The Journal of Nutrition, Health & Aging Volume 13, Number 6, 2009

JNHA: CLINICAL TRIALS AND AGING

HEALTH AND NUTRITIONAL PROMOTION PROGRAM FOR PATIENTS WITH DEMENTIA (NUTRIALZ STUDY): DESIGN AND BASELINE DATA
A. SALVA1, S. ANDRIEU2,3, E. FERNANDEZ1, E.J. SCHIFFRIN4, J. MOULIN5, B. DECARLI5, Y. GUIGOZ4, B. VELLAS2,6 AND THE NUTRIALZ GROUP*
1. Institut de l'Envelliment, Universitat Autnoma de Barcelona, Barcelona, Spain; 2. Inserm U558, F-31073 Toulouse, France; 3. CHU Toulouse, Service dpidmiologie et de sant publique, F-31073 Toulouse, France; 4. Nestl Nutrition, Nestec Ltd, CH-1800 Vevey, Switzerland; 5. Nestl Research Center, CH-1000 Lausanne 26, Switzerland; 6. Grontople, Hpitaux de Toulouse, F-31073 Toulouse, France. Corresponding Autor: Antoni Salv, Institut de l'Envelliment, Universitat Autnoma de Barcelona, St. Antoni M. Claret 171, 08041 Barcelona, Spain, E-mail: antoni.salva@uab.es

Abstract: Background: There is a lack of data on global weight loss prevention programs for patients with dementia or clear evidence about their impact on a functional level, caregiver burden or the use of healthcare and social resources. NutriAlz is a socio-educative and nutritional intervention program to prevent weight loss and loss of function in dementia patients. Study Design and Methods: A cluster randomized multi-centre study, which will allow the comparison of a group benefiting from the intervention with a control group after a year of monitoring. Patients were recruited from 11 hospitals in the ambulatory diagnostic units and day care centres. The baseline interview include: sociodemographic and socioeconomic variables (age, gender, educational level, marital status); diagnostic, treatments, MMS, a list of comorbid conditions; activities of daily living (ADL, IADL), Zarit Scale, brief-NPI, Cornell scale and nutritional status as measured by the Mini Nutritional Assessment. All participants or their family signed the inform consent form. Baseline characteristics: Total of 946 patients were included, with a mean ( SD) of 79 7.3 year of age; 68,1 % were women; 44,9% lives with their partner, only 3% lives alone; 79.8% had Alzheimers dementia, 5.25 3.0 years since symptoms of dementia and 2.8 2.11 years since diagnosis. Mean MMSE score was 15.4 6.2; mean weight was 64.4 12.5 kg; mean BMI was 27.0 4.5 (with 3% below 19, 5% between 19-21, 10% between 21-23, and 82% above 23). Mean ADL without difficulties was 3.2 2.1; mean IADL without difficulties was 0.7 1.6; mean number of symptoms in the NPI was 4.4 2.59, with severity score of 7.9 5.9 and distress score of 11.3 9.0; mean Zarit scale was 27.4 15.5; mean MNA was 23.2 3.5 with 5 % as malnourished, 32 % at risk of malnutrition, and 63 % with adequate nutritional status. Key words: Alzheimer disease, dementia, nutritional program.

Introduction As the population ages, there is an increase in the number of people with disability (1) and specially of those diagnosed with chronic neurodegenerative disorders, Alzheimer's disease (AD) and other forms of dementia (2, 3). In Europe the prevalence rates for dementia is between 6% to 10 % in subjects aged 65 and over, with approximately 60% of those have AD (4-6). Median estimated survival time was 4.5 years for all people with dementia of age and 10.7 years for elderly aged 65-69 years (7), and 50% of dependence in the elderly is related to AD (8), which indicate the increasing need of care for elderly with dementia Protein-energy malnutrition (PEM) is extremely frequent among elderly people with chronic illnesses. Screening for malnutrition show that incidence of malnutrition is low in the community (2% 0.1 (mean SE); 21 studies, n = 14149 elderly), while a high prevalence is present in hospitalized and institutionalized elderly patients (hospital: 23 0.5%; 35 studies, n = 8596 and institutions: 21 0.5%; 32 studies, n = 6821 elderly) (9). PEM has multiple causes. Among the problems most frequently detected are: dependency on feeding, depression, dementia and associated eating behaviour problems, polymedication, without forgetting specific
Received February 11, 2009 Accepted for publication February 17, 2009

inflammatory reactions produced by some chronic illnesses. Alzheimer's disease can be considered a risk factor for suffering PEM. In cognitively impaired elderly subjects prevalence of malnutrition was 15 0.8% (10 studies, n = 2051 elderly subjects), and 44 1.1% of risk of malnutrition (9). Impaired cognitive function induces dependence in the activities of everyday life, particularly related to eating (10-12), and low nutrient intakes relate to frailty (13). Various studies show that patients with AD have higher weight loss percentages than healthy people of the same age (14, 15) and weight loss is also present early in disease or even preceded dementia (16-19), suggesting weight loss as preclinical marker of dementia (20, 21). Correlation was found between the stage of dementia and weight loss so that the severer the dementia the greater the weight loss. Involuntary weight loss has been correlated with a worsening in the state of health, elderly who had lost more than 4% of their weight in a year had higher morbi-mortality (17, 22). Weight loss predicts functional decline (23) and elderly with weight loss related malnutrition have a greater risk of being institutionalised (24). In AD patients besides changes in metabolic state and appetite, causes of weight loss in AD are related to the changes in feeding behaviour which entail a nutrient-poor intake (12, 2527). Intervention with caregivers seems to be effective in the

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HEALTH AND NUTRITIONAL PROMOTION PROGRAM FOR PATIENTS WITH DEMENTIA (NUTRIALZ STUDY) prevention of weight loss in people with AD (28). The administration of nutritional supplements is effective at improving the anthropometric parameters in elderly people (29, 30). Nutritional intervention programs have been effective in prevention of weight loss in AD (29, 31, 32), and very recently practical guidelines were published (33). However, there are not enough data about the use of global Nutrition programs for patients with dementia or clear evidence about their impact on a functional level, the quality of life or the use of healthcare and social resources. Consequently, NutriAlz study was planned to determine the effectiveness of a teaching and training intervention of health and nutrition program directed both to physician and main caregiver, and person affected by Alzheimer's disease or other dementias. The main objective of this study is to assess the effectiveness of the Nutrition Program on functional level in elderly people with dementia living at home, as well as, improve nutritional status and change clinical practice related to nutrition. This report describe the study design, intervention program, recruitment, randomization and baseline characteristics the patients entered in the NutriAlz study. Methods Study design and setting It is a prospective cluster randomised multi-centre study, which will allow the comparison of a group benefiting from the intervention with a control group after a year of monitoring. Ten hospitals have agreed to participate in the study, representing different specialities (neurology, geriatrics and psychiatry) in order to take into account the diversity of the patients taken on and the practices of the different medical specialities. They have been chosen depending on the capacity for recruiting patients affected by Alzheimer's disease. Four centres of neurology, 4 geriatric centres and 2 psychiatric centres. Each centre was required to recruit an identical numbers of patients with an inclusion period of 6 months. Randomization was done by centre to prevent contamination due to the intervention training of the different healthcare professionals, taking into account the centre speciality. Just before starting study recruitment, one centre withdraw from the study and was replace by a another centre and due to low recruiting capacity of one centre in the intervention group, an additional centre was added to the study. Both centres were taken from the reserve list, and were of the same speciality as the corresponding centres. Study population Patients were consecutively recruited at the outpatient clinics (ambulatory diagnostic unit and day hospital care). Inclusion criteria The study included patient who were diagnosed with dementia according to DSM IV criteria and who were 530 considered to have mild to moderate dementia with MMSE less than or equal to 26. Only ambulatory community-dwelling subjects living at home and who had an identified caregiver were included. Informed consent for participation in the study was given by the responsible relative and, if possible, from the patient or legal guardian. Exclusion criteria Not included were patient who had an MMSE over 26, lived in an institution at entry, and had no identified main carer, as well as patient having naso-gastric tube feeding or in a terminal situation, and patient participating in another nutritional intervention study. Determination of sample size The number of patients necessary for a loss of 0.5 points on the Activity of Daily Living (ADL) scale, which is clinically significant, was estimated as followed: According to the French cohort of AD patients, REAL.FR Study (8), 43.8% loose at least 0.5 points after a one year follow-up period. To reduce this proportion to 30% with error type I of 5% and a type II error of 10% (power of 90%) 300 subjects should be included. Then taking into account a drop out rate of 30% after one year, at least 438 subjects per group should be followed, or 876 subjects in total. The objective was then set to 100 patients per centre to reach about 1000 patients (500 per group). Intervention program Intervention: the NutriAlz program In the centres of the "intervention" group, a standardised protocol for feeding and nutrition was proposed, which included: 1. A personalized presentation and hand over of a briefcase containing: information about Alzheimer's disease (booklet 1), about nutrition in particular (booklet 2), physical exercise (booklet 3), available aid and services, specifically about the program (booklet 4), schedule for collecting data such as weight and height, product samples, coupons for monitoring in a database, etc. This information was given to patients and their relatives with oral information on hotline access, Nutrition Program newsletter. 2. Training for families, caregivers were requested to attend at least 4 sessions of educational intervention done by a dietician which were divided into the following sessions and topics: - Session 1: Presentation of the participants, presentation of the nutritional support program, presentation of the available resources (hotline, etc.), information on weight loss with Alzheimer's disease, how to realise nutritional monitoring, how to weigh, how to fill in the nutritional schedule, on lifestyle habits, on a balanced diet and the food pyramid - Session 2: Continuous information on lifestyle habits, on a balanced diet and the food pyramid, and program on creation of menus, conservation of food, cooking methods, how to

The Journal of Nutrition, Health & Aging Volume 13, Number 6, 2009

JNHA: CLINICAL TRIALS AND AGING increase calorific and protein intake, how to substitute foods that are rejected, nutritional support preparations, and nutritional supplements (what they are for, who prescribes them, how and when to take them, where they can be obtained) further motivation for interest in physical exercise - Session 3: Information on Eating behaviour problems (EBP), practical recommendations on how to cope with EBPs, nutrition and medication, nutrition and illnesses or chronic problems, as well as diabetes, constipation, hypertension, and dyslipidemia. - Session 4: General review, practical examples, problemsolving in the creation of menus. 3. Support in weight monitoring. A voluntary individual weight monitoring system was established through the postal dispatch to the Aging Institute (Autonomous University of Barcelona) of coupons with information about the weight of the person affected. According to weight curve evolution written recommendation will be send by mail and if weight loss is identified as susceptible to making the illness worse, they will be asked to visit a doctor. 4. Periodic information for the families. A voluntary system was established (which was accessed through signing a coupon) through which the people (carers) who so desire received from the Program general information about nutrition, nutritional needs of those with Alzheimer's or other problems related with nutrition. The resulting register was of the caregivers (not the patients) and complied with all legal requirements. The management of this section was by the Aging Institute (Autonomous University of Barcelona). 5. Action protocols and standardised help decision trees for professionals was designed with the participation of at least one person of each intervention centre. Each centre was asked to designate a senior member of the medical and/or nursing staff. The healthcare professionals in the intervention group received training and followed the program recommendations through these forms and action standards. Control group The control group did not benefit from the intervention; the subjects were followed by the centre according to each centre's usual practice. Subjects must not participate in any other research program which entails intervention. Data Collection Each centre appointed a nurse and/or doctor to carry out the evaluations, and data collection was controlled and monitored by the study supervisor. At entrance into study, at 6 months and 12 months of study following data will be recorded (see Figure 1): Socio-demographic and personal characteristics (age, sex, living accommodations, education, income, medication, hospitalisation) Medical history, including comorbidities and Charlson Index (34, 35) and treatment received. Anthropometry (weight, height, mid-arm and calfcircumference) Cognitive state: Mini Mental State Examination (MMSE, (36)) and Clinical Dementia Rating scale (CDR, (37, 38)); with CDR score of 0.5 representing questionable dementia, CDR score of 1 mild dementia, CDR score of 2 moderate dementia and CDR score of 3 severe dementia. Nutritional evaluation: Mini Nutritional Assessment (MNA, (37-40)) and the Eating Behaviour Scale (EBS, (41, 42)) Behavioural problems: Neuropsychiatric Inventory questionnaire (NPI-Q, (43-45)) Depression: Cornell scale (46, 47) Autonomy in daily activities: Activities of Daily Living scale (48) and Instrumental Activities of Daily Living scale (49) Health care cost: Resource Utilisation in Dementia (RUD, (34, 35, 50) Caregiver burden: Zarit scale (51) and information on main caregiver (age, activity..) Figure 1 Study design: Multicentre cluster randomized study: Eleven AD centres with follow up for one year

Multi-component intervention targeted at healthcare professional and AD patients families (Briefcase: Information/recommendation on nutrition and Alzheimer disease; ADL: Activities of Daily Living; IADL: Instrumental Activities of Daily Living; MNA: MiniNutritional Assessment; MMSE: Mini-Mental State Examination; Zarit: Zarit scale (caregiver burden); RUD: Resource Utilization in Dementia; EBS: Eating Behavior Scale;). Time 0 (T0): date of screening; Time 1 (T1): T0 + 2-4 weeks.

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HEALTH AND NUTRITIONAL PROMOTION PROGRAM FOR PATIENTS WITH DEMENTIA (NUTRIALZ STUDY) Outcome measures Main outcome measures The main evaluation criteria which will allow the effectiveness of this intervention to be evaluated are the reduction in the loss of autonomy measured by the ADL/IADL scales. Secondary outcome measures The secondary objectives of this study are: Improvement in the patient's state of nutrition: The measurement criteria which will allow the patient's nutritional state to be evaluated will be their weight, BMI and MNA Reducing the burden on caregiver: The Zarit scale will be used for this evaluation. Evaluation of the use of healthcare and social resources: The RUD scale will be used. Improvement of medical practice regarding nutrition: % of doctors who use instruments such as the MNA, weight curve, anthropometric or biological markers before and after the program, % of doctors who prescribe a treatment or action if the MNA is less than normal, % of doctors who evaluate the nutritional state. Statistical Methodology Analysis sets All subjects included in the study (with a visit T0) constitute the global population. Intervention analysis will be done on Intention-to-treat population (ITT) and protocol population (PP). All subjects included in the study (with a visit T0) will constitute the ITT population and all subjects included in the study without major protocol deviation will constitute the PP population. Primary outcome and all other tests will be considered significant at 5% of significance (p 0.05). Analysis of bivariance and mixed models, adjusted for confounding factors, and randomisation by centre will be taken into account in the comparison of the intervention group and the control group (52;53). For quantitative outcome variables: mixed covariance analysis (parametric) or, if the assumptions (normality and homogeneity of the variances) are not met, mixed covariance analysis performed on rank data (non-parametric), will be used with centre as random factor. Other covariates (fixed factors) will be defined in the appropriate section. For binary outcome variables: Mixed logistic model with centre as random factor will be used. Other covariates (fixed factors) will be defined in the appropriate section. Statistical analyses are performed with SAS V8 and AdClin 3.2. Results Baseline Characteristics Population studied and Socio-economic information The study population was composed of 946 communitydwelling AD patients recruited by 11 Alzheimer outpatients

Table 1 Baseline characteristics - Socio-demographic information of the randomized NutriAlz Study Patients
Characteristics n Age Age groups (years) <65 65-74 75-79 80-84 85-89 >=90 Mean age SD (years) Gender Male Female Education (years in formal education) Mean SD Number of years in education 0-1 2-4 5-10 >10 Living arrangements Lives alone Lives with a partner, as caregiver a caregiver a caregiver & other relatives or friends Other 40 191 221 296 145 53 79.0 7.3 302 644 4.8 4.3 279 190 397 80 30 425 229 228 34 (29.5) (20.1) (42.0) (8.5) (3.2) (44.9) (24.2) (24.1) (3.6) 113 83 222 30 20 183 90 150 5 (33.5) (1.1) (31.9) (68.1) 148 300 4.95 3.9 (25.2) (18.5) (49.6) (6.7) (4.5) (40.8) (20.1) 166 107 175 50 10 242 139 78 29 (4.2) (20.2) (23.4) (31.3) (15.3) (5.6) 14 87 105 136 79 27 79.4 7.0 (33.0) (67.0) 154 344 4.6 4.55 (33.3) (21.5) (35.1) (10.0) (2.0) (48.6) (27.9) (15.7) (5.8) (3.1) (19.4) (23.4) (30.4) (17.6) (6.0) 26 104 116 160 66 26 78.6 7.5 (30.9) (69.1) (5.2) (20.9) (23.3) (32.1) (13.3) (5.2) All n = 946 (%) n Intervention n = 448 (%) n Control n = 498 (%)

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JNHA: CLINICAL TRIALS AND AGING Table 2a Baseline Clinical Characteristics of the randomized NutriAlz Study Patients
Characteristics n Type of dementia Alzheimer Vascular Mixed (vascular & Alzheimer) Other Time since symptoms of dementia (years) mean SD Time since diagnosis (years) mean SD MMSE score (mean SD) MMSE score <11 11-20 20-26 CDR global score (mean SD) CDR score 0.5 1 2 3 608 119 131 88 5.25 3.0 2.8 2.1 15.4 6.2 189 533 204 1.8 0.8 82 293 374 197 (8.7) (31.0) (39.5) (20.8) 26 145 177 100 (20.4) (57.6) (22.0) 99 262 74 1.8 0.8 (5.8) (32.4) (39.5) (22.3) 56 148 197 97 All n = 946 (%) (64.3) (12.6) (13.8) (9.3) n n 305 48 64 31 5.1 3.0 2.7 2.1 14.7 6.0 (22.8) (60.2) (17.0) 90 271 130 1.7 0.8 (11.2) (29.7) (39.6) (19.5) Intervention n = 448 (%) (%) (68.1) (10.7) (14.3) (6.9) n n 303 71 67 57 5.35 3.0 2.9 2.1 16.0 6.25 (18.3) (55.2) (26.5) Control n = 498 (%) (%) (60.8) (14.3) (13.5) (11.4)

and day care centres (figure 1 & table 1). The mean age was 79 7 years of age (mean SD) with 68 % women and 32% men. Fifty percent of the AD patients had 5 years or more of education. Forty five percent live with their spouse, 48% with a caregiver with or without another relative, while 3%still live alone. No significant difference was observed between the intervention and control group for the socio-demographic variables (table 1). Clinical characteristics A summary of the clinical characteristics of the subjects are presented in table 2a-f. As expected the major dementia types were of Alzheimer (64.3%) and vascular (12.6%) type, without significant difference between intervention and control group (table 2a). The majority of subjects had moderate to severe dementia with MMSE mean score of 15.4 6.2 and CDR score of 1.8 0.8, again without difference between groups. Staging of dementia is as followed: very mild or questionable dementia (CDR score 0.5) 9%, mild dementia (CDR score 1) 31%, moderate dementia (CDR score 2) 39.5%, and severe dementia (CDR score 3) 21%. Time since symptoms was 5.25 3.0 years and the time since diagnostic of 2.8 2.1. Medications are present in 93% of the subjects, with 66% concomitant medication related with dementia (Menantime 12%, Donepezil 26%, Rivastigmine 16% and Galantamine 16% of the patients) (table 2b).Vitamin supplement and nutritional complement were not frequently administered (only to 7% of the patients). Most patients had comorbid chronic problems (with a mean number of 4.4 2.4) and a Charlson Comorbidity index of 2.1 1.4 (table 2b), and 37% had fallen during the last year, suggesting a rather frail group of patients. This is confirmed by the ADL score of 4.0 1.75 and IADL score of 2.4 2.2 (table 2c). Ninteen percent were independent in ADL,

but only 3% were rather independent in IADL. However 68% were independent in feeding (ADL scale) and 59% needed to have food prepared (IADL scale). A significant difference was observed for ADL score between the intervention and control group (p = 0.0103), with more independent subjects in the control group (24% versus 14% in the intervention group) (table 2c). Psychosocial and behavioural disturbances assessed by the NPI-Q showed high frequency of apathy (64%), irratibility/instability (50%), depression (49%), agitation/aggression (42%) and appetite disorders (40%), with a NPI-Q score of 4.4 2.6, a NPI-Q severity score of 7.9 5.9 and a NPI-Q distress score of 11.3 9.0 ( table 2d). Social, family, caregiver burden were assessed by the Zarit scale with a mean score of 27.4 15.5, and with an indication of higher burden in the intervention (Zarit score of 30.6 15.4 vesrus 24.5 15.0 in the control, p = 0009) (table 2e). Time since taken care by a caregiver was 4.1 3.3 years and the caregivers were in high majority (88%) either the spouse (39%) or the children (son/daughter) (48.5%). Only 1.6% were paid caregivers. The mean time spent supervising was 263 253 hours per month (~9 hours per day) and the mean time spent with the patient was 397 257 hours. Nutrition Evaluation of the risk for malnutrition using the MNA resulted in 5% of malnourished patients, 37% at risk for malnutrition and 58% well nourished subjects. The MNA score was significantly different between the two group: Intervention 22.3 3.8 and control group 24.0 3.0, p = 0007 (table 2f). This difference was marked by the higher percentage of malnourished patients (8% versus 3%) and of patients at risk of malnutrition (47% versus 29%) in the intervention group. The 533

