Cost-effectiveness Study of a Lifestyle Change Program for the Treatment of OSA and Obesity: Hospital-Primary Care.

HYPOTHESIS The implementation of an intensive weight loss program, initiated under the supervision of an expert nutritionist and continued under the supervision of a trained primary care nurse can help obese patients with severe obstructive sleep apnea (OSA) undergoing continuous positive airway pressure (CPAP) treatment to achieve significant weight loss and will result in a reduction in OSA severity in a significant percentage of patients leading to the possibility of their ceasing CPAP treatment.

The program will also improve the control of comorbidities, hypertension, diabetes and dyslipidemia and inflammation.

OBJECTIVES

Primary objective Assess whether a lifestyle change program, carried out in a combined and coordinated way with the hospital and primary care environments, can be cost-effective in the medium and long term for the treatment of OSA in obese patients with severe OSA who are already receiving CPAP treatment. In particular, to demonstrate that the program is able to achieve sufficient improvement in OSA to provide at least 25% of patients with a reduction of apnea hypopnea index (AIH <30/h).

Secondary objectives Assess whether a lifestyle change program in obese patients with OSA who are already receiving CPAP treatment can achieve lower blood pressure levels, improve blood lipids and glycemic control and reduce C reactive protein and central obesity.

Assess the OSA improvement predictor factors of an OSA improvement associated with weight loss.

STUDY SETTING:

The study will be performed at a tertiary hospital Sleep Unit and the Department of Endocrinology and Nutrition, and 5 primary care centers in the area of influence of the hospital. A community nurse and a referring physician will be selected at each center.

The study has been approved by the hospital's Ethics Committee. All participants will give their informed written consent.

All the study variables will be collected at baseline and the lifestyle change program will begin for patients in the treatment arm. Patients in the control group will continue with their regular visits. At three months and at one year after the beginning of treatment, sleep studies will be performed again and all of the other variables will be recorded for all of the patients. In order to prevent control group drop outs, at the end of the study, patients from the control group will invited to join the lifestyle change program.

Sample size estimation is based on comparing the percentage of patients that meet the primary outcome definition (patients who achieve an apnea hypopneas index (AHI) under 30 apneas-hypopneas per hour after 12 months of intervention) in two randomized groups. In the literature, no effect beyond 5% in AHI reduction has been observed with a regular dietary recommendation. So, in the control group, the expected percentage of patients that will meet the primary outcome is 2%. Kuna et al (Sleep 2013 36(5):64) observed a reduction in AHI to under 30 apneas-hypopneas per hour in 50% of patients undergoing an intensive diet intervention. In the investigators' context, with a severe population with a higher AHI at baseline, the investigators expect to reduce the apnea-hypopnea index (AHI) to under 30 apneas-hypopneas per hour in 25 % of patients undergoing the intervention.

Therefore, 90 patients (45 in each group) are required in order to have an 80% chance of detecting an increase in the primary outcome measure from 2% in the control group to 25% in the experimental group, with a significance of 5%. This estimation takes into account a dropout rate of 10%. The investigators will use an uncorrected chi-squared statistic to evaluate the null hypothesis that the primary outcome measures for experimental and control subjects are equal.

Lifestyle Change Program:

The life style change program will consist of two stages. The first will consist of a 3-month period of intensive diet and progressive exercise with biweekly consultations with a nutritionist (in groups or individually). The second stage will last for 9 months, until completion, with a diet that is progressively higher in calories, with more intense exercise, under the supervision of a community nurse. Five community nurses from the area of influence of our center will participate in a 6-hour course on nutrition and lifestyle interventions in which they will become familiarized with the educational materials used in primary care group visits. In the second stage, the group visits performed in primary care will reinforce the main hygienic-dietetic concepts introduced previously in the nutritionist sessions. After each group visit, a telephone meeting between the nutritionist and the community clinical nurse will be held to resolve doubts.

Diet: First Phase: 3 months.

• First 15 days: Very low calorie diet. A diet that is very low in calories will be started (600-800 Kcal, based on gender and level of physical activity) with low calorie shakes that will substitute the three main meals (breakfast, lunch and dinner) and the necessary food to make up the total calorie intake.
• Up to week 12: 1200 Kcal diet with a low calorie shake replacing dinner. Exercising begins. Every nutrition session will last from 60 to 90 minutes and will be conducted by a nutritionist.

The nutritionist will follow up on compliance with the program and monitor for potential adverse events at each visit. Also at each visit, the nutritionist will provide advice on diet and lifestyle, with a special emphasis on diet and exercise. Visits with the nutritionist will be biweekly group or individual. Group consultation will include 4 to 10 patients. (see Chart 1 attached).

At three months into the intervention, patients will be given dietary guidelines of 1200-1500 kcal. These will be adapted individually by the dietician according to the nutritional requirements estimated by applying the Mifflin-St Jeor/Harris Benedict, formula without the hypercaloric shake. Calories intake will be based on the Mediterranean diet with the following percentages of macronutrients: 15-20 % Proteins,44-55 % carbohydrates and a maximum of 35% lipids (<7% saturated fatty acids <7%, 15-20% monounsaturated fatty acids, <7% polyunsaturated faty acids according Spanish obesity society (SEEDO).

Second phase: 3 months to 1 year. Follow up at the Primary Health Centre (CAP) by a nursing team.Visits will take place every 1,5 months maintaining a group format in each center with an individual consultation with the nutritionist at 9 months.

The nurse responsible for the group will lead the group sessions in which the objectives of the treatment will be reinforced and will record patients' anthropometric data at each session.

Exercise Each training session will consist of stretching, 5-10' of warm-up (50-60% of the maximum HR), 40-50' of aerobic exercise performed at 70-80% of the maximum heart rate and 5-10 'of cooling down (50-60% of the maximum HR). The practice of at least 150 minutes / week of moderate activity according to World Health Organization (WHO) recommendations (World Recommendations on Physical Activity for Health WHO-Geneva 2009) will be advised. If during the exercise program there are musculoskeletal complaints that are considered relevant (an Visual Analog Scale for pain (VAS) score ≥4 on three consecutive occasions) they will be visited by the rehabilitation service. In order to promote the practice of physical exercise and the acquisition of this habit, Discounts will be offered for local municipal gyms that will offer adequate physical exercise programs for obese people, monitored by physiotherapists or technicians.

Control group: Patients will be managed according to the usual recommendations: The common written diet (designed by a hospital nutritionist) and an exercise advice will be given according to patient age and level of activity, without any other assessment or additional visits. Visits to the Sleep Disorders Unit will be scheduled to coincide with the assessments at 3 and 12 months, the same as for the intervention group.

Criteria for withdrawal from the study:

• Onset of osteoarticular pain that prevents a patient from continuing to exercise
• A patient's continued refusal to follow the recommended guidelines.

ETHICAL ISSUES: The study will be conducted in accordance with the principles of the Declaration of Helsinki, as well as of the Data Protection Act (Law 15/1999). All patients will be asked to provide informed consent, in accordance with the rules of the Ethics Committee at our institution. Since all of the patients will be receiving CPAP treatment, there should be no ethical concerns about evaluating the effectiveness of an alternative treatment that in principle is less effective than CPAP, in patients with severe OSA.

STATISTICAL ANALYSIS:

In order to evaluate the effectiveness of a change in lifestyle (diet and exercise) in obese patients with OSA, we will first perform a descriptive analysis of the demographic variables and baseline characteristics according to the number of cases and percentages for the qualitative variables and we will use measures of central tendency (mean, median) and dispersion (standard deviation and interquartile range) for the quantitative variables. In order to address the primary and secondary objectives of this study, we will run an inferential analysis comparing data at baseline, at 3 months and at one year in the two treatment groups. Tests for independent samples will be used in every case comparing the control and experimental groups). Either the chi-square test or Fisher's exact test will be used, as appropriate, to compare categorical variables and Student's T-test will be used to compare continuous variables; if the variable under study does not meet the conditions for the applicability of parametric tests, a non-parametric alternative, the Mann Whitney U test, will be used. An estimate of treatment effect in relation to the primary and secondary endpoints will be obtained from the confidence interval (95% CI) of the difference between means and percentages, as appropriate. The efficacy assessment will be based on an analysis of the per protocol populations (PP) and intention-to-treat (ITT), with the ITT population being the main analysis. For the population analysis using ITT, the missing data will be filled in and a sensitivity analysis will be conducted if more than one method of imputation is used. The PP population will be determined in accordance with compliance with visits, as well as with diet and exercise. A safety assessment will be made by identifying the adverse effects that are considered to be most significant due to their frequency or severity. In all cases, the significance level used will be 5% <0.05) with a bilateral approach. The statistical software used for the analysis will be IBM SPSS Statistics 21.

We will carry out two cost-effectiveness analyses, since we will use two effectiveness variables, The Short Form-36 Health Survey (SF-36) and the % decrease in AHI below 30, in the population studied in patients with severe OSA with a one-year follow-up. At first the database will be cleaned up and the cost allocation will be carried out by applying the flowchart. Then the analysis will determine the cost-effectiveness ratios (ICERs) acceptability curves, confidence ellipses and sensitivity analysis. A study of the costs will also be carried out taking into account the different hidden items.