Clinical Trial Results:
Efficacy and safety of liraglutide in combination with metformin versus metformin monotherapy on glycaemic control in children and adolescents with type 2 diabetes
Summary
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EudraCT number |
2011-002605-29 |
Trial protocol |
GR GB HU DE BE ES DK NO SE PL AT FR PT NL |
Global end of trial date |
20 May 2020
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Results information
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Results version number |
v3(current) |
This version publication date |
04 Jun 2021
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First version publication date |
05 Dec 2018
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Other versions |
v1 , v2 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NN2211-3659
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01541215 | ||
WHO universal trial number (UTN) |
U1111-1121-8743 | ||
Sponsors
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Sponsor organisation name |
Novo Nordisk A/S
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Sponsor organisation address |
Novo Allé, Bagsvaerd, Denmark, 2880
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Public contact |
Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Scientific contact |
Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000128-PIP01-07 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Nov 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
15 Nov 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
20 May 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To confirm the superiority of liraglutide at the maximum tolerated dose (0.6 mg, 1.2 mg or 1.8 mg)versus placebo when added to metformin with or without basal insulin treatment in controlling glycaemia in children and adolescents (ages 10–17 years) with type 2 diabetes
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice, including archiving of essential documents and FDA 21 CFR 312.120.
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Background therapy |
Metformin was characterised as background treatment. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
13 Nov 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
2 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 1
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
Canada: 3
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Hungary: 3
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Country: Number of subjects enrolled |
Israel: 13
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Country: Number of subjects enrolled |
India: 6
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Country: Number of subjects enrolled |
Lebanon: 3
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Country: Number of subjects enrolled |
North Macedonia: 6
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Country: Number of subjects enrolled |
Mexico: 16
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Country: Number of subjects enrolled |
Malaysia: 2
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Country: Number of subjects enrolled |
New Zealand: 6
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Country: Number of subjects enrolled |
Poland: 1
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Country: Number of subjects enrolled |
Portugal: 1
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Country: Number of subjects enrolled |
Russian Federation: 13
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Country: Number of subjects enrolled |
Thailand: 1
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Country: Number of subjects enrolled |
Turkey: 5
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Country: Number of subjects enrolled |
Taiwan: 3
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Country: Number of subjects enrolled |
United States: 45
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Country: Number of subjects enrolled |
Morocco: 4
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Worldwide total number of subjects |
135
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EEA total number of subjects |
7
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
16
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Adolescents (12-17 years) |
119
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was conducted at 84 sites in 25 countries. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Eligible subjects entered an 11- to 12-week run-in period where they were to undergo a 3-4 week titration of metformin to a maximum tolerated dose of metformin (≥1000 mg and ≤2000 mg per day) followed by an 8-week maintenance period. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Treatment period (52 weeks)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||
Blinding implementation details |
The trial was designed to be double-blind during the first 26 weeks of randomised treatment
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Liraglutide 1.8 mg | ||||||||||||||||||||||||
Arm description |
After the run-in period, subjects were randomized to receive liraglutide subcutaneous injections once daily (in combination with metformin with or without basal insulin, on a background of diet and exercise) for 52 weeks (26 weeks double blind treatment period followed by a 26-week open-label extension period). Subjects treated with liraglutide for more than 3 months were asked to return for follow-up visits one and two years after the end of the open label period (after trial drug cessation at week 52). | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Liraglutide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Liraglutide (6.0 mg/ml solution) was administered once daily by s.c. injections, either in the abdomen, thigh or upper arm. The liraglutide dosing was started at 0.6 mg/day during the first week and escalated in weekly increments of 0.6 mg over the following 2-3 weeks. Dose escalation was based on tolerability, as judged by the investigator and on the average of three fasting plasma glucose (FPG) measurements performed by the subject at home on the 3 consecutive days before the dose escalation visit being >6.1 mmol/L (110 mg/dL). Subjects were treated with doses of 0.6, 1.2 or 1.8 after dose escalation.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