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HEALTH AND NUTRITIONAL PROMOTION PROGRAM FOR PATIENTS WITH DEMENTIA (NUTRIALZ STUDY) Table 2b Baseline Clinical Characteristics of the randomized NutriAlz Study Patients
Characteristics n Charlson Comorbidity Index Number of comorbid problems Comorbidities Hypertension Arthrosis Cardiovascular diseases* Cerebrovascular disease Diabetes Fracture/Joint prothesis Number of medications At least one medication Concomitant medication related with dementia Memantine Donepezil Rivastigmine Galantamine Vitamin supplement or nutritional complement Fallen over the last year 882 621 114 245 148 152 62 348 2.1 1.4 4.4 2.4 410 392 223 163 153 138 4.4 2.9 (93.2) (65.6) (12.1) (25.9) (15.6) (16.1) (6.6) (36.8) 414 279 48 106 89 46 34 186 43.3 41.4 23.6 17.2 16.2 14.6 196 192 126 84 75 69 4.6 3.0 (92.4) (62.3) (10.7) (23.7) (19.9) (10.3) (7.6) (41.5) 468 342 66 139 59 106 28 162 All n = 946 (%) n 2.2 1.5 4.6 2.2 43.8 42.9 28.1 18.8 16.7 15.4 214 200 97 79 78 69 4.3 2.8 (94.0) (68.7) (13.3) (27.9) (11.8) (21.3) (5.6) (32.5) Intervention n = 448 (%) n 2.0 1.3 4.2 2.6 43.0 40.2 19.5 15.9 15.7 13.9 Control n = 498 (%)

*Cardiovascular diseases includes heart attack, heart failure and peripheral arterial disease

Table 2c Baseline Clinical Characteristics of the randomized NutriAlz Study Patients

Characteristics n ADL score (mean SD) Number of activities without difficulties No dependency 1 dependency 2 dependencies 3 dependencies Independent for Bath Dressing Toilet use Mobilisation Continence Feeding Lawton IADL score (mean SD Number of activities without difficulties 0-2 dependencies 6 dependencies 4.0 1.75 3.24 2.1 181 153 126 483 311 413 608 700 383 646 2.4 2.2 0.71 1.6 25 915 (2.7) (97.3) 5 442 (19.2) (16.2) (13.4) (51.2) (32.9) (43.7) (64.3) (74.1) (40.5) (68.3) 64 67 61 255 126 178 263 310 152 259 2.2 2.1 0.55 1.3 (1.1) (98.9) 20 473 All n = 946 (%) n 3.75 1.8 2.9 2.1 (14.3) (15.0) (13.6) (57.1) (28.1) (39.7) (58.7) (69.4) (33.9) (57.8) 117 86 65 228 185 235 345 390 231 387 2.50 2.3 0.85 1.8 (4.0) (96.0) Intervention n = 448 (%) n 4.2 1.7 3.6 2.0 (23.6) (17.3) (13.1) (46.0) (37.1) (47.3) (69.4) (78.3) (46.4) (77.7) Control n = 498 (%)

Table 2d Baseline Clinical Characteristics of the randomized NutriAlz Study Patients

Characteristics n NPI-Q score (mean SD) Delusions Hallucinations Agitation/Aggression Depression/dysphoria Anxiety Exaltation/euphoria Apathy/indifference Desinhibition Irratibility/instability Aberrant motor behaviour Sleep symptoms Appetite disorders NPI-Q severity score (mean SD) NPI-Q distress score (mean SD) 11.3 9.0 11.9 8.9 10.8 9.1 7.9 5.9 8.1 5.7 7.6 6.1 282 211 397 462 481 99 606 205 475 293 285 381 4.4 2.6 (29.9) (22.3) (42.0) (48.9) (50.9) (10.5) (64.2) (21.7) (50.4) (31.1) (30.2) (40.4) 155 117 202 228 241 54 271 83 239 129 158 223 All 946 (%) N 4.7 2.6 (34.8) (26.2) (45.2) (51.1) (53.9) (12.1) (60.5) (18.5) (53.3) (28.8) (35.3) (49.3) 127 94 195 234 240 45 335 122 236 164 127 158 Intervention n = 448 (%) N 4.2 2.6 (25.5) (18.9) (39.2) (47.0) (48.2) (9.1) (67.5) (24.6) (47.7) (33.1) (25.7) (31.9) Control n = 498 (%)

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JNHA: CLINICAL TRIALS AND AGING Table 2e Baseline Clinical Characteristics of the randomized NutriAlz Study Patients
Characteristics n Zarit score (mean SD) Time since the caregiver took care of the patient (years) Age of caregiver Women caregivers Caregiver relationship with patients Spouse Son or daughter Friend Other (unpaid) Paid caregiver During last month, time spent by caregiver supervising the patient Hours/day Days/month Hours/month Total time dedicated to patient during the last month (hours) Hospitalisation within last month Cornell scale score (mean SD) Score 12 All n = 946 (%) n 30.6 15.4 4.1 3.3 58.35 13.3 353 149 242 8 40 9 (78.8) (33.3) (54.0) (1.8) (8.9) (2.0) 354 221 217 4 50 6 27.4 15.5 4.1 3.3 60.1 13.6 707 (74.7) 370 459 12 90 15 (39.1) (48.5) (1.3) (9.5) (1.6) Intervention n = 448 (%) n 24.5 15.0 4.1 3.3 61.7 13.6 (71.1) (44.4) (43.6) (0.8) (10.0) (1.2) Control n = 498 (%)

8.9 8.4 26.0 9.9 263 253 397 257 55 8.25 6.1 179 (23.6) 103 (5.8) 44

10.1 9.4 25.4 10.6 297 282 428 265 (9.8) 9.9 6.6 (33.8) 76 11

7.9 7.35 26.5 9.2 234 220 369 247 (2.2) 7.1 5.4 (16.8)

Table 2f Baseline Clinical Characteristics of the randomized NutriAlz Study Patients

Characteristics n MNA score (mean SD) MNA score <17 17-23.5 24 Weight (kg) (mean SD) BMI ((Kg/m2) (mean SD) <19 19 -20.9 21-22.9 23 > 25 Eating behaviour scale Score (mean SD) Duration of the meal (minutes) (mean SD) Independent for finishing meal Fallen over the last year 729 348 30 12.9 (77.1) (36.8) 307 186 30 14.3 (68.5) (41.5) 422 162 29 11.4 (84.7) (32.5) 16.0 3.7 15.45 3.8 16.4 3.5 49 347 544 23.2 3.5 (5.2) (36.9) (57.9) 64.35 12.5 27.0 4.5 (2.8) (5.2) (9.4) (82.6) (66.3) 35 204 208 63.5 12.5 26.6 4.4 17 23 46 362 287 (3.8) (5.1) (10.3) (80.8) (64.1) All n = 946 (%) n 22.3 3.8 (7.8) (45.6) (46.6) 14 143 336 65.1 12.5 27.3 4.6 (1.8) (5.3) (8.7) (84.2) (68.4) Intervention n = 448 (%) n 24.0 3.0 (2.8) (29.0) (68.2) Control n = 498 (%)

26 49 89 777 624

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mean weight was 64.35 12.5 kg and the mean BMI was 27.0 4.5 with 83% of the subjects with a BMI equal or over 23. Independence for finishing meals was 77% and the duration of the meal 30 13 minutes, and the EBS score was 16.0 3.65. The independence for finishing meals was higher in the control group than the intervention group, 85% versus 68.5% respectively. In general the patients showed moderate severity of dementia with numerous comorbidity and dependence in the

IADL. A significant difference is observed at baseline between the intervention group and the control group for the number of activities in ADL, with higher dependency for feeding, a higher caregiver burden measured with the Zarit scale, and a higher risk for malnutrition and more feeding problems. This suggests a more frail intervention group compared to control group even with cluster randomization.

