Conditions: Pediatric Obesity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 339
Healthy volunteers: no

Brief summary:
This study expects to evaluate the use of metformin in the management of obese children. Insulin resistance among obese Sri Lankan children (south Asian origin) is high, which had been shown in the investigators previous work.

This study will look at the effect of metformin on changes in insulin resistance, fatty liver state, body fat content, BMI and other metabolic derangement.

Detailed description:
1\. General objective To study the prevalence of Non Communicable Disease (NCD) related metabolic derangements among obese children and assess the outcome of two different management (metformin vs placebo alongside dietary and physical activity changes) modalities among 8 to16 year old obese children living in Negombo educational division of Negambo educational zone of Gampaha district in Sri Lanka.

1.1 Specific objectives

1. To study the prevalence of obesity related metabolic derangements among obese children.
2. To compare the effectiveness of the use of metformin vs placebo in the change of fat content and BMI among obese children.
3. To compare the effectiveness in the use of metformin vs placebo in the reversal of insulin resistance and metabolic derangements among obese children.

2 Methods 2.1 Study design A double blind randomized prospective placebo control study

2.2 Subjects and Study setting Obese (more than +2 Standard Deviation (SD) of BMI to age on World Health Organization (WHO) standards) school children from Negombo educational zone of district of Gampaha.

Obese children had been identified in a separate screening programme (it will be carried out during Sep-Dec 2013 and Sri Lanka College of Paediatricians, ethical review committee has approved the study protocol) carried out in this same educational division and are invited to participate in this study. Children not of Sri Lankan origin or who are not planning to live in Sri Lanka during the next one year or has a secondary underlying cause for the overweight/obesity, will be excluded.

Parents will be informed about the importance of participating in the study from the point of receiving treatment as well as participating in the research (written information sheet will given) and informed written consent from parents/guardians and assent from child will be obtained. Any parent, child who wishes not to participate will allowed doing so.

2.3 Sample size and sampling method: All children who were detected to be obese in a previous screening programme will be invited and a minimum sample size of 120 children will be recruited.

The sample size is calculated, that among obese children, a total sample size of 60 participants would detect a between-group difference of 0.09 BMI SD score units (approximately equivalent to a 2 kg/m2 difference) with 80% power. Participant accrual was set at 120 participants to allow as much as 50 percent loss to follow-up. However, the investigators will take maximum effort to trace the patients.

2.4 Measurements: These children will be invited to participate in a follow up programme as part of clinical service as well as research. Their parents will be informed to bring their children to the Loins Club of Negambo Host, Diabetes Screening and Vocational Training Centre, Negambo by appointment.

Measurements will be done at the Loins Club of Negambo Host, Diabetes Screening and Vocational Training Centre, Negamboafter an overnight fast. Height, weight, waist circumference and hip circumference will be measured. Percentage fat mass will be measured using Bio Electrical Impedance (BIA) assay using platform type InBody 230 instrument (InBody®, Biospace, South Korea). Once the impedance value is measured, total body water will be calculated using the locally validated BIA prediction equation (Wickramasinghe et al 2008). From Total Body Water (TBW), Fat Free Mass (FFM) and hence Fat Mass (FM) was calculated using age and gender specific water content of FFM (Lohman, 1989). Blood pressure will be measured using a mercury sphygmomanometer in seated position after 10-15 minute rest. Male and female children will be assessed by trained male and female investigators respectively.

Metabolic derangements will be assessed by means of: total cholesterol, LDL-C levels, HDL-C levels, triglyceride, insulin, Alanine amino transferase (ALT) and Aspartate amino transferase (AST) (8ml of blood into a plain bottle) fasting blood sugar (2ml of blood into a NaF containing bottle). Oral Glucose Toerance Test (OGTT) test will be done after giving anhydrous glucose 1.75g (1.92g of monohydrous glucose) to max of 75g (max 82.5g of monohydrous glucose) and blood will be taken 2 hour later for random blood sugar (2ml of blood into a NaF containing bottle) and serum insulin (2ml of blood into a plain bottle). Serum will be separated immediately and stored at -20 degree of Celcius and analysis will be done at Loins Club of Negambo Host, Diabetes Screening and Vocational Training Centre, Negambo in batches. Blood will be drawn after applying lignocaine (Emla®) anesthetic cream.

Insulin resistance will be calculated using Homeostatic model Insulin Resistance (HOMA-IR= fasting blood sugar × fasting insulin ÷ 22.5) (Matthews et al 1985). An Ultra sound scan of abdomen will be done to identify hepatic steatosis by a consultant radiologist.

