Efficacy and Safety of Liraglutide in Combination With Metformin Compared to Metformin Alone, in Children and Adolescents With Type 2 Diabetes
- Conditions
- DiabetesDiabetes Mellitus, Type 2
- Interventions
- Registration Number
- NCT01541215
- Lead Sponsor
- Novo Nordisk A/S
- Brief Summary
This trial is conducted globally. The aim of this trial is to assess the efficacy and safety of liraglutide in the paediatric population in order to potentially address the unmet need for treatment of children and adolescents with type 2 diabetes.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 135
- Children and adolescents between the ages of 10-16 years. Subjects cannot turn 17 years and 11 months before the end of treatment (52 weeks) - Diagnosis of type 2 diabetes mellitus and treated for at least 30 days with: diet and exercise alone, diet and exercise in combination with metformin monotherapy, diet and exercise in combination with metformin and a stable (Stable is defined as basal insulin adjustments up to 15%) dose of basal insulin, diet and exercise in combination with a stable (Stable is defined as basal insulin adjustments up to 15%) dose of basal insulin - HbA1c: 7.0-11% (inclusive) if diet and exercise treated or 6.5-11% (inclusive) if treated with metformin as monotherapy, basal insulin as monotherapy or metformin and basal insulin in combination - Body mass index (BMI) above 85% percentile of the general age and gender matched population
- Type 1 diabetes - Maturity onset diabetes of the young (MODY) - Use of any antidiabetic agent other than metformin and/or basal insulin within 90 days prior to screening - Recurrent severe hypoglycaemia or hypoglycaemic unawareness as judged by the investigator - History of chronic pancreatitis or idiopathic acute pancreatitis - Any clinically significant disorder, except for conditions associated with type 2 diabetes history which in the investigator's opinion could interfere with results of the trial - Uncontrolled hypertension, treated or untreated above 99th percentile for age and gender in children - Known or suspected abuse of alcohol or drugs/narcotics
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Lira + Met liraglutide - Placebo + Met placebo - Placebo + Met metformin - Lira + Met metformin -
- Primary Outcome Measures
Name Time Method Change in HbA1c (Glycosylated Haemoglobin) Week 0, week 26 Change in HbA1c from baseline to week 26. All available data were used for the primary analysis, including data collected after treatment discontinuation and initiation of rescue medication.
- Secondary Outcome Measures
Name Time Method Change From Baseline in 7-point Self-measured Plasma Glucose Week 0, week 52 Change in mean 7-point self-measured plasma glucose after 52 weeks. Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime. Mean 7-point SMPG was defined as the area under the profile (calculated using the trapezoidal method) divided by time. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change in Mean Post-prandial Increment Across All Three Meals (Breakfast, Lunch, and Dinner) Week 0, week 52 Change in mean post-prandial increment across all three meals (breakfast, lunch, and dinner) after 52 weeks. Post-prandial increment for each meal (breakfast, lunch, and dinner) was derived from the 7-point SMPG profile as the difference between post-prandial plasma glucose values and the plasma glucose values before the meal. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: HOMA-B Week 0, week 52 Ratio to baseline (HOMA-B) after 52 weeks. HOMA-B is an index of beta-cell function and was calculated from fasting insulin. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Homeostasis Model Assessment as an Index of Insulin Resistance (HOMA-IR) Week 0, week 26 Ratio to baseline (HOMA-IR) after 26 weeks. HOMA-IR is an index of insulin resistance and was calculated from fasting insulin. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: HOMA-IR Week 0, week 52 Ratio to baseline (HOMA-IR) after 52 weeks. HOMA-IR is an index of insulin resistance and was calculated from fasting insulin. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Total Cholesterol Week 0, week 52 Ratio to baseline (total cholesterol) after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Low Density Lipoprotein (LDL) Cholesterol Week 0, week 26 Ratio to baseline (LDL cholesterol) after 26 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: LDL Cholesterol Week 0, week 52 Ratio to baseline (LDL cholesterol) after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Very Low-density Lipoprotein (VLDL) Cholesterol Week 0, week 26 Ratio to baseline (VLDL cholesterol) after 26 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: VLDL Cholesterol Week 0, week 52 Ratio to baseline (VLDL cholesterol) after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change in Bone Age Assessment (X-ray of Left Hand and Wrist) Week 0, week 52 Change in bone age from baseline to week 52. If the baseline (week 0) bone age assessment indicated that all epiphyses were fused, then the assessment was not repeated at week 52.