After the run-in period, subjects were randomized to receive placebo (in combination with metformin with or without basal insulin, on a background of diet and exercise) for a 26 weeks double blind treatment period. After 26 weeks, participants discontinued placebo and continued treatment with metformin (with or without basal insulin) during the open-label period. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Liraglutide placebo was administered once daily by s.c. injections, either in the abdomen, thigh or upper arm. The liraglutide placebo was administered once daily subcutaneously in equivalent volume as liraglutide.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: In total, 135 subjects were randomised (66 subjects to liraglutide and 69 subjects to placebo); of these, one subject in the placebo group was not exposed to treatment. Thus, 134 subjects were exposed to either liraglutide or placebo (66 subjects to liraglutide and 68 subjects to placebo). |
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Period 2
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Period 2 title |
Follow up 1 (Week 104)
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Arm title
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Liraglutide 1.8 mg: Follow-up 1 | ||||||||||||||||||||||||
Arm description |
Subjects treated with liraglutide for more than 3 months during the treatment period; were followed up until week 104 after trial drug cessation at week 52. | ||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Notes [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Subjects who received liraglutide for more than 3 months during the treatment period (week 0-52), were followed-up at week 104. |
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Period 3
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Period 3 title |
Follow up 2 (Week 156)
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Arm title
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Liraglutide 1.8 mg: Follow-up 2 | ||||||||||||||||||||||||
Arm description |
Subjects treated with liraglutide for more than 3 months during the treatment period; were followed up until week 156 after trial drug cessation at week 52. | ||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Notes [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Subjects who received liraglutide for more than 3 months during the treatment period (week 0-52), were followed-up at week 156. |
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Baseline characteristics reporting groups
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Reporting group title |
Liraglutide 1.8 mg
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Reporting group description |
After the run-in period, subjects were randomized to receive liraglutide subcutaneous injections once daily (in combination with metformin with or without basal insulin, on a background of diet and exercise) for 52 weeks (26 weeks double blind treatment period followed by a 26-week open-label extension period). Subjects treated with liraglutide for more than 3 months were asked to return for follow-up visits one and two years after the end of the open label period (after trial drug cessation at week 52). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
After the run-in period, subjects were randomized to receive placebo (in combination with metformin with or without basal insulin, on a background of diet and exercise) for a 26 weeks double blind treatment period. After 26 weeks, participants discontinued placebo and continued treatment with metformin (with or without basal insulin) during the open-label period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Liraglutide 1.8 mg
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Reporting group description |
After the run-in period, subjects were randomized to receive liraglutide subcutaneous injections once daily (in combination with metformin with or without basal insulin, on a background of diet and exercise) for 52 weeks (26 weeks double blind treatment period followed by a 26-week open-label extension period). Subjects treated with liraglutide for more than 3 months were asked to return for follow-up visits one and two years after the end of the open label period (after trial drug cessation at week 52). | ||
Reporting group title |
Placebo
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Reporting group description |
After the run-in period, subjects were randomized to receive placebo (in combination with metformin with or without basal insulin, on a background of diet and exercise) for a 26 weeks double blind treatment period. After 26 weeks, participants discontinued placebo and continued treatment with metformin (with or without basal insulin) during the open-label period. | ||
Reporting group title |
Liraglutide 1.8 mg: Follow-up 1
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Reporting group description |
Subjects treated with liraglutide for more than 3 months during the treatment period; were followed up until week 104 after trial drug cessation at week 52. | ||
Reporting group title |
Liraglutide 1.8 mg: Follow-up 2
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Reporting group description |
Subjects treated with liraglutide for more than 3 months during the treatment period; were followed up until week 156 after trial drug cessation at week 52. | ||
Subject analysis set title |
Liraglutide 1.8 mg: Follow-up 1 and 2
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received liraglutide for more than 3 months during the treatment period (week 0-52), were followed-up at weeks 104 and 156.
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End point title |
Change in HbA1c - week 26 | ||||||||||||
End point description |
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. Full analysis set (FAS) – included all randomised subjects receiving at least one dose of liraglutide/placebo.
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End point type |
Primary
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End point timeframe |
From baseline to week 26
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Statistical analysis title |
Liraglutide 1.8 mg vs. Placebo | ||||||||||||
Statistical analysis description |
Analysis using a pattern mixture model of observed data with missing observations imputed from the placebo arm based on multiple (x10.000) imputations. The data for week 26 were then analysed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. The estimated treatment differences and confidence intervals were combined using Rubins formula.
