the commute occurring between 4 am and 11 am. The algorithm obtains a general minimization of travel distances via local optimization, simulating individuals pursuing a job closer to home. For each traffic analysis zone, the calculation was done twice: once with the zone considered as an origin (outbound travel), and once with the zone considered as a destination (inbound travel). The first computed value is seen as an approximation for the proximity of housing within the zone in relation to the Flemish and Brussels labour market, while the second value is representative of the proximity of the labour market of the zone in relation to housing in Flanders and Brussels.

  H) is the minimized commuting distance per zone.

  the scale effect of the MAUP, and is inherent in any quantitative analysis of spatially aggregated data.

Figures 1

 1 Figures 1, 2, 3 and 4 for one example (i.e. trip length). The results of a spatial correlation

  4 about here -remark: figures should preferably be presented in small format and tabulated >

  presence of spatial autocorrelation is a violation of the assumption of independence of successive observations, which must be satisfied before applying classical statistical techniques such as correlation and regression analysis. Positive spatial autocorrelation leads too often to positive results of significance tests, and thus to the unjustified rejection of null to an overestimation of regression and determination coefficients (ANSELIN

  The software was developed by dr. Luc Anselin, School of Geographical Sciences and Urban Planning, Arizona State University.

Figure 7 .

 7 Figure 7. Therefore, there seems to be a link between high residential densities and short

  inherent multicollinearity, and because of the difficulties regarding interpretation, we will not apply multiple regression techniques but confine ourselves to a bivariate correlation analysis.

  show a significant relation with the distance travelled per trip. Below we

  long and short commuting distances. This paradox stems from our assumption of linearity, which appears unjustified.

  industrial and port areas. This is different with regard to the residential areas,

  market and clearly evolves parallel with the observed commuting distances. Since the minimum commuting distance is determined by the spatial patterns of housing, jobs and infrastructure, we can conclude that commuting over short distances can be facilitated by changes in the spatial structure.

Figure 1 :Figure 2 :Figure 3 :Figure 4 :Figure 14 :Figure 15 :Figure 16 :

 1234141516 Figure 1: Average commuting distance (dpt), origin zones, aggregation level = 1 km

  , we used the Strucnet file of the NGI (NATIONAL GEOGRAPHICAL INSTITUTE OFBELGIUM, 2009) that contains all buildings represented on the official Belgian topographic maps with scale 1:10000. Different categories of buildings are distinguished but the accuracy of categorization is limited. All buildings that are morphologically part of a group of houses are listed as "ordinary building". All other as such recognizable buildings (industry, schools, hospitals, public services etc.) have their own feature class. In practice this means that many commercial functions, offices and services that are interwoven with housing are not recognizable. Nevertheless, this inventory can be used to approximate diversity of functions in a given zone, and is without doubt the best currently available area-wide data set in Belgium.

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http://mc.manuscriptcentral.com/cres Email: regional.studies@fm.ru.nlRegional Studies

Acknowledgments

This research has been made possible within the Flemish Policy Research Centre for Housing and Space, funded by the Ministry of the Flemish Community. The authors wish to express their thanks to the Flemish Traffic Control Centre for the assistance, to Grégory

R14 -Land Use Patterns < R1 -General Regional Economics < R -Urban, Rural, and Regional Economics, R23 -Regional Migration|Regional Labor Markets|Population < R2 -Household Analysis < R -Urban, Rural, and Regional Economics, R40 -General < R4 -Transportation Systems < R -Urban, Rural, and Regional Economics


M.D. Konstantin ; Articus
email: konstantin.articus@novartis.com

Monika Baier

Ferenc Tracik

Frank ; Kühn

Ulrich Preuss

Alexander Kurz

Facharzt

Psychiatrie Preuß

Ulrich W Preuß

A 24-week, multicentre, open evaluation of the clinical effectiveness of the rivastigmine patch in patients with probable Alzheimer's disease

Rivastigmine is approved for the symptomatic treatment of persons with mild-to-moderate AD and PDD and has recently been approved in patch formulation for treatment of the same groups in the USA. Rivastigmine patch provides similar efficacy to the highest dose of rivastigmine capsule (12 mg/day) but with a superior tolerability profile. A sub-study of the IDEAL trial showed that the majority of caregivers preferred patches to capsules for drug delivery.