Pubertal Assessment/Progression (Tanner Staging) Week 0, week 26, week 52 Pubertal development was assessed in 3 areas (breast, penis and pubic hair development) by the Tanner staging in accordance with stages I-V. The Tanner staging assessment was no longer required to be performed once a subject reached the Tanner stage V, as judged by the investigator. Reported results are number of participants at different Tanner stages at week 0, week 26 and week 52.
Growth (Height Velocity) Week 0, week 52 Growth (i.e., height velocity) is the change in height per year and is measured in cm/year. The height velocity was calculated as the difference between current height and height at baseline (week 0) divided by the time (in days) between those measurement time points and multiplied by 365 days.
Change From Baseline in Fasting Plasma Glucose (FPG) Week 0, week 26 Change in FPG from baseline to week 26. All available data were used for the analysis, including data collected after treatment discontinuation and initiation of rescue medication.
Number of Subjects Having HbA1c Below 7.0% Week 52 Number of subjects achieving HbA1c \<7.0% after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Number of Subjects Having HbA1c Below 7.0% Without Severe or Minor Hypoglycaemic Episodes Week 52 Number of subjects achieving HbA1c \<7.0% without severe or minor hypoglycaemic episodes after 52 weeks.
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Minor hypoglycaemia was defined as meeting either of the below criteria:
1. an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose \<2.8 mmol/L (50 mg/dL) or plasma glucose \<3.1 mmol/L (56 mg/dL), and which was handled by the subject him/herself
2. any asymptomatic blood glucose value \<2.8 mmol/L (50 mg/dL) or plasma glucose value \<3.1 mmol/L (56 mg/dL) All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.Number of Subjects Having HbA1c Below 7.5% Week 52 Number of subjects achieving HbA1c \<7.5% after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change in HbA1c Week 0, week 52 Change in HbA1c from baseline to week 52. All available data were used for the analysis, including data collected after treatment discontinuation and initiation of rescue medication.
Change From Baseline in Body Mass Index (BMI) Standard Deviation Score (SDS) Week 0, week 26 Change in BMI SDS from baseline to week 26. BMI SDS was calculated using the following formula: Z=\[(value /M)\^L - 1\] / S\*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents' BMI provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the world health organisation (WHO) Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below -3 and above 3, the score was adjusted as described in the WHO instruction. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Number of Subjects Having HbA1c Maximum 6.5% Week 52 Number of subjects achieving HbA1c \<=6.5% after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change in FPG Week 0, week 52 Change in FPG from baseline to week 52. All available data were used for the analysis, including data collected after treatment discontinuation and initiation of rescue medication.
Change From Baseline in Body Weight Week 0, week 52 Change from baseline in body weight after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change From Week 52 in Bone Age Assessment (X-ray of Left Hand and Wrist)- Week 104 Week 52, week 104 Change in bone age from week 52 to week 104. This outcome is applicable only for the Liraglutide 1.8 mg treatment arm.
Change in Mean 7-point Self-measured Plasma Glucose Week 0, week 26 Change in mean 7-point self-measured plasma glucose after 26 weeks. Subjects were instructed to measure their plasma glucose at following timepoints: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner and at bedtime. Mean 7-point SMPG was defined as the area under the profile (calculated using the trapezoidal method) divided by time. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: High-density Lipoprotein (HDL) Cholesterol Week 0, week 26 Ratio to baseline (HDL cholesterol) after 26 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: HDL Cholesterol Week 0, week 52 Ratio to baseline (HDL cholesterol) after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Triglycerides Week 0, week 52 Ratio to baseline (triglycerides) after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Free Fatty Acids Week 0, week 52 Ratio to baseline (free fatty acids) after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change From Baseline in Pulse Week 0, week 52 Change from baseline in pulse 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change From Baseline in Height SDS Week 0, week 52 Change in height SDS from baseline to week 52. Height SDS was calculated using the following formula: Z=\[(value /M)\^L - 1\] / S\*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents' height provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the WHO Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below -3 and above 3, the score was adjusted as described in the WHO instruction. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change in Post-prandial Increments (From Before Meal to 90 Min After Breakfast, Lunch, and Dinner) Week 0, week 52 Change in post-prandial increments (from before meal to 90 min after breakfast, lunch, and dinner) after 52 weeks. Post-prandial increment for each meal (breakfast, lunch, and dinner) was derived from the 7-point SMPG profile as the difference between post-prandial plasma glucose values and the plasma glucose values before the meal. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change From Baseline in BMI Standard Deviation Score (SDS) Week 0, week 52 Change in BMI SDS from baseline to week 52. BMI SDS was calculated using the following formula: Z=\[(value /M)\^L - 1\] / S\*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents' BMI provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the WHO Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below -3 and above 3, the score was adjusted as described in the WHO instruction. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Change in Blood Pressure (Systolic and Diastolic Blood Pressure) Week 0, week 52 Change in blood pressure (systolic and diastolic blood pressure) after 52 weeks. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Fasting Insulin Week 0, week 52 Ratio to baseline (fasting insulin) at week 52. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Fasting Pro-insulin Week 0, week 52 Ratio to baseline (fasting pro-insulin) at week 52. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Pro-insulin/Insulin Ratio Week 0, week 52 Ratio to baseline (Pro-insulin/insulin ratio) after week 52. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Fasting Glucagon Week 0, week 52 Ratio to baseline (fasting glucagon) at week 52. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Fasting C-peptide Week 0, week 52 Ratio to baseline (fasting C-peptide) at week 52. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Ratio to Baseline: Homeostasis Model Assessment of Beta-cell Function (HOMA-B) Week 0, week 26 Ratio to baseline (HOMA-B) after 26 weeks. HOMA-B is an index of beta-cell function and was calculated from fasting insulin. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Height Velocity SDS Week 0, week 52 Height velocity SDS scores at week 52. Height velocity is change in height per year. The height velocity was calculated as the difference between current height and height at baseline (week 0) divided by time between those measurement time points and multiplied by 365 days. Height velocity SDS was calculated using following formula: Z=\[(value /M)\^L - 1\] / S\*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents' height provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the WHO Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below -3 and above 3, the score was adjusted as described in the WHO instruction. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
Number of Hypoglycaemic Episodes 0-52 weeks Total number of hypoglycaemic episodes according to American Diabetes Association (ADA) classification from baseline (week 0) to week 52.
Number of Adverse Events (Week 0-26) 0-26 weeks Total number of adverse events during 26 weeks.
Number of Adverse Events (Week 0-52) 0-52 weeks Total number of adverse events during entire treatment period.
Number of Serious Adverse Events (Week 0-26) 0-26 weeks Total number of serious adverse events during 26 weeks.
Number of Serious Adverse Events (Week 0-52) 0-52 weeks Total number of serious adverse events during entire treatment period.
Number of Adverse Events (Week 53-104) Week 53-104 This outcome is applicable only for the Liraglutide 1.8 mg treatment arm. Number of adverse events reported during follow-up 1 (week 53 to 104).
Number of Serious Adverse Events (Week 53-104) Weeks 53-104 This outcome is applicable only for the Liraglutide 1.8 mg treatment arm. Number of serious adverse events reported during follow up 1 (week 53 to 104).
Growth (Height Velocity)- Week 104 Week 0, week 104 Growth (i.e., height velocity) is the change in height per year and is measured in cm/year. The height velocity was calculated as the difference between current height and height at baseline (week 0) divided by the time (in days) between those measurement time points and multiplied by 365 days. This outcome is applicable only for the Liraglutide 1.8 mg treatment arm.
