GOOD-DAY Trial in Paediatric Obesity
GOOD-DAY Trial in Paediatric Obesity
Alongside efforts in public health and policy to reverse the childhood obesity epidemic,
 medical providers seek to play effective roles in prevention and treatment. Limited
 interventional studies with effective long-term maintenance of weight loss in children are
 available. Moreover, interventions should focus on modifying lifestyle, by improving also
 ludic educational training. In fact, the knowledge, attitudes, behaviors and skills developed
 through effective health programs may result in a better quality of life and empower children
 to make correct choices to promote the health of the individual the family and the community.
 For this reason, in a cohort of obese pediatric subjects with visceral adiposity, the aim of
 the study is to assess the efficacy of an educational training inspired to Mediterranean diet
 and based on gamification (as "The Mediterranean Goose") with respect to a conventional
 treatment on weight loss and improvement of cardio-metabolic risk factors.
Study design: A single-center pilot open-label randomized control trial. Population: The
 study will comprise a total of 60 subjects of both sexes, between 10 and 18 years of age,
 obese, according to the IOTF criteria (Cole TJ et al., 2000) and with visceral adiposity, as
 waist circumference ≥ 90th percentile (Cook S et al., 2003 - Cruz ML, Goran MI, 2004 - de
 Ferranti SD et al., 2004), diet naïve or with failure of weight loss (defined as -1 kg/m2 BMI
 in 1 year).

 Inclusion/ Exclusion criteria (see Eligibility Criteria). Intervention: Patients will be
 randomized in a open-label, into two groups homogeneous for number and sex of the subjects.
 One group (group SD) will receive Standard Diet according to routine care and practice, and
 one group (group SD+MSD) will receive a standard diet according to routine clinical practice
 + a 30 minutes Mediterranean-Style Diet educational training with explanation of
 Mediterranean pyramid + gamification to Mediterranean diet inside the Hospital and at home
 throughout "The Mediterranean Goose".

 Dietary restriction: Thestandard diet will be distributed with 55-60% of carbohydrates
 (45-50% complex and no more than 10% refined and processed sugars), 25-30% lipids and 15%
 proteins, and will be performedin accordance with the calories of an isocaloric balanced diet
 calculated throughout the Italian LARN Guidelines for age and gender (Società Italiana di
 Nutrizione Umana, 2014), inspired to Mediterranean pyramid.The standard diet will be given as
 diet plans in writing, after explanation by a well-trained and experienced clinical
 paediatric endocrinologist.

 Education in Hospital: As well as receiving the aforementioned recommendations, the SD+MSD
 group will also receive a simple visual guide of Mediterranean food pyramid explained by a
 dietitian/nutritionist for 30 minutes (Bach-Faig A et al., 2011).

 Gamification: The MSD Group will be involved inside the Hospital in an educational and
 playful training playing to "The Mediterranean Goose" in the ludic area of the Pediatric
 Department; this game has been proposed in an educational project known as "Mediterranean
 diet and enhancement of traditional foodstuff - MedDiet", founded by European Union in the
 framework of the ENPI CBC Mediterranean Sea Basin Programme (www.med-diet.eu). This material
 will be given to the family for continue to play also at home.

 Physical activity: all subjects will receive general recommendations about performing
 physical activity. Exercise will be conducted daily and will consist of 30 minutes of aerobic
 physical activity.

 Randomization: Alternately per week, participants will be randomly assigned in a 1:1 to one
 of the two dietary intervention groups.

 Timing: Patients will be evaluated firstly at time of enrollment (V0) and, during the first 2
 weeks of study (V1), biochemical and ultrasound evaluations will be completed. During the
 year of intervention, patients will be evaluated after 3 months, 6 months and 12 months (V2,
 V3, V4).The following anthropometric measures, biochemical and ultrasound evaluations and
 questionnaires will be obtained:

 1. Anthropometric measures:

 -  height (V0, V2, V3, V4);

 -  weight (V0, V2, V3, V4);

 -  body mass index (BMI; Kg/m2) (V0, V2, V3, V4);

 -  waist and hip circumferences (V0, V2, V3, V4) for the calculation of the following
 ratios: waist/hip, waist/height;

 -  Tanner stage (V0, V2, V3, V4) (Tanner JM, 1961);

 -  blood pressure and heart rate (V0, V2, V3, V4).

 2. Biochemical evaluations (after a 12-h overnight fast): CBC with formula, serum
 insulin-like growth factor 1 (IGF1, ng/mL), 25-hydroxy (OH) vitamin D (ng/mL), uric acid
 (mg/dL), alkaline phosphatase (U/L), ACTH (pg/mL), cortisol (microg/dL), TSH (uuI/mL),
 fT4 (ng/dL) (V1, V3, V4); aspartate aminotransferase (AST, IU/L), alanine
 aminotransferase (ALT, IU/L); AST-to-ALT ratio will be calculated as the ratio of AST
 (IU/L) and ALT(IU/L)(V1, V3, V4); serum creatinine concentration (mg/dL) will be
 measured with the enzymatic method; according to the NKF-K/DOQI Guidelines for CKD in
 children and adolescents (Hogg RJ et al., 2003), the eGFR will be calculated using
 updated Schwartz's formula (Schwartz GJ et al., 2009): eGFR (mL/min/1.73 m2) = [0.413 x
 patient's height (cm)] / serum creatinine (mg/dL)(V1, V3, V4); glucose (mg/dL), insulin
 (μUI/mL); insulin-resistance (IR) will be calculated using the formula of Homeostasis
 Model Assessment (HOMA)-IR: (insulin [mU/L] x glucose [mmol/lL) / 22.5)(V1, V3, V4);
 lipid profile: total cholesterol (mg/dL), High-Density Lipoprotein (HDL)-cholesterol
 (mg/dL), triglycerides (mg/dL); Low-Density Lipoprotein (LDL)-cholesterol will be
 calculated by the Friedwald formula and non-HDL (nHDL)-cholesterol will be also
 calculated(V1, V3, V4); oral glucose tolerance test (OGTT: 1.75 g of glucose solution
 per kg, maximum 75 g) and samples willbe collected for the determination of glucose and
 insulin every 30 min. The area under the curve (AUC) for parameters after OGTT will be
 calculated according to the trapezoidal rule. Insulin sensitivity at fasting and during
 OGTT will be calculated as the formula of the Quantitative Insulin-Sensitivity Check
 Index (QUICKI) and Matsuda index (ISI). The stimulus for insulin secretion in the
 increment in plasma glucose as insulinogenic index will be calculated as the ratio of
 the changes in insulin and glucose concentration from 0 to 30 min (InsI). Βeta-cell
 compensatory capacity will be evaluated by the disposition index defined as the product
 of the ISI and InsI (DI) (Kahn SE et al., 1993)(V1, V4); a collection at rest of
 first-morning urine sample. Physical and chemical urinalysis; urine albumin (mg/L) will
 be determined by an advanced immunoturbidimetric assay and urine creatinine (mg/dL) will
 be measured using the enzymatic method. Urine albumin to creatinine ratio (u-ACR -
 mg/g), will be calculated using the following formula: [urine albumin (mg/dL) / urine
 creatinine (mg/dL)] x 1000. For these calculations both albumin and creatinine will be
 in the same unit. The subjects whose urine will be found positive, they will undergo a
 collection of two more samples and will be considered the u-ACR mean value of these (V1,
 V3, V4).

 3. Ultrasound evaluations:

 -  liver ultrasound(V1, V4);

 -  echocardiography and carotid sonography(V1, V4).

 4. Nutritional and physical activity measurements:

 -  KIDMED questionnaire for children and adolescents; the index comprises 16 yes or no
 questions (Serra-Majem L et al., 2004), and the total score of the KIDMED index
 ranged from -4 to 12 and is classified into 3 levels: 1)≥8: optimal Mediterranean
 diet; 2) 4-7: improvement is needed to adjust intake to the Mediterranean diet; 3)
 ≤3: very low diet quality; the Italian version is reported and approved by Istituto
 Superiore Sanità in Rapporti ISTISAN 12/42(Istituto Superiore della Sanità,
 Rapporti ISTISAN 12/42, 2012)(V0, V2, V3, V4);

 -  the Food Frequency Questionnaire section of the Children's Eating Habits
 Questionnaire (CEHQ-FFQ), performed by Identification and prevention of Dietary and
 lifestyle-induced health Effects In Children and infantS (IDEFICS) study, on which
 parents or other caregivers will be asked to report the number of meals the
 children usually consumed at home or at other people's homes, such as of
 grandparents and friends, in a typical week of the previous month (Huybrechts I et
 al., 2011) (V0, V2, V3, V4);

 -  24-hour recall and a list of all foods and constituents included in the Dietary
 Inflammatory Index (DII) along with the respective adjusted score will be
 evaluated. Food- and constituent-specific scores will be multiplied by the intake
 for each subject. and then will be summed to create the overall Inflammatory Index
 score (Cavicchia PP et al., 2009 - Shivappa N et al., 2014) (V0, V2, V3, V4);

 -  the Mediterranean Adequacy Index (MAI) will be obtained by dividing the sum of the
 percentage of total energy from typical Mediterranean food groups by the sum of the
 percentage of total energy from non-typical Mediterranean food groups, according to
 the following equation (Alberti-Fidanza A, Fidanza F, 2004) (V0, V2, V3, V4);

 -  the International Physical Activity Questionnaire (IPAQ) developed, validated for
 Italian adolescents (IPAQ-A) will be developed; It covers four domains of physical
 activity: (1) school-related physical activity, including activity during physical
 education classes and breaks, (2) transportation, (3) housework and (4) leisure
 time (Hagstromer M et al., 2008 - Mannocci A et al, Accepted to Minerva Pediatrica)
 (V0, V2, V3, V4).

 Outcomes (see Outcome Measures). Information retrieval: A case report form (CRF) will be
 completed for each subject included in the study. The source documents will be the hospital's
 or the physician's chart.

 Statistical e sample size: A sample of 60 individuals (30 in each group) has been estimated
 to be sufficient to demonstrate a difference of 0.4kg/m2 in BMISDS with a SD of 0.65 (Prodam
 F et al, 2013) with 90% power and a significance level of 95% and a drop-out rate of 20%
 using the Student test. Statistical significance will be assumed at P< 0.05. The statistical
 analysis will be performed with SPSS for Windows version 17.0 (SPSS Inc., Chicago, IL, USA).

 Organization characteristics: The study will be conducted at the Pediatric Endocrine Service
 of Division of Pediatrics, Department of Health Sciences, University of Piemonte Orientale,
 in Novara.

 All blood samples will be measured evaluated using standardized methods in the Hospital's
 Chemistry Laboratory, previously described (Prodam F et al., 2014 - Prodam F et al., 2016).

 Good Clinical Practice: The protocol will be conducted in accordance with the declaration of
 Helsinki. Informed consent will be obtained from all parents prior to the evaluations after
 careful explanations to each patient.
Inclusion Criteria:

 -  obesity, according to the IOTF criteria;

 -  waist circumference ≥ 90th percentile;

 -  diet naïve or with failure of weight loss (defined as -1 kg/m2 BMI in 1 year).

 Exclusion Criteria:

 -  specific causes of endocrine or genetic obesity;

 -  type 1 diabetes;

 -  previous kidney diseases.