Evaluation of Metformin Hydrochloride Extended Release and Immediate Release in Pediatric Obesity: A Randomized, Multicenter, Parallel-Group Study

The primary objective of this study is to compare the effect of **metformin** extended release (XR) plus lifestyle intervention with lifestyle intervention alone on the change in Body Mass Index Standard Deviation Score (BMI-SDS) from baseline to the 6-month visit at the end of treatment. This is clinically relevant as it aims to determine the efficacy of metformin XR in managing obesity in children and adolescents, potentially offering a pharmacological adjunct to lifestyle modifications.

Secondary objectives include:

• Comparing the effect of metformin immediate release (IR) plus lifestyle with lifestyle alone on BMI-SDS change.
• Evaluating safety and tolerability of the interventions.
• Comparing the effect of metformin IR plus lifestyle with metformin XR plus lifestyle on BMI-SDS change.
• Assessing the impact of plasma and urine concentrations of metformin XR and IR on BMI-SDS change.
• Evaluating the influence of age, sex, puberty, duration of obesity, and metformin concentration on BMI-SDS change.
• Comparing changes in glucose and insulin metabolism, cardiovascular risk factors, renal and liver function, inflammation factors, growth metabolism, energy turnover, and body composition among the different intervention groups.
• Assessing changes in lifestyle and health-related symptoms, including nutritional parameters and physical activity.
• Evaluating changes in quality of life across the intervention groups.

The clinical trial involves **children and adolescents with obesity**, specifically targeting individuals aged 6 to less than 17 years and 3 months. Both male and female participants are included in the study, with a requirement for a body weight of at least 40 kg and a **Body Mass Index Standard Deviation Score (BMI-SDS)** greater than 2.0, as defined by the World Health Organization (WHO). Participants must have maintained a stable body weight, with less than a 5 kg change, in the 90 days preceding the screening visit. The trial population is considered vulnerable, and the selection process includes obtaining signed informed consent prior to any study-specific procedures. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations are integral to the study, as the trial aims to compare the effects of metformin extended release (XR) combined with lifestyle modifications against lifestyle changes alone. Female participants of childbearing potential are required to adhere to effective contraceptive methods or maintain sexual abstinence throughout the study period. The trial does not provide specific data on dietary habits or physical activity levels beyond the general lifestyle component. The sponsor has not disclosed the total number of participants involved in the study.

The clinical trial is designed as a **randomized**, parallel, three-arm study conducted over a period of six months. The trial aims to evaluate the efficacy of **metformin** extended release (XR) plus lifestyle intervention, metformin immediate release (IR) plus lifestyle intervention, and lifestyle intervention alone in children and adolescents with obesity. The study is structured to be **double-blind** and controlled, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is set to conclude by May 8, 2025, with recruitment having commenced on September 9, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, body weight, and **body mass index** (BMI) standard deviation score (SDS). Following successful screening, participants will be randomized into one of the three study arms. Throughout the trial, follow-up visits will be scheduled to monitor the primary endpoint, which is the change in BMI-SDS from baseline to the end of the treatment period. Secondary endpoints include assessments of adverse events, vital signs, and various biochemical parameters.

The expected duration of participant involvement is six months, with regular follow-up visits to ensure adherence to the study protocol and to monitor safety and efficacy outcomes. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events that compromise participant safety, or withdrawal of consent. The end-of-study visit will involve a comprehensive evaluation of the primary and secondary endpoints, ensuring a thorough analysis of the treatment effects.

The clinical trial involves the administration of two formulations of **metformin hydrochloride**. The first experimental medication is **GLUCOPHAGE 500 mg film-coated tablets**, which contain the active substance **metformin hydrochloride**. These tablets are administered orally. The maximum daily dose is 3000 mg, and the treatment period extends up to 24 months. The tablets are manufactured by Merck Serono Limited and are not a pediatric formulation. The pharmaceutical form is a film-coated tablet, ensuring ease of ingestion and controlled release of the active ingredient.

The second experimental medication is **Glucophage SR 500mg prolonged release tablet**, also containing **metformin hydrochloride** as the active substance. This formulation is designed for prolonged release, allowing for a sustained therapeutic effect. The tablets are administered orally, with a maximum daily dose of 3000 mg, similar to the immediate-release formulation. The treatment duration is also up to 24 months. Manufactured by Merck Serono Limited, these tablets are not intended for pediatric use. The prolonged-release formulation is designed to maintain stable plasma concentrations of the active substance over an extended period.

In addition to the experimental medications, the study includes a non-experimental treatment arm involving lifestyle modifications alone. This arm serves as a comparator to evaluate the efficacy of the metformin formulations in conjunction with lifestyle changes. Participant compliance with the dosing schedules and lifestyle interventions is monitored throughout the study to ensure adherence and accurate assessment of treatment outcomes.

The efficacy of the clinical trial will be assessed primarily through the change in **BMI-SDS** (Body Mass Index Standard Deviation Score) according to WHO standards, from baseline to the 6-month visit at the end of treatment. This primary endpoint will provide a direct measure of the intervention's impact on obesity in children and adolescents. Secondary endpoints will include a comprehensive range of parameters such as adverse events, vital signs (systolic and diastolic blood pressure, heart rate), physical examination results, fasting plasma glucose, alanine aminotransferase (ALAT), creatinine, lactate, cobalamin levels, clinical chemistry, hematology, urine analysis, and plasma metformin concentration. Additionally, pharmacokinetic assessments will be conducted, including plasma and urine concentration of metformin and area under the curve (AUC).

Further secondary endpoints will evaluate glucose and insulin levels at fasting and during an oral glucose tolerance test (OGTT), insulin secretion and sensitivity derived from OGTT, and HbA1c levels. Lipid profiles, including triglycerides, total cholesterol, HDL, and LDL, will also be measured. Other biochemical markers such as creatinine, cystatin C/GFR, ALAT, gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LD), bilirubin, and high-sensitivity C-reactive protein (Hs-CRP) will be assessed. Hormonal levels including IGF-1, SHBG, FSH, LH, testosterone, and estrogen will be monitored. Anthropometric measurements, including waist and hip circumference, sagittal abdominal diameter, bioimpedance, indirect calorimetry, and skinfold measurements, will be performed at selected sites. Patient-reported outcomes will be collected using questionnaires such as the Food Frequency Questionnaire (FFQ), Regular Meals, Portion Size, Physical Activity, Medipal®, and PedsQL™.