The primary objective of the METFORMIN study is to determine the efficacy of metformin in combination with lifestyle-intervention in obese children and adolescents with insulin resistance versus placebo with lifestyle-intervention. The secondary…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Bariatrie (Obesitas)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study endpoint for efficacy is the reduction in BMI, which is
calculated from the anthropometric measurements.
Other primary endpoints for efficacy are insulin resistance, calculated by the
HOMA-IR, which is a generally accepted index to determine insulin resistance in
children and adolescents, percentage of body fat measured by bio-impedance,
HbA1C value, β-cell function, calculated by HOMA-β%, oral disposition index,
insulin secretion calculated by the insulinogenic index, physical fitness
measured by validated fitness tests, basal metabolic rate measured by
calorimetry and quality of life measured by validated quality of life
questionnaire.
Secondary outcome
Secondary outcome parameters for safety of metformin treatment are hepatic and
renal function tests, and for tolerability the number of adverse effects (in
relation to the achieved dose level).
Tertiary outcome parameters are the pharmacokinetic parameters of metformin in
obese children and adolescents. These parameters are estimated using population
PK-PD modelling techniques in which a comprehensive covariate analysis will be
performed allowing to account for variability in PK parameters on the basis of
individual characteristics such as age, bodyweight, BMI, percentage of body
fat, gender, Tanner stage and genetic constitution.
Quaternary outcome parameters for long-term efficacy and long-term safety and
tolerability of metformin are BMI, insulin resistance calculated by the
HOMA-IR, percentage of body fat measured by bio-impedance, HbA1C, β-cell
function, calculated by HOMA-β%, oral disposition index, insulin secretion
calculated by the insulinogenic index, physical fitness measured by validated
fitness tests, quality of life measured by validated quality of life
questionnaire, hepatic and renal function tests and number of side effects. In
addition, the percentage of patients that has developed impaired fasted
glucose, impaired glucose tolerance (2-hrs plasma glucose during an OGTT), T2DM
and the development of micro-vascular complications detected by
micro-albuminuria and macro-vascular complications detected by using pulse wave
velocity (PWV) and augmentation index (AIx) is evaluated.
Background summary
The prevalence of obesity in children and adolescents is increasing rapidly and
is associated with significant medical and psychosocial consequences persisting
into adulthood.
Obesity may lead to metabolic complications, such as insulin resistance, which
can progress via impaired fasted glucose and impaired glucose tolerance to type
2 diabetes mellitus (T2DM) and to the development of micro- and macro-vascular
complications.
Metformin, an oral anti-diabetic licensed for adults and children from 10 years
onwards, is already used off label in obese children and adolescents with
insulin resistance, even though the specific effects of metformin in these
obese children and adolescents have not been elucidated, particularly upon
long-term use.
The rationale for this study is based on the hypothesis that metformin may
reduce body mass index (BMI), insulin resistance and percentage of body-fat in
obese children and adolescents with insulin resistance. Further more it is
anticipated that metformin may delay the progression to T2DM and thereby micro-
and macro-vascular complications in obese children and adolescents with insulin
resistance.
The rationale for this study is based on the hypothesis that metformin may
reduce body mass index (BMI), insulin resistance and percentage of body-fat in
obese children and adolescents with insulin resistance. Further more it is
anticipated that metformin may delay the progression to T2DM and thereby micro-
and macro-vascular complications in obese children and adolescents with insulin
resistance.
Study objective
The primary objective of the METFORMIN study is to determine the efficacy of
metformin in combination with lifestyle-intervention in obese children and
adolescents with insulin resistance versus placebo with lifestyle-intervention.
The secondary objective of the METFORMIN study is to determine the safety and
tolerability of metformin in combination with lifestyle-intervention in obese
children and adolescents with insulin resistance versus placebo with
lifestyle-intervention.
The tertiary objective of the METFORMIN study is to study the population
pharmacokinetics (PK) of metformin in obese children and adolescents.
The quaternary objective of the METFORMIN study is to determine the long-term
efficacy and long-term safety and tolerability of metformin in obese children
and adolescents with insulin resistance.
Other objectives are to compare body fat measured using bio-impedance with a
body fat measured using dual energy X-ray absorptiometry (DEXA scan), to
compare insulin sensitivity measured by the whole body insulin sensitivity
index (WBISI) with insulin sensitivity using HOMA-IR in obese children and
adolescents .
Study design
The proposed multi-centre project is divided in two consecutive studies: a
double-blind randomized placebo-controlled study (study of 18 months duration)
and an open study (follow up study of 18 months duration), when metformin will
be offered to all patients, for whom metformin is still indicated.
Intervention
In the initial study, the study population will be assigned to either placebo
or Metformin. All subjects will follow the same lifestyle-intervention program
during the entire study period of 18 months. Metformin and placebo will be
administered in increasing dosages. The initial dose is 500 mg and will be
increased weekly with 500 mg to a maximum dose of 1000 mg bid. The dose of 1000
mg bid will be administered till the end of the study unless the study subject
develops adverse effects.
In the follow up study metformin will be offered to all study subjects, if
indicated.
Study burden and risks
Metformin is licensed for children >= 10 years with T2DM while there is world
wide experience with off-label use of metformin in obese children and
adolescents with and without insulin resistance.
The potential benefits of using metformin are faster stabilisation of weight or
weight loss and possibly slower progression to T2DM and the development of
micro- and macro vascular complications.
Expected adverse effects of metformin are mainly gastro-intestinal symptoms,
such as diarrhoea, nausea and vomiting.
During the initial study of 18 months, there are three extra visits with two
extra blood samples (extra blood collected 50 ml) compared to children and
adolescents that are being prescribed metformin in an off-label manner. Total
number of visits is 9, during which at 8 visits blood will be collected (6
times by venous puncture and twice using a venous catheter for OGTT and
metformin day-curve). Total amount of blood taken will be approximately 125 ml
over 18 months). There are no extra OGTTs compared to treatment with off-label
metformin.
Compared to current lifestyle intervention program, the subjects are offered a
18 months fitness program instead of 6 months, and undergo a validated fitness
test (30 minutes) during the first training, in week 37 and at the end of the
initial and the follow up study.
The subjects have to fulfil a quality of life questionnaire, dietary
questionnaire (approximately 30 minutes) at study entry, week 37 and at the end
of the initial and the follow up study.
During the follow up study, there will be 6 times contact with the subjects.
Children using metformin will visit the hospital every 3 months, this number of
visits is similar to children and adolescents that are being prescribed
metformin in an off-label manner. Children not using metformin, will visit the
hospital 3 times and will receive phone calls in between the visits. Total
number of visits is including blood sampling is 3(twice by venous puncture and
once using a venous catheter for OGTT), this is equal for all children, and
similar to children and adolescents that are being prescribed metformin in an
off-label manner. Total amount of blood taken will be approximately 50 ml over
18 months.
Koekoekslaan 1
Nieuwegein 3435 CM
NL
Koekoekslaan 1
Nieuwegein 3435 CM
NL
Listed location countries
Age
Inclusion criteria
The inclusion criteria are subject*s age >= 10 and <= 16 years at study entry, from Caucasian descent, with obesity defined as BMI SDS > 2.3 and with insulin resistance defined as HOMA-IR >= 3.4. In addition an obtained informed consent from subjects and/or parents/caregivers.
Exclusion criteria
The exclusion criteria are presence of T2DM (American Diabetes Association criteria); presence of endocrine disorders with steroid therapy; suspicion of polycystic ovarium syndrome; height < -1.3 SD of target height; psychiatric illness and eating disorders in particular; use of anti-hyperglycaemic drugs; pregnancy (pregnancy test will be performed, if applicable); (history of) alcohol abuse; impaired renal and/or hepatic function (defined as GFR<80ml/min and ALAT >= 150% of normal value for age); use of ritonavir; use of ACE inhibitors; insufficient knowledge of the Dutch language.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023980-17-NL |
| CCMO | NL34811.100.11 |