Metformin Intervention in children and adolescents with obesity. A parallel, three arms, randomized, 6 months, multi-center study with metformin extended release (XR) plus lifestyle or metformin immediate release (IR) plus lifestyle or lifestyle alone.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Region Uppsala

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

9 Sep 2021 → 6 May 2025

Decision date (initial)

2024-10-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-517787-29-00

EudraCT number

2019-003940-61

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To compare the effect between metformin extended release (XR) plus
lifestyle, and lifestyle alone on the BMI-SDS change, from baseline to the
6 months visit at end of treatment.

Secondary objectives 13

1. To compare the effect between metformin immediate release (IR) plus lifestyle, and lifestyle alone on the BMI-SDS change, from baseline to the 6 months visit at end of treatment
2. To evaluate safety and tolerability.
3. To compare the effect between metformin immediate release (IR) plus lifestyle and metformin extended release (XR) plus lifestyle on the BMI-SDS change, from baseline to the 6 months visit at end of treatment.
4. To evaluate the effect of plasma (area under the curve (AUC), PK) and urine concentration of metformin XR and metformin IR on the BMI-SDS change from baseline to the 6 months visit at end of treatment.
5. To evaluate the effect of age, sex, puberty, duration of obesity and metformin concentration on BMI-SDS change comparing metformin XR and IR and lifestyle alone from baseline to the 6 months visit at end of treatment.
6. To compare changes between metformin XR plus lifestyle and IR plus lifestyle and lifestyle alone from baseline to 6 months regarding Glucose and insulin metabolism.
7. To compare changes between metformin XR plus lifestyle and IR plus lifestyle and lifestyle alone from baseline to 6 months regarding Cardiovascular risk factors.
8. To compare changes between metformin XR plus lifestyle and IR plus lifestyle and lifestyle alone from baseline to 6 months regarding Renal and liver function factors.
9. To compare changes between metformin XR plus lifestyle and IR plus lifestyle and lifestyle alone from baseline to 6 months regarding Inflammation factors.
10. To compare changes between metformin XR plus lifestyle and IR plus lifestyle and lifestyle alone from baseline to 6 months regarding Growth metabolism and puberty.
11. To compare changes between metformin XR plus lifestyle and IR plus lifestyle and lifestyle alone from baseline to 6 months regarding Energy turnover anthropometrics and body composition.
12. To compare changes between metformin XR plus lifestyle and IR plus lifestyle and lifestyle alone from baseline to 6 months regarding Lifestyle and health related symptoms (nutritional parameters, physical activity).
13. To compare changes between metformin XR plus lifestyle and IR plus lifestyle and lifestyle alone from baseline to 6 months regarding Quality of life.

Conditions and MedDRA coding

Children and Adolscents with obesity.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Signed informed consent prior to any study-specific procedures.
2. Males or females of age 6 to less than 17 years and 3 months at the time of signing informed consent.
3. Body weight ≥ 40 kg.
4. Obesity (BMI-SDS >2.0) according to WHO.
5. Stable body weight during previous 90 days before screening visit 1 (< 5kg measured or self-reported weight change).
6. If female of childbearing potential: Not sexually active or usage of adequate anticonception and having negative pregnancy tests. Methods that can achieve a failure rate of less than 1% per year (Pearl index <1), when used consistently and correctly, are considered as highly effective birth control methods. Such methods include: •Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal. •Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable. •Intrauterine device (IUD). • Intrauterine hormone-releasing system (IUS). • Bilateral tubal occlusion. • Vasectomised partner. • Sexual abstinence (if refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the preferred and usual lifestyle).

Exclusion criteria 19

1. Known syndromal obesity (e.g. Prader-Willi syndrome, Bardet-Biedl syndrome or Laurence-Moon syndrome).
2. Pregnancy or lactation.
3. Indigestion-causing diseases.
4. Severe gastrointestinal disease, as judged by investigator.
5. Total or partial gastric or small intestine resection.
6. Type 1 diabetes mellitus.
7. Kidney disease or renal dysfunction, acute or chronic (eGFR <60ml/min/1,73m2 ).
8. Hypo-/hyperthyroidism, unless stable treatment.
9. Severe depression, severe anxiety or other psychiatric disorder referred to or undergoing special treatment, as judged by investigator.
10. Severe sleep apnea, as judged by investigator.
11. Chronic disease, as judged by investigator.
12. Any concomitant medication influencing blood glucose (e.g. metformin and acarbose), influencing other parameters of metabolic syndrome (e.g. orlistat) or interfering with the investigational medicinal product from 3 months prior to screening until the end of the treatment period at visit 11.
13. Steroid treatment (oral or injected).
14. Antidepressants that can lead to weight gain, as judged by investigator.
15. Unstable treatment for neuropsychiatric disorders such as ADHD/ADD, and/or treatment started within 3 months prior to screening visit.
16. Known hypersensitivity to metformin or any of the excipients.
17. Language difficulties, impaired mental ability or not willing to understand or comply with the study procedures.
18. Participation in another clinical study involving an Investigational Medicinal Product (IMP) within three months prior to screening.
19. Subject from the same household participating in this trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. BMI-SDS (according to WHO).

Secondary endpoints 12

1. 1 and 3: BMI-SDS (according to WHO).
2. 2. Adverse Events, vital signs (systolic and diastolic blood pressure (SBP and DBP) and heart rate), physical examination, fP-glucose, ALAT, creatinine, lactate, cobalamin, clinical chemistry, haematology and urine analysis and plasma metformin concentration.
3. 4. Plasma and urine concentration of metformin (PK), area under the curve (AUC), BMI-SDS (according to WHO).
4. 5. Demographics, tanner stage, anthropometrics and growth chart. Plasma and urine concentration of metformin (PK), area under the curve (AUC) and BMI-SDS (according to WHO).
5. 6. Glucose and insulin at fasting and during OGTT. Insulin secretion and sensitivity derived from OGTT. HbA1c.
6. 7. Triglycerides, Total cholesterol, High-Density Lipoprotein (HDL), Low-Density Lipoprotein (LDL), SBP and DBP.
7. 8. Creatinine, Cystatin C/GFR, Alanine Aminotransferase (ALAT), Gamma Glutamyl Transpeptidase (GGT), Lactate Dehydrogenase (LD) and Bilirubin.
8. 9. Hs-CRP.
9. 10. IGF-1, SHBG, FSH, LH, Testosterone and Estrogen.
10. 11. Anthropometrics, waist- and hip circumference (including ratio), and sagittal abdominal diameter (SAD). Bioimpedance, indirect calorimetry and skin fold measurement will be performed at selected sites
11. 12. Questionnaires: Food Frequency (FFQ), Regular meals, Portion Size, Physical Activity, Medipal®.
12. 13. PedsQL™.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Region Uppsala

Sponsor organisation

Region Uppsala

Address

Storgatan 27, Uppsala Domkyrkofors. Uppsala Domkyrkofors.

City

Uppsala

Postcode

753 31

Country

Sweden

Scientific contact point

Organisation

Region Uppsala

Contact name

Obesity Unit f Children&Adolescents

Public contact point

Organisation

Region Uppsala

Contact name

Obesity Unit f Children&Adolescents

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications