Use of Metformin in Treatment of Childhood Obesity
Condition: Pediatric Obesity
MeSH terms: Obesity; Pediatric Obesity
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Metformin in the form of 500mg tablets were administer to the Metformin group; A Placebo tablet physically and chemically similar to Metformin tablets except for the absence of the active ingredient was used
Other intervention name(s): Generic Metformin Produced by SPMC, Sri Lanka; Placebo manufactured by SPMC, Sri Lanka
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment