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Efficacy and Safety of Liraglutide in Combination With Metformin Compared to Metformin Alone, in Children and Adolescents With Type 2 Diabetes (Ellipse™)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01541215
Recruitment Status : Completed
First Posted : February 29, 2012
Results First Posted : December 11, 2018
Last Update Posted : October 1, 2020
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Tracking Information
First Submitted Date  ICMJE February 23, 2012
First Posted Date  ICMJE February 29, 2012
Results First Submitted Date  ICMJE November 15, 2018
Results First Posted Date  ICMJE December 11, 2018
Last Update Posted Date October 1, 2020
Actual Study Start Date  ICMJE November 13, 2012
Actual Primary Completion Date November 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 15, 2018)
Change in HbA1c (Glycosylated Haemoglobin) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 28, 2012)
Change in HbA1c (Glycosylated Haemoglobin) [ Time Frame: Week 0, week 14 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2020)
  • Change From Baseline in Fasting Plasma Glucose (FPG) [ Time Frame: 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% [ Time Frame: Week 26 ]
    Percentage of subjects having HbA1c <7.0%. 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) [ Time Frame: 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 Below 7.0% [ Time Frame: 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 Maximum 6.5% [ Time Frame: Week 26 ]
    Number of subjects achieving HbA1c <=6.5% after 26 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 Maximum 6.5% [ Time Frame: 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.
  • Number of Subjects Having HbA1c Below 7.0% Without Severe or Minor Hypoglycaemic Episodes [ Time Frame: Week 26 ]
    Number of subjects achieving HbA1c <7.0% without severe or minor hypoglycaemic episodes after 26 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 7.0% Without Severe or Minor Hypoglycaemic Episodes [ Time Frame: 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% [ Time Frame: Week 26 ]
    Number of subjects achieving HbA1c <7.5% after 26 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 7.5% [ Time Frame: 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 [ Time Frame: 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 in FPG [ Time Frame: 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 in Mean 7-point Self-measured Plasma Glucose [ Time Frame: 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.
  • Change From Baseline in 7-point Self-measured Plasma Glucose [ Time Frame: 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 Post-prandial Increments (From Before Meal to 90 Min After Breakfast, Lunch, and Dinner) [ Time Frame: Week 0, week 26 ]
    Change in post-prandial increments (from before meal to 90 min after breakfast, lunch, and dinner) after 26 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 in Post-prandial Increments (From Before Meal to 90 Min After Breakfast, Lunch, and Dinner) [ Time Frame: 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 in Mean Post-prandial Increment Across All Three Meals (Breakfast, Lunch, and Dinner) [ Time Frame: Week 0, week 26 ]
    Change in mean post-prandial increment across all three meals (breakfast, lunch, and dinner) after 26 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 in Mean Post-prandial Increment Across All Three Meals (Breakfast, Lunch, and Dinner) [ Time Frame: 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.
  • Change From Baseline in Body Weight [ Time Frame: Week 0, week 26 ]
    Change from baseline in body weight after 26 weeks. 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 [ Time Frame: 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 Baseline in BMI Standard Deviation Score (SDS) [ Time Frame: 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) [ Time Frame: Week 0, week 26 ]
    Change in blood pressure (systolic and diastolic blood pressure) after 26 weeks. 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) [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Ratio to baseline (fasting insulin) at week 26. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
  • Ratio to Baseline: Fasting Insulin [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Ratio to baseline (fasting pro-insulin) at week 26. 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 [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Ratio to baseline (Pro-insulin/insulin ratio) after week 26. 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 [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Ratio to baseline (fasting glucagon) at week 26. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication.
  • Ratio to Baseline: Fasting Glucagon [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Ratio to baseline (fasting C-peptide) at week 26. 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 [ Time Frame: 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) [ Time Frame: 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.
  • Ratio to Baseline: HOMA-B [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Ratio to baseline (total 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: Total Cholesterol [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Ratio to Baseline: High-density Lipoprotein (HDL) Cholesterol [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Ratio to baseline (triglycerides) 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: Triglycerides [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Ratio to baseline (free fatty acids) 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: Free Fatty Acids [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Change from baseline in pulse 26 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 [ Time Frame: 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 [ Time Frame: Week 0, week 26 ]
    Change in height SDS from baseline to week 26. 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 From Baseline in Height SDS [ Time Frame: 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 Bone Age Assessment (X-ray of Left Hand and Wrist) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Week 0, week 26 ]
    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.
  • Growth (Height Velocity) [ Time Frame: 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.
  • Height Velocity SDS [ Time Frame: Week 0, week 26 ]
    Height velocity SDS scores at week 26. 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.
  • Height Velocity SDS [ Time Frame: 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 [ Time Frame: 0-26 weeks ]
    Total number of hypoglycaemic episodes according to American Diabetes Association (ADA) classification from baseline (week 0) to week 26.
  • Number of Hypoglycaemic Episodes [ Time Frame: 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) [ Time Frame: 0-26 weeks ]
    Total number of adverse events during 26 weeks.
  • Number of Adverse Events (Week 0-52) [ Time Frame: 0-52 weeks ]
    Total number of adverse events during entire treatment period.
  • Number of Serious Adverse Events (Week 0-26) [ Time Frame: 0-26 weeks ]
    Total number of serious adverse events during 26 weeks.
  • Number of Serious Adverse Events (Week 0-52) [ Time Frame: 0-52 weeks ]
    Total number of serious adverse events during entire treatment period.
  • Number of Adverse Events (Week 53-104) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Change From Week 52 in Bone Age Assessment (X-ray of Left Hand and Wrist)- Week 104 [ Time Frame: 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.
  • Number of Adverse Events (Week 53-156) [ Time Frame: Weeks 53-156 ]
  • Number of Serious Adverse Events (Week 53-156) [ Time Frame: Weeks 53-156 ]
  • Growth (Height Velocity)- Week 156 [ Time Frame: Week 0, week 156 ]
  • Height Velocity SDS- Week 156 [ Time Frame: Week 0, week 156 ]
  • Change From Week 52 in Height SDS- Week 156 [ Time Frame: Week 52, week 156 ]
  • Pubertal Assessment/Progression (Tanner Staging)- Week 156 [ Time Frame: Week 52, week 156 ]
  • Change in Bone Age Assessment (X-ray of Left Hand and Wrist)- Week 156 [ Time Frame: Week 52, week 156 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2012)
  • Number of subjects having HbA1c below 7.0% [ Time Frame: Week 14 ]
  • Number of Subjects Having HbA1c Below 7.0% [ Time Frame: Week 26 ]
  • Number of Subjects Having HbA1c Below 7.0% [ Time Frame: Week 52 ]
  • Number of subjects having HbA1c maximum 6.5% [ Time Frame: Week 14 ]
  • Number of Subjects Having HbA1c Maximum 6.5% [ Time Frame: Week 26 ]
  • Number of Subjects Having HbA1c Maximum 6.5% [ Time Frame: Week 52 ]
  • Number of subjects having HbA1c below 7.0% without severe or minor hypoglycaemic episodes [ Time Frame: Week 14 ]
  • Number of Subjects Having HbA1c Below 7.0% Without Severe or Minor Hypoglycaemic Episodes [ Time Frame: Week 26 ]
  • Number of Subjects Having HbA1c Below 7.0% Without Severe or Minor Hypoglycaemic Episodes [ Time Frame: Week 52 ]
  • Change from baseline in fasting plasma glucose (FPG) [ Time Frame: Week 0, week 14 ]
  • Change From Baseline in Fasting Plasma Glucose (FPG) [ Time Frame: Week 0, week 26 ]
  • Change from baseline in fasting plasma glucose (FPG) [ Time Frame: Week 0, week 52 ]
  • Change from baseline in 7-point self-measured plasma glucose [ Time Frame: Week 0, week 14 ]
  • Change from baseline in 7-point self-measured plasma glucose [ Time Frame: Week 0, week 26 ]
  • Change from baseline in 7-point self-measured plasma glucose [ Time Frame: Week 0, week 52 ]
  • Number of adverse events (AEs) [ Time Frame: Week 53 ]
  • Number of adverse events (AEs) [ Time Frame: week 104 (1 year follow-up) ]
  • Number of adverse events (AEs) [ Time Frame: Week 156 (2 year follow-up) ]
  • Number of serious adverse events (SAEs) [ Time Frame: Week 53 ]
