Effectiveness of an Intensive Weight Loss Program for Obstructive Sleep Apnea Syndrome (OSAS) Treatment.
Effectiveness of an Intensive Weight Loss Program for Obstructive Sleep Apnea Syndrome (OSAS) Treatment.
The purpose of this study is to determine if a lifestyle change program for obese patients
 who are already receiving continuous positive airway pressure (CPAP) treatment can achieve
 weight loss and overall improvement of obstructive sleep apnea syndrome (OSAS).
Calculating the sample size:

 The primary endpoint is the reduction of final apnea-hypopnea index (AHI) with respect to
 baseline. Assuming an alpha level of 0.05 and a bilateral approach to have 80% statistical
 power, the investigators estimate a final sample size of 42 patients is required to detect a
 15 point difference in AHI between the intervention and control groups (clinically relevant
 difference), with a standard deviation of 15 (visit 9) and accounting for a 25% rate of
 attrition. Balanced groups are expected.

 Lifestyle Change Program:

 This will consist of a 3-month long first stage of intensive diet and progressive exercise
 with visits to a nutritionist every 15 days. A second stage will last until completion of one
 year, with a diet that is progressively higher in calories, more intense exercise,
 appointments that are spaced further apart and are alternatively individual and group visits.

 Diet First stage: 12 weeks

 1. first 15 days: Very low calorie diet. A diet that is very low in calories will be
 started (600-800 kilocalories (Kcal), based on gender and level of physical activity)
 with low calorie shakes. Supplementing the diet with herbal teas and sugar-free
 beverages will be allowed.

 2. Up to week 12: 1200 Kcal diet with a low calorie shake replacing the evening meal.
 Exercising begins.

 At each visit the nutritionist will provide advice on diet and lifestyle, with special
 emphasis on diet and exercise. Visits to the nutritionist will be every 15 days. The first
 two will be group visits and afterwards individual visits will alternate with group visits
 every 15 days (see chart below). On alternate weeks a nurse will phone the patients to remind
 them of the diet's basic guidelines.

 Every session will last from 60 to 90 minutes and will be conducted by a nutritionist. The
 subjects will be asked to keep a 3 day log of what they eat at the start of the study and at
 and at each visit in order to estimate nutrient intake. Every patient will be provided with
 information about the entire program and the different group and individual sessions with the
 nutritionist. At each visit the participants will be weighed and asked for the results of the
 tests for ketones in the urine once a week. The nutritionist will follow compliance with the
 program and monitor for potential adverse events at each visit.

 Second stage: from 12 weeks to 1 year A 1200-1500 Kcal diet will be maintained, based on
 gender and level of physical activity, without the low calorie shake. Calorie intake will be
 based on a Mediterranean diet, recommending a maximum fat intake of 30% and high consumption
 of fruit, vegetables, poultry, fish, lean meat and legumes, in accordance with the
 recommendations of the American Dietetic Association.

 Visits to the nutritionist will take place monthly from the third to the sixth month and
 every 3 months from the sixth to the 12th month, with individual visits alternating with
 group visits (see chart below).

 They will also receive a phone call every month, alternating with the visits, which will be
 made by the company that supplies the CPAP equipment.

 Exercise

 The following exercise program will be recommended:

 1. Walk briskly for at least 50-60 minutes at a time, at least 3 times per week, ideally 5
 days a week. Exercising is to increase gradually, starting with 10 minute periods,
 repeated on the same day and that will be gradually increased as tolerated by the
 patient. Heart rate will be used to monitor exercise intensity, it is recommended that
 aerobic exercise be performed at 70-80% of maximum heart rate. (Lung (2014)
 192:175-184).

 2. Every workout session will consist of stretching, 5-10' of warm up (50-60% of maximum
 heart rate (HR)), 40-50' of aerobic exercise performed at 70-80% of maximum HR and 5-10'
 of cool down (50-60% of maximum HR). The table for stretches to be performed before and
 after exercising will be given in writing. The patients will receive information on how
 to perform the exercises and everything related to it at a group training session before
 the start of the program.

 3. To encourage exercise, the chance to perform it at least once a week in guided groups,
 in the patient's town of residence, will be offered.

 Follow up:

 1. On each visit to the nutritionist, in addition to data regarding adherence to the diet,
 data regarding adherence to the exercise program will be recorded: number of sessions
 and minutes/week.

 2. During the group sessions, the nurse in charge of the study will respond any questions
 that may arise concerning the development of the exercise program.

 3. Patients who have a smart phone will also be able to record their activity using an app
 (Endomondo) , which the nurse and the nutritionist will be able to access (see the
 section on variables). In addition to tracking their own exercise history, patients will
 be able to see that of the other patients in the study if they opt voluntarily to choose
 that option.

 If any musculoskeletal complaints that are deemed relevant should occur during the course of
 the exercise program, the Rehabilitation Services will attend to the patients. The pain
 visual analogue scale (VAS) will be used for assessment. A VAS score equal to or greater than
 4 (moderate pain) would require assessment to be made by the Rehabilitation Services.

 Assessment of exercise capacity:

 1 To measure the response to exercise an exercise tolerance test will be performed: the six
 minute walk test (6MWT), which will be evaluated using the reference values for obese
 individuals. It will be conducted before starting the program and at 3 and 12 months.

 Sleep habits Subjects will be reminded of the need to sleep enough hours and of keeping a
 regular sleep schedule. Sleep hygiene guidelines will be provided in writing.

 Control group: They will be managed according to the usual recommendations: they will be
 given a diet and exercise plan in writing, which is the one commonly used in the Dietetics
 Unit, established by the Dietetics Unit according to patient age and level of activity,
 without any other assessment or additional visits by the Dietetics Unit. 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:

 -  occurrence of osteoarticular pain that prevents a patient from continuing to exercise

 -  a patient's continued refusal to follow the recommended guidelines

 RECRUITMENT PERIOD: Potential candidates will be selected from among patients who are being
 followed by their doctor or nurse for CPAP treatment. All potential candidates will be
 invited to participate in the study in consecutive order until the required number of
 patients has been reached.

 MONITORING PERIOD: All patients will complete the one year of monitoring. If any adverse
 effects occur during the monitoring period, they will be recorded and discontinuation of the
 protocol will be assessed. Diet-related adverse effects are not expected as the patients will
 be followed very closely by the nutritionist. In the event any exercise-related
 osteoarticular pain should occur, the Rehabilitation Services will assess the patients and
 determine whether the exercise should be modified or discontinued.

 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 OSAS.

 STATISTICAL ANALYSIS:

 In order to evaluate the effectiveness of a change in lifestyle (diet and exercise) in obese
 patients with OSAS, the investigators 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 the investigators will use measures of central
 tendency (mean, median) and dispersion (standard deviation and interquartile range) for the
 quantitative variables.

 In order to answer the primary and secondary objectives of this study, the investigators 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 (between 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 answer to the primary and secondary endpoints will be
 obtained from the confidence interval (95% CI) of the difference between means and
 percentages, as appropriate.

 Efficacy assessment will be based on an analysis of the per protocol populations (PP) and
 intention-to-treat (ITT), with ITT the population being the main analysis. For the population
 analysis using ITT, the missing data will be filled in and 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 the 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% (α=0.05) with a bilateral approach.

 The statistical software that will be used for the analysis will be International Business
 Machines Corporation (IBM) Statistical Package for the Social Sciences (SPSS) Statistics 21.
Inclusion Criteria:

 -  Patients who have been diagnosed with severe obstructive sleep apnea syndrome (AHI >
 30) and are already receiving CPAP treatment (since at least 6 months), who have class
 I and class II obesity (body mass index (BMI) >= 30 kg /m2 y <= 40 kg/m2).

 Exclusion Criteria:

 -  diseases that limit exercising or diet,

 -  cognitive impairment that prevents understanding the program,

 -  psychiatric disorders,

 -  severe diseases, major cardiovascular disease,

 -  clinical instability within the previous month,

 -  prior bariatric surgery,

 -  refusal to participate in the study,

 -  participation in another clinical trial.