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HEALTH AND NUTRITIONAL PROMOTION PROGRAM FOR PATIENTS WITH DEMENTIA (NUTRIALZ STUDY) Discussion Cluster randomised trial form was chosen in order not to disturb the normal daily function of the different clinical centres participating to the study and to prevent the treat of contamination of the intervention protocol in the control group. The CONSORT statement extension to cluster analysis was, however, published after the start of the study, therefore not all methodological requests reported in the statement are fulfilled, mainly in the sample size procedure (54). But clustering is and will be taken into account in the analysis (52, 53). In comparison with other studies such as Real.FR (8, 37), PLASA (55) and the ICTUS (56) studies following remarks can be made: While the population age is similar, only 3% of our population lives alone, but 31% in the PLASA study, 28% in the Real.Fr study and 20% in the ICTUS study were living alone. This might represent a cultural difference between south of France and northern Spain, with a different role of the family in the care of the elders. Even the patients were living at home, they are of moderate dementia stage according to CDR scores (0 = no impairment, 0.5, 1, 2, and 3 indicating very mild, mild, moderate and severe dementia respectively) (37), while in the 3 mentioned cohorts they were of very mild to mild stage of dementia; CDR score 1, 31% against 42% in Real.Fr study and 44% in the ICTUS study, while CDR score 2-3 represents 60% of our population and only 22% and 13% in Real.Fr and ICTUS studies respectively. Psychiatric disturbances, measured on the NPI, were also more frequent, and a graded level of problems was observed between ICTUS, Real.FR, PLASA studies and NutriAlz respectively, with incidence of depression of 23%, 40%, 48% and 49%, and presence of apathy of 13%, 23%, 31% and 40%, respectively. The presence of comorbid conditions was higher than in the ICTUS study, 4.4 versus 1.4, The prevalence of hypertension was, however, similar (43% versus 39%), but prevalence of diabetes was somewhat higher (16% versus 11.8%). We observed a rather high degree of dependence (IADL and ADL scales), and compared to the Real.Fr study we observed a greater loss of independence in NutriAlz, 19% had no disability on the ADL scale, compared to 54%. Further only 6% were dependent on feeding in the Real.Fr study compared to 68% in the present study. This was also observed in the percentage of patients at risk of malnutrition (MNA score <23.5), 35% and 42%, respectively. A higher degree of dependence was also observed by the level of caregiver burden, measured by a Zarit score of 21.1 14.7 for the ICTUS study, 22.6 16 for the Real.Fr study and 27.4 15.5 in the present study. The caregivers were in majority the spouse or children (88%) and rarely a friend (1.3%) or a paid caregiver (1.6%), as in the Real.Fr and PLASA studies. 536 In conclusion, the NutriAlz baseline population was more dependent, showed a moderate to severe dementia stage, with a high risk of malnutrition, compared to the ICTUS, PLASA and Real.Fr studies. The advantage of the cluster study, no contamination of the intervention program in the control group, is however shadowed by an intervention group which is slightly more dependent, as measured by the ADL scale and the caregiver burden (Zarit scale), and which shows more feeding problems and a higher risk of malnutrition.
Author Contributions: Salv A: Study concept and design, Acquisition of data, Analysis and interpretation of data, Drafting of the manuscript. Andrieu S.: Study concept and design, Statistical analysis, Analysis and interpretation of data, Drafting of the manuscript. Fernandez E.: Study supervision, Acquisition of data, Data handling. Schiffrin E.J.: Study concept and design, Analysis and interpretation of data, Drafting of the manuscript. Moulin J.: Statistical analysis, Analysis of data. Decarli B.: Administrative support, Data handling, Analysis of data. Guigoz Y.: Analysis and interpretation of data, Drafting of the manuscript. Vellas B.: Study concept and design, Analysis and interpretation of data, Drafting of the manuscript. NutriAlz Study Group: Acquisition of data Acknowledgement: We thank the patients and their caregivers, as well as the study centres for their participation. We thank MAPI-NAXIS for data handling, performing the cleaning of the database and performing the statistical analysis on the advice of J Moulin and S Andrieu. Funding/Support: Nestl Nutrition, Vevey, Switzerland. Trial Registration: ClinicalTrials.gov Identifier: NCT00479843

Appendix A
NutriAlz Group: Carmen Espinosa. Isabel Fort. Salvador Altimir. Mercel Rossich. Jess Ruiz. Consol Almenar. Pau Sanchez. Llus Trraga. Miquel Aguilar. Secund Lpez Pousa. Sergio Ario. Hospital Sant Jaume. Matar. Centre Socisanitari El Carme. Badalona Hospital Germans Tries i Pujol. Badalona Institut Pere Mata. Reus Policlnica de la Merc. Barcelona Benito Menni CASM. Sant Boi Consorci Sanitari Integral. Hospitalet Fundaci ACE. Barcelona Hospital Mtua de Terrassa Institut Dassistncia Sanitria. Girona Hospital de Granollers

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