  • Number of adverse events (AEs) [ Time Frame: Week 156 (2 year follow-up ) ]
  • Growth velocity [ Time Frame: Week 104 (1 year follow-up) ]
  • Growth velocity [ Time Frame: Week 156 (2 year follow-up) ]
  • Pubertal progression [ Time Frame: Week 104 (1 year follow-up) ]
  • Pubertal progression [ Time Frame: Week 156 (2 year follow-up) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Liraglutide in Combination With Metformin Compared to Metformin Alone, in Children and Adolescents With Type 2 Diabetes
Official Title  ICMJE Efficacy and Safety of Liraglutide in Combination With Metformin Versus Metformin Monotherapy on Glycaemic Control in Children and Adolescents With Type 2 Diabetes
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Diabetes
  • Diabetes Mellitus, Type 2
Intervention  ICMJE
  • Drug: liraglutide
    Administered subcutaneously (s.c., under the skin) once daily.1.8 mg or maximum tolerated dose (MTD: 0.6 mg, 1.2 mg, 1.8 mg) for 26 weeks. Subjects will continue treatment in a 26 week open-labelled extension. Rescue treatment will be allowed if rescue criteria are met.
  • Drug: placebo
    Administered subcutaneously (s.c., under the skin) once daily for 26 weeks. Subjects will discontinue placebo treatment in the open-labelled extension. Rescue treatment will be allowed if rescue criteria are met.
  • Drug: metformin
    Tablets administered for 26 weeks. Maximum tolerated dose (MTD) between 1000-2000 mg at the discretion of the investigator. Subjects will continue treatment in a 26 week open-labelled extension.
Study Arms  ICMJE
  • Experimental: Lira + Met
    Interventions:
    • Drug: liraglutide
    • Drug: metformin
  • Placebo Comparator: Placebo + Met
    Interventions:
    • Drug: placebo
    • Drug: metformin
Publications * Tamborlane WV, Barrientos-Pérez M, Fainberg U, Frimer-Larsen H, Hafez M, Hale PM, Jalaludin MY, Kovarenko M, Libman I, Lynch JL, Rao P, Shehadeh N, Turan S, Weghuber D, Barrett T; Ellipse Trial Investigators. Liraglutide in Children and Adolescents with Type 2 Diabetes. N Engl J Med. 2019 Aug 15;381(7):637-646. doi: 10.1056/NEJMoa1903822. Epub 2019 Apr 28.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 25, 2018)
135
Original Estimated Enrollment  ICMJE
 (submitted: February 28, 2012)
172
Actual Study Completion Date  ICMJE May 20, 2020
Actual Primary Completion Date November 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE Inclusion Criteria: - 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 Exclusion Criteria: - 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 10 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Brazil,   Canada,   Croatia,   Denmark,   Egypt,   France,   Germany,   Greece,   Hungary,   India,   Israel,   Italy,   Lebanon,   Malaysia,   Mexico,   Morocco,   Netherlands,   New Zealand,   North Macedonia,   Norway,   Poland,   Portugal,   Puerto Rico,   Romania,   Russian Federation,   Serbia,   Spain,   Sweden,   Taiwan,   Thailand,   Turkey,   United Kingdom,   United States
Removed Location Countries Macedonia, The Former Yugoslav Republic of
 
Administrative Information
NCT Number  ICMJE NCT01541215
Other Study ID Numbers  ICMJE NN2211-3659
2011-002605-29 ( EudraCT Number )
P/288/2010 ( Other Identifier: EMA (PDCO) )
U1111-1121-8743 ( Other Identifier: WHO )
CTRI/2013/10/004082 ( Registry Identifier: Clinical Trials Registry - India (CTRI) )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com
URL: http://novonordisk-trials.com/sharing-results
Responsible Party Novo Nordisk A/S
Study Sponsor  ICMJE Novo Nordisk A/S
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novo Nordisk A/S
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP