This study was designed as a prospective, open, multicenter, 6-month randomized, controlled clinical trial registered at the Chinese Clinical Trial Registry (ChiCTR1800017463), and approved by the First Affiliated Hospital Ethics Committee of Nanjing Medical University (Nanjing, Jiangsu, China) (2018-SR-069). The recruitment period was from August 1, 2018 to June 31, 2019. Recruitment strategies included advertisements in social media, e.g. WeChat, along with posters and referrals from the outpatient clinic. Written informed consent was obtained from all participants.
This clinical trial was conducted primarily in 11 tertiary care hospitals across China, including (1) 86 patients from the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital, Primary center), (2) 20 patients from the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, with 4 withdrawn, (3) 28 patients from the First Affiliated Hospital of Soochow University, with 3 withdrawn, (4) 20 patients from Suzhou Municipal Hospital Affiliated to Nanjing Medical University, with 1 withdrawn, (5) 10 patients from the Affiliated Suzhou Science &Technology Town Hospital of Nanjing Medical University, with 1 withdrawn, (6) 19 patients from the Affiliated Hospital of Jiangsu University, (7) 13 patients from the Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University, (8) 27 patients from the Second People's Hospital of Huai'an, the Affiliated Huai'an Hospital of Xuzhou Medical University, (9) 15 patients from Northern Jiangsu People’s Hospital, (10) 25 patients from the First People’s Hospital of Chuzhou, with 9 withdrawn, and (11) 9 patients from the Second Affiliated Hospital of Dalian Medical University.
The duration of the study was from July 1, 2018 to December 30, 2019.
Inclusion and exclusion criteria
Eligible adults with obesity aged between 18 and 50 years with BMI ≥28.0 kg/m2, capable of using smartphones and operating the mobile application “Medical Weight Management” (Guangzhou ND-fit Nutrition and Health Consulting Co. Ltd) were included. Participants additionally needed to follow the guidance of dietitians and health managers, and monitor relevant indicators in accordance with the program requirements throughout the study. The complete inclusion and exclusion criteria are presented in Figure 1.
A multi-aspect team comprising physicians, dietitians, and health managers delivered the program over a 6-month period. Participants in the CIMWM group were provided with two Fit Nutrition Bars (Guangzhou ND-fit Nutrition and Health Consulting Co. Ltd) per day in the first 3 months as well as monthly face-to-face guidance and daily online instructions via the mobile application “Medical Weight Management”, which allowed uploading of daily weight data and food diaries. This information helped our team of experts to manage and guide the subjects online in real time. The TMWM group underwent a separate program with monthly face-to-face guidance by the same multi-aspect team and the same meal replacements, but with daily self-monitoring instead of a real-time guidance via mobile application. In the final 3 months, all participants were transferred to the self-monitoring period of the program. All participants were followed up at 1, 2, 3, and 6 months after randomization for assessment. Details of the interventions are presented in Figure 1.
Features of the diet and exercise intervention programs are described below. Based on age, sex, standard body weight, typical caloric intake, and physical activities, participants received an individualized calorie-restricted diet (CRD) plan with 1200–1800 kilocalories per day, which was developed by registered dietitians, providing 40%–55% of daily calories from carbohydrates, 20%–30% from fat, and 15%–20% from protein. Fit Nutrition Bars consisting of whey protein, soy protein isolate, chia seeds, oligosaccharides, collagen, and konjac extract rich in dietary fiber and γ-aminobutyric acid were provided as meal replacements for participants from both groups in the first 3 months. A single bar weighs 30 g and provides 111 kcal with 9.15 g protein, 1.8 g fat, 12.48 g carbohydrate, and 3.93 g dietary fiber. Both groups were additionally provided with calcium, vitamin D, and multivitamin mineral tablets.
Individualized exercise plans were created by health managers for each participant based on their health status and exercise capacity. The exercise plan included a weekly 160 min group exercise session. Over 6 months, participants were instructed to exercise for 40 min/day, 4 days a week, starting with 5 min warm-up exercises, followed by 10 min and 30 min of resistance and aerobic exercises, respectively, and ending with 5 min muscle stretching exercises.
Assessments were conducted face-to-face at baseline, 1, 2, 3, and 6 months by physicians.
Clinically-significant weight loss (defined as weight loss ≥5%) in different weight managements groups was one of the primary outcomes. Body mass index (BMI), body weight (BW), body fat percentage (BFP), body fat mass (BFM), free-fat weight (FFW), skeletal muscle mass (SMM), and visceral fat area (VFA) were measured in participants while standing on an automated hand-to-foot bioelectrical impendence device (JAWON IOI353 Body composition analyzer, Korea) with bare feet and light clothing.
Anthropometric measurements, such as height, waist (WC) and hip circumference (HC) accurate to the nearest 0.01 cm, were obtained using standard techniques. Blood pressure (while seated) was recorded as the average of two measures. Blood samples were obtained in the morning after an overnight fast. The BECKMAN-AU5800 automatic biochemical analyzer was used for determination of fasting plasma glucose (FPG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], creatinine (Cr), uric acid (UA), platelet (PLT), and albumin (ALB) levels. Fasting insulin (FINS) and C peptide (FCP) contents were determined via chemiluminescence, and glycated hemoglobin (HbA1c) was detected using high-performance liquid chromatography (Bole, USA). The non-alcoholic fatty liver disease score (NFS) was calculated as follows:
-1.675+0.037×age (years)+0.094×BMI (kg/m2)+1.13×impaired fasting glucose/diabetes (yes=1, no=0)+0.99×AST/ALT ratio−0.013×platelet count (×109/L)−0.66×albumin (g/dL).
Advanced fibrosis was accurately excluded by applying the NFS low cut-off point (-1.455) while its presence was diagnosed with high accuracy by applying the NFS high cut-off point (0.676) . HOMA-IR was calculated using the formula: FPG (mmol/L) ×FINS (mIU/L)/22.5.
Diabetes mellitus was defined as either FPG ≥7 mmol/L or 2 h oral glucose tolerance test (OGTT) blood glucose ≥11.1 mmol/L, while impaired fasting glucose was defined as 6.1 mmol/L≤FPG<7 mmol/L.
This study was powered using two previous technology-based weight management studies [16, 17], based on the percentage of individuals with clinically-significant weight loss (defined as weight loss ≥5%) in groups using different weight managements. A sample size of 214 subjects, 107 in each arm, is sufficient to detect a clinically important difference of about 20% between groups using a two-tailed z-test of proportions with 90% power and a 5% level of significance. Considering a dropout rate of 20% the sample size required is 272 (136 per group). Accordingly, competitive enrollment was initiated at each branch center. Enrolled patients were numbered in adjacent sequences using the randomized block design (block size=4). Random assignment codes were generated by statistics professionals using the SAS 9.2 software proc plan program according to a 1:1 allocation ratio .
Analyses were performed using SPSS for Macintosh version 25.0 (SPSS Inc, Chicago, IL, USA) and SAS 9.2 software proc plan program. Demographic and baseline characteristics were evaluated with the aid of descriptive statistics. Data are represented as mean ± SD for continuous variables and as percentages for categorical variables. Data sets involving the baseline, 1-month, 2-month, 3-month, and 6-month index of the participants in each group were assessed using repeated measurement ANOVA. Spearman’s rank correlation was performed to evaluate the relationships between the changes of physical examination and hematology indices at the 6-month point. To compare the characteristics of continuous variables between the two groups, the differences of changes from baseline to 1, 2, 3, and 6 months between two groups were assessed with mixed model controlling for baseline index using SAS 9.2. For categorical variables, the chi-square test was used. Two-sided P values <0.05 were considered statistically significant.