What's new? (70 words)

This study investigated the safety and tolerability of the rivastigmine patch in persons with AD in an open-label setting. To complement findings from controlled clinical trials, this study was designed to mimic as closely as possible under the conditions of a clinical trial the situation in real life. The proportion of patients able to reach and maintain the maximum dose with patch exceeded previous demonstrations with an equivalent oral dose.

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most frequent form of senile dementia [START_REF] Fratiglioni | Incidence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group[END_REF]. The classic clinical features of AD include impairment of cognition and memory, language deterioration, decreased ability to perform activities of daily living, motor and sensory abnormalities and gait disturbances [START_REF] Cummings | Alzheimer's disease[END_REF].

The cholinesterase inhibitors galantamine, donepezil and rivastigmine form the mainstay of treatment for persons with mild-to-moderate AD [START_REF] Bassil | Novel regimens and delivery systems in the pharmacological treatment of Alzheimer's disease[END_REF][START_REF] Klafki | Therapeutic approaches to Alzheimer's disease[END_REF]. Rivastigmine is approved for the symptomatic treatment of persons with mild-to-moderate AD and Parkinson's disease dementia (PDD) and has recently been approved in patch formulation for treatment of the same groups in the USA. In 2007, a six-month, double-blind, randomized, placebo-controlled study (IDEAL; ENA713D2320) demonstrated the 9.5 mg/24 h rivastigmine patch to provide similar efficacy to the highest dose of rivastigmine capsule (12 mg/day) but with a superior tolerability profile [START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF]. In addition, the caregiver preference sub-study of the IDEAL trial showed that 72% of caregivers preferred patches to capsules for drug delivery [START_REF] Winblad | Caregiver preference for rivastigmine patch relative to capsules for treatment of probable Alzheimer's disease[END_REF].

There is an increasing awareness of the importance of reaching and maintaining an optimal therapeutic dose of cholinesterase inhibitor [START_REF] Small | Defining optimal treatment with cholinesterase inhibitors in Alzheimer's disease[END_REF]. However, non-compliance with AD therapies is a wide-spread problem and is often a barrier to effective therapy [START_REF] Small | A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch[END_REF]. It is hoped that the favourable tolerability profile and convenience of use of the rivastigmine patch could translate not only to increased compliance with AD therapies, but also to a greater proportion of patients reaching and maintaining an efficacious dose. The objective of this study was to investigate the safety and tolerability of the 9.5 mg/24 h rivastigmine patch in patients with probable AD in an open-label setting. We aimed to establish the proportion of patients who reached and maintained the target rivastigmine patch dose of 9.5 mg/24 h for at least 8 weeks compared with the proportion observed to reach the target 12 mg/day capsule dose in previous trials of rivastigmine oral applications [START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF][START_REF] Corey-Bloom | A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease[END_REF][START_REF] Rösler | Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial[END_REF]. Patient compliance and caregiver preference and satisfaction with the patch in this open-label setting were also evaluated. with a cholinesterase inhibitor (patients prescribed both rivastigmine and memantine were permitted) or had failed to benefit from previous cholinesterase inhibitor treatment. These included patients that had experienced a tolerability issue with other cholinesterase inhibitors or were at high risk of drug-drug interactions, patients treated with other cholinesterase inhibitors or memantine that had cognitive, behavioural or functional worsening, or patients that did not reach the 12 mg/day rivastigmine capsule dose due to tolerability issues. All patients were cooperative, willing to complete all aspects of the study, and capable of doing so, either alone or with the aid of a responsible caregiver. In instances where patients were living in the community alone, they were required to have contact with a responsible caregiver on a daily basis to oversee treatment.

Exclusion criteria included the patient not being treated according to the product monograph for rivastigmine capsules, being involved in a clinical trial, or having a current diagnosis of an active skin lesion or disorder that would prevent accurate assessment of adhesion and potential skin irritation of the rivastigmine patch. Other exclusion criteria included a history or presence of any contraindication for the application of the study drug, use of other investigational drugs at the time of enrolment or within 30 days (or 5 half-lives) of enrolment, history of malignancy within the past 5 years, or history of hypersensitivity to any of the study drugs or to drugs with similar chemical structures.

Patients were recruited from 32 centres in Germany. The study was designed to mimic as closely as possible under the conditions of a clinical trial the situation in real life. Thus no placebo or other control group was selected and physicians were not blinded to the medication of the patient. In addition physicians were able to adjust the dosage as needed within the study.

The clinical study was designed, implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations

Interventions

This was a multicentre, 24-week, open-label study. After assessments for eligibility during a 1 to 14 day screening period, patients underwent baseline assessments and entered a 24-week open-label treatment phase. For the first four weeks, patients were treated with 4.6 mg/24 h (5 cm²) rivastigmine patch. After the Week 4 assessment, dosage was increased to 9.5 mg/24 h (10 cm²) with adjustments as necessary for safety and tolerability. Patients were then maintained at their highest well-tolerated patch-dose (according to physicians' judgment of tolerability) at or below the target dose of 9.5 mg/24 h for an additional 20 weeks.

Study drug dose adjustments and interruptions were permitted. If tolerability problems arose, the patch was removed, the dose was skipped and tolerability was reassessed following the skipped dose. If tolerability problems improved (≤ 3 days missed dose) treatment could be restarted at the same dose level. If tolerability was still an issue, and the patient had been treated with the 4.6 mg/24 h patch, the patient was considered for withdrawal from the study. If the patient had been treated with 9.5 mg/24 h patch, treatment could be re-started at the lower dose level. If tolerability was still an issue, further attempts to increase the dose upward were at the investigator's discretion. If a patient had not reached his/her target dose level during the titration period, but later had resolution of tolerability problems, the investigator could perform the dose increase during the maintenance period. Dose level decreases required for tolerability problems were allowed at any time during the maintenance period.

Outcomes

The primary outcome of this study was the proportion of patients treated with 9.5 mg/24 h rivastigmine patch for at least 8 weeks at Week 24. Evaluation of the secondary outcome Safety was monitored at all visits and assessments were based mainly on the frequency of adverse events (AEs). AEs were coded by primary system organ class and preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA). An AE related to study drug was defined as one considered to have a suspected relationship with the study drug.

Sample size and statistics

Based on the results of earlier clinical trials,(5) it was estimated that at least 65% of patients would reach and maintain the target 9.5 mg/24 h transdermal patch dose. To reach 90% power with a two-sided, one group chi-squared test with a 0.050 two-sided significance level to detect the difference between the null hypothesis proportion of 0.530 and the alternative proportion of 0.650, 176 patients were required. To account for some drop-out and protocol violations, a population of 200 patients was targeted. The study was not powered for secondary efficacy variables.

For the primary endpoint, the intent-to-treat (ITT) and per-protocol (PP) populations were analyzed. The PP population consists of all patients from the ITT population for whom no major protocol violations were reported. Results are reported for the ITT population. The complementary null hypothesis was tested by the asymptomatic z-test for a binomial proportion as implemented in the BINOMIAL option in SAS (PROC FREQ). The observed proportion was reported, together with a 95% confidence interval and a p-value from the z-test. Patients who permanently discontinued the trial were counted as not having reached the target patch size.

The efficacy variables for the secondary objectives were descriptively analyzed using summary statistics. Summary statistics included, number of observations (n), mean, standard deviation, median, minimum and maximum values for continuous variables, as well as frequencies and percentages for categorical variables. For the secondary endpoints, missing values were not replaced.

The safety variables were presented using summary statistics. All safety analyses were performed on the safety population, defined as all patients that received at least one dose of study drug and had at least one post-baseline safety assessment. AEs were summarized by the number and percentage of patients in each primary system organ class and preferred term. For summaries by severity of event, the most severe occurrence for a particular preferred term was used for a given patient. Multiple occurrences of the same AE or serious AE (SAE) in the same patient were counted only once, using the worst severity and drug relationship. There were 39 patients (18.8%) with AEs that led to permanent discontinuation of the study (serious in 6 patients). Consistent with the known safety profile of the rivastigmine patch, the most common AEs leading to discontinuation were skin and subcutaneous tissue disorders (7.2% of patients), psychiatric disorders (4.8% of patients), nervous system disorders (4.3% of patients), and gastrointestinal disorders (4.3% of patients). Three SAEs were associated with the study drug. There was one death during the study period, but the participant died of natural causes and a relationship with the study drug was not suspected.

Cognitive and global outcomes

The change from baseline at Week 24 on cognitive and global outcomes outcome scores (ITT population) are summarized in Table 3. Mean MMSE scores improved from screening (19.6 points) through to Week 8 (21.4 points) and remained improved compared with baseline at Week 24 (20.9 points). Mean ADCS-ADL scores improved from baseline (50.3 points) through to Week 8 (51.5 points) and remained improved compared with baseline at Week 24 (51.4 points). The TMT-A scores improved from baseline at each visit through to Week 24.

Improvements on the ADCS-CGIC (minimal, moderate or marked) at Week 24 were seen in 34.6% of patients when assessed by the patient, and 29.7% of patients when assessed by the caregiver. There were a total of With respect to tolerability, mean ADCPQ scores improved from baseline (12.2 points) at Week 4 (30.5 points) and showed further improvements at Week 24 (30.7 points). The Zarit Burden Interview Score improved slightly at each visit from baseline to Week 24 (Table 3).

International

Discussion

The results of this multicentre, open-label study in patients with probable AD show that the patch formulation enables an increased proportion of patients to reach and maintain the highest available dose of rivastigmine. We found that 74.2% of patients treated with the 9.5 mg/24 h rivastigmine patch were able to reach and maintain the maximum dose for 8 weeks, which exceeds previous demonstrations with an equivalent oral dose obtained with 12 mg/day rivastigmine capsules (e.g. 55-65% of participants on target dose at Week 24/26 study endpoint) [START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF][START_REF] Corey-Bloom | A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease[END_REF][START_REF] Rösler | Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial[END_REF]. In particular, our results are consistent with the pivotal IDEAL trial, which demonstrated that 95.9% of patients in the 9.5 mg/24 h patch group and only 64.4% of patients in the 12 mg/day capsule group achieved their target therapeutic dose at the end of the maintenance period at Week 24 [START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF][START_REF] Kurz | Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer's disease: a review[END_REF]. In the IDEAL study, 83.8% of participants receiving the 9.5 mg/24 h rivastigmine patch stayed in their target dose for at least 8 weeks, compared with only 53.1% of those receiving 12 mg/day rivastigmine capsules (Novartis data on file) (5). Our findings, therefore, support the clinical effectiveness of the rivastigmine patch for the treatment of patients with mild-to-moderately severe AD because it may allow patients easier access to higher doses, thereby enabling patients to stay on and benefit from effective treatment for longer [START_REF] Kurz | Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer's disease: a review[END_REF].

With respect to secondary outcomes, at Week 24, patients treated with the rivastigmine patch showed improvements in MMSE, ADCS-ADL, ADCS-CGIC and TMT-A scores, indicating improvements in cognition, activities of daily living and general brain function. These data are similar to those in the IDEAL study, which demonstrated statistically significant differences versus placebo for both rivastigmine patch and rivastigmine capsule on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), ADCS-CGIC, ADCS-ADL, MMSE and TMT-A [START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF]. In support of the caregiver preference sub-study of the IDEAL trial, which demonstrated 72% of caregivers to prefer patches to capsules for drug delivery (6), we found that the ADCPQ improved at Week 4 and then remained stable over the course of the study, also indicating caregiver acceptance, preference, and satisfaction with the patch. The Zarit Burden Interview Score showed minimal, but consistent improvement during the course of the study indicating a decrease in caregiver burden associated with use of the rivastigmine patch.

The most frequent AEs were diarrhoea, nausea, vomiting, erythema and pruritus. Psychiatric disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders were the most common AEs by system organ class while receiving treatment, each occurring in more than Adverse events associated with cholinesterase inhibitors, particularly nausea and vomiting may be dependent on the magnitude of peak plasma concentrations (C max ) or the rapid rate of rise of the plasma concentration after oral administration. These effects should be lessened with the patch formulation, as C max and rate of rise of plasma concentrations are lower than with oral dosing with rivastigmine capsule [START_REF] Mercier | Rivastigmine exposure provided by a transdermal patch versus capsules[END_REF][START_REF] Lefèvre | Pharmacokinetics and bioavailability of the novel rivastigmine transdermal patch versus rivastigmine oral solution in healthy elderly subjects[END_REF]. Recent studies have demonstrated that the rivastigmine patch allows steady and continuous drug delivery through the skin into the bloodstream, avoiding first-pass effects in the gut and the liver [START_REF] Cummings | Pharmacokinetic rationale for the rivastigmine patch[END_REF]. Pharmacokinetic studies in AD patients have reported that the 9.5 mg/24 h rivastigmine patch delivers comparable drug exposure to the highest dose of capsules (12 mg/day), with a lower C max and slower times to C max (t max ) [START_REF] Mercier | Rivastigmine exposure provided by a transdermal patch versus capsules[END_REF]. In the 2007, six-month, double-blind, randomized, placebo-controlled study of rivastigmine patch versus capsule (IDEAL; ENA713D2320) the 9.5 mg/24 h rivastigmine patch demonstrated similar effectiveness to the highest dose of rivastigmine capsule (12 mg/day) but with a superior tolerability profile [START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF]. Further investigations of the efficacy and safety of higher doses of rivastigmine (e.g. 13.3 mg/24 h patch) are ongoing [START_REF] Kurz | Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer's disease: a review[END_REF].

In this study we have demonstrated the 9.5 mg/24 h rivastigmine patch to have similar efficacy and safety profile as demonstrated in the IDEAL study [START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF]. The application of rivastigmine in a patch formulation therefore significantly reduces the rate of gastrointestinal side effects compared with oral cholinesterase inhibitors while considerably increasing the adherence to higher dose therapy. Reaching a target dose of cholinesterase inhibitor and staying on it longterm may be pivotal in delaying the symptoms of AD. Higher doses of oral rivastigmine have been associated with better scores on the ADAS-cog, Clinician Interview-Based Impression of Change-plus carer interview and MMSE [START_REF] Anand | Dose-response effect of rivastigmine in the treatment of Alzheimer's disease[END_REF]. Patients should be encouraged to reach what is considered to be an optimal therapeutic dose and to stay on treatment long-term [START_REF] Small | Defining optimal treatment with cholinesterase inhibitors in Alzheimer's disease[END_REF].

The favourable tolerability, safety and efficacy profile of the rivastigmine patch may not only allow access to therapeutic doses of cholinesterase inhibitor, but may also increase treatment compliance among persons with AD and their caregivers. Non-compliance with AD therapies is a wide-spread problem and is often a barrier to effective therapy [START_REF] Small | A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch[END_REF][START_REF] Singh | Treatment persistency with rivastigmine and donepezil in a large state medicaid program[END_REF][START_REF] Mauskopf | Drug persistency patterns for patients treated with rivastimgine or donepezil in usual care settings[END_REF]. However, patients who continue on rivastigmine treatment for up to 5 years have shown sustained and significant benefits over model-based untreated patients [START_REF] Small | Cognitive performance in Alzheimer's disease patients receiving rivastigmine for up to 5 years[END_REF]. A recent database analysis of a large US health plan determined that only 58% of AD patients stayed on oral treatment for at least a year and concluded that educating caregivers and physicians on the importance of medication compliance is an important intervention to potentially improve patient outcomes [START_REF] Borah | Predictors of adherence among Alzheimer's disease patients receiving oral therapy[END_REF]. The favourable risk-benefit profile of rivastigmine patch may provide a realistic way to increase treatment compliance with AD therapy. Approaches that improve treatment compliance may provide better long-term outcomes for patients with AD, and also offer a better quality of life to caregivers.