Pubertal staging will be assessed using visual charts (Morris and Udry 1980). Girls will be shown a diagram depicting different stages of growth of breasts and pubic hair and ask them to match it with their own (whenever necessary will seek mother's assistance). Similarly boys are shown diagrams of external genitalia and pubic hair and to match with their own. The size of the testis will be measure by the examiner using Prader orchidometer. If both subject and parents were not sure of the staging, with consent, the examiner would examine and the correct pubertal stage assessment would be made. Measurements and examinations in girls and boys will be carried out by female and male investigators respectively.

The whole project will be closely supervised by a two Consultant paediatricians and after the completion of study children who need follow up will be provided the services or if they wish to be followed up at a different institute, would be referred with a complete report.

2.5 Randomization: Once obesity and overweight is diagnosed and investigated, they will be randomly assigned to either of one management protocol on a 1:1 basis. Children will be categorized according to gender and age groups; 8-10.99; 11-13.99; 14-16 years. Using a grid for each age of each sex, sequentially they will be allocated to receive management protocol I or II. Only the field investigators will have information to the allocation. That is; Group I Structured diet + Physical activity+ Metformin Group II Structured diet + Physical activity + Placebo

Dietary advice will be given by a trained nutritionist. It will be based on food based dietary guidelines produced by Ministry of Health (Jayatissa and Wickramasinghe, 2011). Age based portion size guide will be given to parents and children and guide them on the volume they should be eating.

Physical activity training will be conducted by a qualified physical activity instructor. A daily physical activity routine of 20-30 minutes will be given to each student. The programme would be of 3 different types based on their age (11-13 and 14-16. The workout programme will be changed every month in order to break the monotony. There will 4 such different workout schedules.

Medication: 8-10.99 year old children will receive metformin. Initially children will be given 250mg of metformin daily for a week and increased to 250mg twice daily for a week and then to 500 mg twice daily there after. 11-16 year old children will receive 500mg of metformin daily initially for one week which will be increased to 500mg twice daily for a week and then to 1g twice daily. Children will be asked to take medication with their morning and evening meals to reduce gastro intestinal side effects and risk of hypoglycaemia. Response to medication will be evaluated before each dose revision and will monitor for all possible adverse events.

The study will be monitored by a Data and Safety Monitoring Committee comprising of a Paediatrician, Paediatric Endocrinologist and a Bio- Statistician.

Both the nutritionist and physical trainer will be blinded to the medication children will be receiving.

A control group with no treatment will not be employed as it will be unethical not to do any intervention when the diagnosis of obesity is made. A placebo is given to overcome any psychological effects of giving medication. metformin and Placebo will be manufactured by the State Pharmaceutical Manufacturing Company (SPMC). The placebo tablet will be similar to metformin in all aspects except for containing the active pharmacological compound.

These children will be reviewed two weeks after commencement of therapy and dose will be revised and thereafter monthly in order to ensure compliance and identify any adverse events and address issues. In additionally they will be contacted via telephone, weekly during first month and fortnightly afterwards to address concerns/issues and also to motivate them to keep compliance at a higher level. At each of these visits, the anthropometry and body composition will be assessed, while blood investigations will be repeated at 6 and 12 months. At each eveluations, one to one meeting will be held.

2.6 Statistics The distribution of metabolic derangements will be described using descriptive statistics. Spearman Correlation Coefficients will be used to assess the relationship between percentage fat and metabolic derangements related to NCD as well as anthropometric measurements and metabolic derangements. Comparisons of mean values of these measurements will be made using t tests.

Arms:
arm 1: 8-10.99 year old children received metformin. Initially children given 250mg of metformin daily for a week and increased to 250mg twice daily for a week and then to 500 mg twice daily there after. 11-16 year old children received 500mg of metformin daily initially for one week which increased to 500mg twice daily for a week and then to 1g twice daily. The medication was continued for 12 months. arm 2: A placebo tablet which is physically similar to metformin tablets will be given in a similar manner as described above.

Metformin and placebo is manufactured by the State Pharmaceutical Manufacturing Corporation (SPMC)

Interventions: intervention 1: Metformin intervention 2: Placebo
Intervention descriptions: intervention 1: Metformin in the form of 500mg tablets were administer to the Metformin group intervention 2: A Placebo tablet physically and chemically similar to Metformin tablets except for the absence of the active ingredient was used

Protocol document: