DEMETRA - ADVICE-002-2022

DTXO is a medical device designed to deliver digital therapy intervention (DTx) to patients. The DT, as part of Digital Health, utilizes high quality digital technologies to stimulate lifestyle changes in patients. DTXO has been set up to improve the commitment of patients in following therapeutic directives (i.e. nutritional programs, daily/weekly physical activities) to manage the disease of obesity. Moreover, DTXO can improve patient's awareness about patients disease (obesity) so is intended to improve weight loss, weight-loss maintenance, and overall health in patients with obesity by increasing their self-engagement, self-monitoring and adherence to dietary/exercise and behavioral programs. In this prospective, multicenter, pragmatic, randomized, double-arm placebo-controlled, parallel, single-blind study, the App integrates different non-pharmacological approaches, engaging the patient through monitoring of patients non-vital parameters, monitoring of patient diet and exercise, monitoring of patient psychological status, prescription of exercise and diet in a weight-loss program, and configurable data presentation charts for provision of additional information to professional users.

The aim of this study is to monitor patients' non-vital parameters through data collection through patient-reported information, data collection through coupled devices, data processing by a proprietary algorithm based on clinical guidelines and data visualization by a proprietary interface; AND Prescribe diet, exercise and psycho-behavioral support intended for weight loss in obese patients.

The dietary will be a personalized hypocaloric Mediterranean-based dietary program according to sex, ages must be between 18 and 65 years of age, physical activity level, dietary preferences and eating habits and prescribed by the nutritionist physician at baseline (V0), which aims at decreasing weight in obese patients and favoring patients' compliance and adherence to the diet. And regardless of the randomization arm, all patients enrolled in the study will be invited by the investigator to follow a dietary program with a daily caloric intake (kilocalories/day or kcal/day) assigned by a standardized method with a fixed caloric deficit equal to 800 kcal drawn on the suggested values range from 500 to 1000 kcal.

Specifically, the caloric intake is classified starting from the measure of the daily Basal Metabolic Rate (BMR) based on genders (male, female), weight, height and age measured at baseline (V0).

The study will enroll 246 subjects, both genders to obtain 172 overall valuable subjects (86 for each group). The recruitment period will last 4 months. Each patient will be followed for 12 months after baseline, during which lifestyle changes will be implemented with/without DTXO. Regular follow-up visits are foreseen at 3 months ±15 days (V1), 6 months ±15 days (V2), 9 months ±15 days (V3) and 12 months ±15 days (V4) after enrollment, in the end of the study is defined as the date of the last scheduled procedure shown in the Schedule of Activities for the last participant in the study globally.

At the beginning of the study, patients will be evaluated for their body mass index (BMI=weight/height2 ) that according with the literature patients with BMI >45 kg/m2 are in a severe condition that requires a combination of pharmacological and surgical treatment with lifestyle intervention and are therefore excluded from the study. The experimental arm will be compared with a control arm in which dietary and exercise programs will be delivered according to the current standard of care, which foresees, respectively, a standard paper-based approach and clinical recommendations. The control arm will also be equipped with a placebo App to ensure the patient's blindness to treatment allocation.

Benefit/Risk Assessment: Benefits for patients resulting from study implementation is the possibility to provide simultaneous treatment strategies to improve the health status of obese patients. The expected result is that the simultaneous application of these strategies and the possibility of customizing patients' activities based on their habits and feedback will allow greater benefits than the application of separate, non-customized programs and a standard paper-based in-person approach. For this, the composite primary objective/endpoint consists of easily measurable objective markers.

Both treatment arms will receive potential benefits by participating in this study. The control arm will receive the current standard of care (paper-based approach and face-to-face follow-up visits) for obese patients with the addition of a placebo app. However, greater benefits are hypothesized in the experimental arm due to the possibility of customization of physical activity in accordance with the perceptions and feedbacks of the patient, the availability of notifications and reminders for drug intake (dosage, frequency) to improve treatment adherence, the availability of contents to support and favor compliance with the prescribed diet, the possibility to schedule an online visit or communicate with the clinical specialist via chat through the App, and the availability of multimedia psycho-behavioral content (motivational exercises, self-acceptance exercises, mindfulness exercises, interactive emotional eating exercises, self-efficacy exercise).

The main clinical benefit is improved weight loss and the overall health status of obese patients through the prescription of dietary and exercise programs delivered by a mobile App.

Possible risks that can be anticipated in patients in the experimental arm are obsessive feeling about exercise and food intake and anxiety/guilt when not reaching assigned exercise or food intake goals, and interferences with subject's daily activities and/or social life to the higher "pressure" to adhere to the programs given by the DTXO App compared to the standard of care approach.

Primary Objective - To evaluate the effect on weight loss in patients using DTXO compared to patients not-provided after 6 months of DTXO use.

Secondary Objectives

1. To describe the primary objective in each randomized group.
2. To stratify the primary objective results by sex.
3. To stratify the primary objective results by ranges of BMI a baseline.
4. To evaluate the effect on weight-loss maintenance according to weight loss reached at 6 months in patients using DTXO compared to patients not-provided after 12 months of DTXO use.
5. To assess the percentage weight loss in each randomized group during the study.
6. To assess differences in physical function improvements between the two randomized groups during the study.
7. To assess the percentage weight loss between the two randomized groups during the study.
8. To assess the body fat distribution changes in each randomized group during the study.
9. To assess differences in body fat distribution changes between the two randomized groups during the study.
10. To stratify the percentage weight-loss changes by ranges of BMI at baseline.
11. To evaluate the effect on weight loss in patients using DTXO compared to patients not-provided after 12 months of DTXO use.
12. To assess the degree of physical inactivity reduction (IPAQ Questionnaire) in each randomized group during the study.
13. To assess the degree of stress reduction (DASS-21 scale) in each randomized group during the study.
14. To assess differences in the increase of quality of life (PGWBI questionnaire) between the two randomized groups during the study.

Safety 15. To describe the safety profile in the two treatment groups.

Primary Endpoints

• To evaluate the change in absolute body weight (kg) at 6 months (V2) from baseline (V0) in obese DTXO users compared to obese Placebo App users

Safety Endpoint To assess the rate of adverse events, adverse device effects, abnormality of laboratory parameters between the two randomized groups across the study (V1, V2, V3, V4).

Statistical Hypotheses This study is designed to test the null hypothesis that the change in absolute body weight (kg) at 6 months (V2) from baseline (V0) in obese DTXO users compared to the obese placebo control group is equal to zero. The alternative hypothesis is that absolute body weight (kg) change between groups is less than zero.

Sample Size Determination The sample size is estimated to provide statistical power for the primary endpoint. The sample size was computed according to the primary endpoint, namely the change in absolute body weight (kg) at 6 months (V2) from baseline (V0) in obese DTXO users compared to the obese placebo control group.

Based on the primary endpoint, the statistical analysis determined that a total sample size of 172 patients (86 per group) would allow us 80% power and a two-sided type I error of 0.05 to detect a 1.5 kg difference in weight change at 6 months between the groups, assuming an SD of 3.5 kg. For this reasons, the goal is to enrolled 246 patients to account for a dropout rate of 30%.

Data Quality Assurance All participant data relating to the study will be recorded on eCRF unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is responsible for verifying that data entries are accurate and correct by electronically signing the eCRF.

The investigator must permit study-related monitoring, audits, Institutional Review Board/Ethic Committee review, and regulatory agency inspections and provide direct access to source data documents.

The sponsor or designee is responsible for the data management of this study including quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data entered into the eCRF by authorized site personnel are accurate, complete, and verifiable from source documents; that the safety and rights of participants are being protected; and that the study is being conducted in accordance with the currently approved protocol and any other study agreements, ICH (International Conference on Harmonization) GCP (Good Clinical Practice), and all applicable regulatory requirements.