The strengths of our study being open-label and a real-life observational study also provide some limitations; the information it offers in terms of efficacy and tolerability of rivastigmine patch is minimal in comparison to the data from the pivotal study [START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF]. There was no placebo or parallel control group meaning that Week 24 changes in effectiveness in the absence of rivastigmine are unknown. In addition, physicians were not blinded to study treatment and physicians were able to adjust the dosage freely as needed within the study. The 74.5% completion rate may also limit interpretation of the results, but while this discontinuation rate is slightly higher than that reported in the IDEAL study with rivastigmine patch and capsules,(5) it is consistent with or lower than those reported in other clinical trials with cholinesterase inhibitors [START_REF] Corey-Bloom | A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease[END_REF][START_REF] Rösler | Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial[END_REF]20). It is also appreciated that the proportion of patients able to reach and maintain the highest available dose of rivastigmine in this open-label setting may be due to factors additional to the mode of delivery, such as the presence of comorbidities, the level of care of therapeutic teams and the degree of engagement of relatives or caregivers. Longer-term follow-up is required to elucidate the full impact of the rivastigmine patch on treatment adherence, compliance and ability to permit access to optimal therapeutic doses of rivastigmine.

Our study demonstrates that transdermal delivery may allow a greater proportion of patients to reach and maintain therapeutic target doses of rivastigmine compared with oral rivastigmine.

With increasing recognition of treatment compliance and the benefits of reaching a therapeutic dose and staying on treatment long term, the rivastigmine patch should be considered a viable option for the first-line treatment of patients with mild-to-moderately severe AD.

  inclusion criteria for this study were men and women not of child-bearing potential of at least 50 years of age with probable AD (according to criteria of the National Institute of Neurological and Communicative Disorders and Stroke [NINCDS] and Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV]) and a Mini-Mental State Examination (MMSE) score of ≥ 10 and ≤ 26. Patients were initiating therapy for the first time

6 (

 6 including European Directive 2001/83/EC and US code of Federal Regulations Part 21), and with the ethical principles laid down in the Declaration of Helsinki.

  measures were performed at screening (MMSE only), baseline and at Weeks 4, 8 and 24. The secondary outcomes were scores on the MMSE, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), Trail Making Test Part A (TMT-A), and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). Other secondary outcomes were the Alzheimer's Disease Caregiver Preference Questionnaire (ADCPQ) and Zarit Burden Interview Score (mini-Zarit score).

  patients. However, AEs such as nausea and vomiting are common with cholinesterase inhibitors in clinical studies and can usually be managed by dose alteration. The observed SAEs were rare and correlated with the known safety profile of rivastigmine patch[START_REF] Winblad | A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease -rivastigmine patch versus capsule[END_REF].

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	20. Figure Legends Feldman HH, Lane R. Rivastigmine: a placebo controlled trial of twice daily and three
	times daily regimens in patients with Alzheimer's disease. J Neurol Neurosurg
	Psychiatry. 2007 Oct; 78: 1056-63. Figure 1. Flow of participants through the study.
	F o F o F o F o
	r r r r
	P P P P
	e e r e e r e e r e e r
	R e v i e w R e v i e w R e v i e w R e v i e w
	O n O n O n O n
	l y l y l y l y
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[START_REF] Singh | Treatment persistency with rivastigmine and donepezil in a large state medicaid program[END_REF]

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Table 1 .

 1 Baseline demographics of the safety population.

	Variable

Table 2 .

 2 Number and percentage of patients experiencing adverse events (AEs) by system organ class (safety population).

	System organ class

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Table 3 .

 3 Change from baseline at Week 24 on secondary outcome scores (ITT population). Score at Visit 1(screening); † Assessed by patient; ‡ Assessed by caregiver; MMSE: Mini-Mental State Examination; ADCS-CGIC: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change; TMT-A: Trail Making Test Part A; ADCS-ADL: Alzheimer's Disease Cooperative Study-Activities of Daily Living; ADCPQ: Alzheimer's Disease Caregiver Preference Questionnaire. Increased MMSE, ADCS-ADL and ADCPQ scores indicate improvement. Decreased TMT-A and Zarit Burden Interview scores indicate improvement.

	Outcome measure	Mean (SD) baseline score	Mean (SD) change from baseline
			at Week 24
	MMSE*, mean (SD)	19.6 (4.3)	1.3 (3.8)
	ADCS-CGIC † , n (%)
	Missing	-	2 (1.1)
	No change	-	47 (25.8)
	Minimal improvement	-	25 (13.7)
	Moderate improvement	-	23 (12.6)
	Marked improvement	-	15 (8.2)
	Minimal decline	-	37 (20.3)
	Moderate decline	-	12 (6.6)
	Marked decline	-	5 (2.7)
	ADCS-CGIC ‡ , n (%)
	Missing	-	1 (0.5)
	No change	-	21 (11.5)
	Minimal improvement	-	23 (12.6)
	Moderate improvement	-	16 (8.8)
	Marked improvement	-	15 (8.2)
	Minimal decline	-	56 (30.8)
	Moderate decline	-	20 (11.0)
	Marked decline	-	14 (7.7)
	TMT-A	149.2 (131.3)	-8.9 (109.5)
	ADCS-ADL	50.3 (20.1)	1.3 (12.0)
	ADCPQ	12.2 (2.1)	18.5 (7.0)
	Zarit Burden Interview	2.6 (1.6)	-0.4 (1.6)
	*

International Journal of Clinical PracticeInternational Journal of Clinical Practice

Acknowledgements

The study for which the current data were collected and the current data analyses were sponsored by Novartis. Alpha-Plus Medical Communications Ltd (UK) provided medical writing and editorial support in the production of this manuscript; this service was sponsored by Novartis. Page 13 of 20 International Journal of Clinical Practice International Journal of Clinical Practice

Results

Participants

The first patient was enrolled in August 2007 and the last patient completed the study in October 2008. A total of 208 participants received the intended treatment. Of these, 155 (74.5%) completed the study as per protocol (Figure 1). In all, 67 patients had at least one major protocol violation. The most frequent protocol violation was premature discontinuation of the study (53 in total). Other frequent violations were poor compliance. The safety population comprised 208 patients (100.0%), the ITT population comprised 182 patients (87.5%) and the PP population comprised 140 patients (67.3%). No grouping was done, and analyses were performed on the ITT population. Baseline demographic data of the safety population are summarized in Table 1.

Primary objective

Compliance

Within the ITT population, 135/182 patients (adherence rate 74.2%; 95% CI 67.8-80.5%) were treated for at least 8 weeks with the 9.5 mg/24 h rivastigmine patch and completed the study (p < 0.0001). There were 147/182 patients (adherence rate 80.8%; 95% CI 75.0-86.5%) treated for at least 8 weeks with the 9.5 mg/24 h rivastigmine patch regardless of whether they completed the study (p < 0.0001).

Secondary objectives

Safety and tolerability

The number and percentage of patients experiencing AEs by system organ class (safety population) are summarized in Table 2. Only gastrointestinal disorders, psychiatric disorders and skin and subcutaneous tissue disorders were seen in more than 10% of patients. The most common AEs were nausea (10.1% of patients), erythema (8.7% of patients), pruritus (8.2% of patients), vomiting (7.2% of patients), diarrhoea and agitation (both 4.3% of patients). Similarly, the most common AEs with a suspected relation to the study drug were erythema (8.2% of patients), nausea (7.7% of patients), pruritus (7.2% of patients) and vomiting (4.8% of patients).

Within the psychiatric disorders, agitation occurred in 4.3%, anxiety in 1%, depression in 1.4% and hallucination in 0.5% of patients.

Author contributions

All authors contributed to the content, drafting, critical revision and approval of this manuscript.

Monika Baier performed the statistical analyses on which the article is based.