Height Velocity SDS- Week 104 Week 0, week 104 The height velocity was calculated as the difference between current height and height at baseline (week 0) divided by time between those measurement time points and multiplied by 365 days. Height velocity SDS was calculated using following formula: Z=\[(value /M)\^L - 1\] / S\*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents' height provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the WHO Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below -3 and above 3, the score was adjusted as described in the WHO instruction. This outcome is applicable only for the Liraglutide 1.8 mg treatment arm.
Change From Week 52 in Height SDS- Week 104 Week 52, week 104 Change in height SDS from week 52 to week 104. Height SDS was calculated using the following formula: Z=\[(value /M)\^L - 1\] / S\*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents' height provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the WHO Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below -3 and above 3, the score was adjusted as described in the WHO instruction. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. This outcome is applicable only for the Liraglutide 1.8 mg treatment arm.
Change in Pubertal Assessment/Progression (Tanner Staging)- Week 104 Week 52, week 104 Pubertal development was assessed in 3 areas (breast, penis and pubic hair development) by the Tanner staging in accordance with stages I-V, where stage I represents "pre-adoloscent development" and stage V represents "pubertal development equivalent to that of an adult". The Tanner staging assessment was no longer required to be performed once a subject reached the Tanner stage V, as judged by the investigator. Reported results are number of subjects at different Tanner stages at week 52 and week 104. This outcome is applicable only for the Liraglutide 1.8 mg treatment arm.
Number of Adverse Events (Week 53-156) Week 53-156 This outcome measure is applicable only for the Liraglutide 1.8 mg treatment arm. Number of adverse events reported during the follow-up period (weeks 53 to 156).
Number of Serious Adverse Events (Week 53-156) Weeks 53-156 This outcome measure is applicable only for the Liraglutide 1.8 mg treatment arm. Number of serious adverse events reported during the follow up period (week 53 to 156).
Growth (Height Velocity)- Week 156 Week 0, week 156 Growth (i.e., height velocity) is the change in height per year and is measured in cm/year. The height velocity was calculated as the difference between current height and height at baseline (week 0) divided by the time (in days) between those measurement time points and multiplied by 365 days. This outcome measure is applicable only for the Liraglutide 1.8 mg treatment arm.
Height Velocity SDS- Week 156 Week 0, week 156 The height velocity was calculated as the difference between current height and height at baseline (week 0) divided by time between those measurement time points and multiplied by 365 days. Height velocity SDS was calculated using following formula: Z=\[(value /M)\^L - 1\] / S\*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents' height provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the WHO Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below -3 and above 3, the score was adjusted as described in the WHO instruction. This outcome measure is applicable only for the Liraglutide 1.8 mg treatment arm.
Change From Week 52 in Height SDS- Week 156 Week 52, week 156 Change in height SDS from week 52 to week 156. Height SDS was calculated using the following formula: Z=\[(value /M)\^L - 1\] / S\*L; where L, M and S are median (M), skewness (L) and variation coefficient (S) of children/adolescents' height provided for each sex and age. For each subject, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The method is described in the WHO Multicentre Growth Reference, which also contains the values for L, M and S by age and sex. For Z (SDS) scores below -3 and above 3, the score was adjusted as described in the WHO instruction. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. This outcome measure is applicable only for the Liraglutide 1.8 mg treatment arm.
Change in Pubertal Assessment/Progression (Tanner Staging)- Week 156 Week 52, week 156 Pubertal development was assessed in 3 areas (breast, penis and pubic hair development) by the Tanner staging in accordance with stages I-V, where stage I represents "pre-adoloscent development" and stage V represents "pubertal development equivalent to that of an adult". The Tanner staging assessment was no longer required to be performed once a subject reached the Tanner stage V, as judged by the investigator. Reported results are number of subjects at different Tanner stages at week 52 and week 156. This outcome measure is applicable only for the Liraglutide 1.8 mg treatment arm.
Change From Week 52 in Bone Age Assessment (X-ray of Left Hand and Wrist)- Week 156 Week 52, week 156 Change in bone age from week 52 to week 156. This outcome measure is applicable only for the Liraglutide 1.8 mg treatment arm.
Trial Locations
- Locations (1)
Novo Nordisk Investigational Site
🇬🇧Southampton, United Kingdom