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Comparison groups |
Liraglutide 1.8 mg v Placebo
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Pattern Mixture Model | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-1.058
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.653 | ||||||||||||
upper limit |
-0.464 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.304
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Notes [1] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 1: Primary analysis: change from baseline to week 26 in HbA1c Superiority of liraglutide over placebo was to be concluded if the 95% confidence interval for the treatment difference for change from baseline in HbA1c (%) after 26 weeks of randomised treatment was entirely below 0%, implying that the two sided p-value was less than 5%. |
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End point title |
Change from baseline in fasting plasma glucose (FPG) - week 26 | ||||||||||||
End point description |
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. Analysis was based on full analysis set.
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End point type |
Secondary
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End point timeframe |
Week 0, week 26
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Statistical analysis title |
Liraglutide 1.8 mg vs Placebo | ||||||||||||
Statistical analysis description |
Analysis using a pattern mixture model of observed data with missing observations imputed from the placebo arm based on multiple (x10.000) imputations. The data for weeks 26 were then analysed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. The estimated treatment differences and confidence intervals were combined using Rubins formula.
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Comparison groups |
Liraglutide 1.8 mg v Placebo
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
= 0.002 | ||||||||||||
Method |
Pattern Mixture Model | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-1.878
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.093 | ||||||||||||
upper limit |
-0.662 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.62
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Notes [2] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 2: Change from baseline in FPG after 26 weeks of treatment. |
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End point title |
Change in FPG - week 52 | ||||||||||||
End point description |
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. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
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End point type |
Secondary
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End point timeframe |
Week 0, week 52
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No statistical analyses for this end point |
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End point title |
Change from baseline in body mass index (BMI) standard deviation score (SDS) - week 26 | ||||||||||||
End point description |
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. Full analysis set. Number of participants analysed=participants with available data.
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End point type |
Secondary
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End point timeframe |
Week 0, week 26
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Statistical analysis title |
Liraglutide 1.8 mg vs Placebo | ||||||||||||
Statistical analysis description |
Analysis using a pattern mixture model of observed data with missing observations imputed from the placebo arm based on multiple (x10.000) imputations. The data for weeks 26 were then analysed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. The estimated treatment differences and confidence intervals were combined using Rubins formula.
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Comparison groups |
Liraglutide 1.8 mg v Placebo
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.392 | ||||||||||||
Method |
Pattern Mixture Model | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-0.047
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.153 | ||||||||||||
upper limit |
0.06 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.055
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Notes [3] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 4: Change from baseline in BMI SDS after 26 weeks of treatment. |
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End point title |
Change from baseline in BMI standard deviation score (SDS) - week 52 | ||||||||||||
End point description |
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. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
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End point type |
Secondary
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End point timeframe |
Week 0, week 52
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No statistical analyses for this end point |
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End point title |
Number of subjects having HbA1c below 7.0% - week 26 | ||||||||||||
End point description |
Estimated percentage of subjects having HbA1c <7.0% at week 26. All available data were used for the analysis including data collected after treatment discontinuation and initiation of rescue medication. Analysis was based on full analysis set.
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End point type |
Secondary
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End point timeframe |
Week 26
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Statistical analysis title |
Liraglutide 1.8 mg vs Placebo | ||||||||||||
Statistical analysis description |
Missing data was imputed using pattern mixture model. For each imputed data set the binary response was analysed in a logistic regression model using a logit link with treatment and stratification group (gender*age group) as fixed factors and baseline HbA1c as covariate.The estimated treatment effects and confidence intervals were combined using Rubin´s formula.
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Comparison groups |
Liraglutide 1.8 mg v Placebo
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Number of subjects included in analysis |
134
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
Logistic Regression Model | ||||||||||||
Parameter type |
Treatment odds ratio | ||||||||||||
Point estimate |
5.353
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.105 | ||||||||||||
upper limit |
13.615 | ||||||||||||
Notes [4] - Stepwise hierarchical testing procedure was applied for confirmatory endpoints: Step 3: HbA1c < 7.0% after 26 weeks of treatment. |
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End point title |
Number of subjects having HbA1c below 7.0% - week 52 | |||||||||||||||
End point description |
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. Full analysis set. Number of participants analysed=participants with available data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Week 52
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of subjects having HbA1c maximum 6.5% - week 26 | |||||||||||||||
End point description |
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. Full analysis set. Number of participants analysed=participants with available data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Week 26
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of subjects having HbA1c maximum 6.5% - week 52 | |||||||||||||||
End point description |
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. Full analysis set. Number of participants analysed=participants with available data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Week 52
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of subjects having HbA1c below 7.0% without severe or minor hypoglycaemic episodes - week 26 | |||||||||||||||
End point description |
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. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Week 26
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of subjects having HbA1c below 7.0% without severe or minor hypoglycaemic episodes - week 52 | |||||||||||||||
End point description |
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. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Week 52
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change in mean 7-point self-measured plasma glucose - week 26 | ||||||||||||
End point description |
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. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 0, week 26
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in 7-point self-measured plasma glucose - week 52 | ||||||||||||
End point description |
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. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 0, week 52
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in body weight - week 26 | ||||||||||||
End point description |
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. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 0, week 26
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in body weight - week 52 | ||||||||||||
End point description |
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. Analysis was based on full analysis set. Number of participants analysed=participants with available data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 0, week 52
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of adverse events - week 26 | |||||||||
End point description |
Total number of adverse events during 26 weeks. Analysis was based on safety analysis set which included all subjects receiving at least one dose of liraglutide/placebo
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
0-26 weeks
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of adverse events - week 52 | |||||||||
End point description |
Total number of adverse events during entire treatment period (during 52 weeks). Analysis was based on the safety analysis set.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
0-52 weeks
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of adverse events- week 104 | ||||||
End point description |
Total number of adverse events during the follow up 1 period (53 - 104 weeks). Analysis was based on the safety analysis set- Subjects who received liraglutide for more than 3 months during the treatment period (week 0-52) and provided safety follow-up data anytime during week 53-104.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
1 year after last patient last visit (LPLV)
|
||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of adverse events- week 156 | ||||||
End point description |
Total number of adverse events during the follow up period (53 - 156 weeks). Analysis was based on the safety analysis set- Subjects who received liraglutide for more than 3 months during the treatment period (week 0-52) and provided safety follow-up data anytime during week 53-156.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
after 2 years after LPLV
|
||||||
|
|||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of serious adverse events - week 26 | |||||||||
End point description |
Total number of serious adverse events during 26 weeks. Analysis was based on the safety analysis set.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
0-26 weeks
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of serious adverse events - week 52 | |||||||||
End point description |
0-52 weeks
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Total number of serious adverse events during entire treatment period (during 52 weeks). Analysis was based on the safety analysis set.
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Nuber of serious adverse events- week 104 | ||||||
End point description |
Total number of serious adverse events during the follow up 1 period (53 - 104 weeks). Analysis was based on the safety analysis set- Subjects who received liraglutide for more than 3 months during the treatment period week 0-52 and provided safety follow-up data anytime during week 53-104.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
1 year after LPLV
|
||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of serious adverse events- week 156 | ||||||
End point description |
Total number of serious adverse events during the follow up period (53 - 156 weeks). Analysis was based on the safety analysis set- Subjects who received liraglutide for more than 3 months during the treatment period week 0-52 and provided safety follow-up data anytime during week 53-156.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
2 years after LPLV
|
||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Growth velocity- week 104 | ||||||||
End point description |
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 week 0 divided by the time (in days) between those measurement time points and multiplied by 365 days. Analysis was based on the safety analysis set- Subjects who received liraglutide for more than 3 months during the treatment period week 0-52 and provided safety follow-up data anytime during week 53-104.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
1 year after LPLV
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Growth velocity- week 156 | ||||||||
End point description |
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 week 0 divided by the time (in days) between those measurement time points and multiplied by 365 days. Analysis was based on the safety analysis set- Subjects who received liraglutide for more than 3 months during the treatment period week 0-52 and provided safety follow-up data anytime during week 53-156.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
2 years after LPLV
|
||||||||
|
|||||||||
Notes [5] - Number of subjects with available data at week 156. |
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Pubertal progression- week 104 | ||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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 participants at different Tanner stages at week 104. Analysis was based on the safety analysis set- Subjects who received liraglutide for more than 3 months during the treatment period week 0-52 and provided safety follow-up data anytime during week 53-104.
|
||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
1 year after LPLV
|
||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Pubertal progression- week 156 | ||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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 participants at different Tanner stages at week 156. Analysis was based on the safety analysis set- Subjects who received liraglutide for more than 3 months during the treatment period week 0-52 and provided safety follow-up data anytime during week 53-156.
|
||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
2 years after LPLV
|
||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||
Notes [6] - Number of subjects with available data at week 156. |
|||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Week 0 - 156
All presented AEs are TEAEs. A TEAE was defined as an event that had onset date on or after the first day of exposure to trial product and no later than 7 days after the last day of trial product administration.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Results are based on SAS: subjects who received at least one dose of liraglutide or placebo for "Liraglutide 1.8 mg- Treatment period" and "Placebo" and who received liraglutide for more than 3 months and provided follow-up data anytime during weeks 53-156.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Liraglutide 1.8 mg
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
After the run-in period, subjects were randomized to receive liraglutide subcutaneous injections once daily (in combination with metformin with or without basal insulin, on a background of diet and exercise) for 52 weeks (26 weeks double blind treatment period followed by a 26-week open-label extension period). Subjects treated with liraglutide for more than 3 months were asked to return for follow-up visits one and two years after the end of the open label period (after trial drug cessation at week 52). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
After the run-in period, subjects were randomized to receive placebo (in combination with metformin with or without basal insulin, on a background of diet and exercise) for a 26 weeks double blind treatment period. After 26 weeks, participants discontinued placebo and continued treatment with metformin (with or without basal insulin) during the open-label period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Liraglutide 1.8 mg: Follow-up 1
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Reporting group description |
Subjects treated with liraglutide for more than 3 months during the treatment period; were followed up until week 104 after trial drug cessation at week 52. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Liraglutide 1.8 mg: Follow-up 2
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Reporting group description |
Subjects treated with liraglutide for more than 3 months during the treatment period; were followed up until week 156 after trial drug cessation at week 52. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Aug 2012 |
Protocol changes were primarily driven by the EMA PDCO’s acceptance of the request for PIP modification. Some of the changes to the trial design were requested by the FDA. Other
minor changes concerned inconsistencies and typos. The key changes involved:
- extension of metformin titration period and lowering the lower limit for metformin MTD.
- allowing subjects entering the trial on >2000 mg/day of metformin to continue on current dose.
- extension of metformin maintenance period during the run-in from 3 to 8 weeks.
- extension of liraglutide dose escalation period from 2 to 3 weeks
- changing the timing of the anti-liraglutide antibody measurement from week 52 to week 53
- extension of the double-blind treatment period from 14 to 26 weeks
- allowing liraglutide dose escalation (to maximum 1.8 mg) as a rescue option
- for subjects treated with placebo, allowing the addition of a second anti-diabetic agent as a rescue option
- inclusion of testicular volume assessment by trained personnel in the Tanner staging assessment
- requirement for the 52-week treatment period completion prior to subject reaching 17 years and 11 months
- requirement of 30% of subjects to be aged between 10-14 years
- exclusion from the trial of subjects previously treated with liraglutide (new exclusion criterion added)
- use of another primary analysis method that does not rely on LOCF for the handling of missing data. A multiple imputation approach was to be used to handle missing data in the new primary analysis. |
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19 Nov 2012 |
Protocol changes were primarily driven by the FDA Paediatric Committee’s request to include yearly bone age assessment due to a potential nonclinical safety signal for liraglutide of advancement of puberty. In addition, the text regarding the use of rescue medication was clarified. Other minor corrections and clarifications were implemented. The key changes involved:
- inclusion of X-ray of left hand and wrist at randomisation and week 52 (all subjects) and at 1- and 2-year follow-up visits for subjects treated with liraglutide for >3 months
- update of withdrawal criterion and rewording of the section on rescue medication |
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22 Jun 2013 |
An additional blood sample was included to ensure that FPG, biochemistry parameters an calcitonin were monitored during the open-label period. In addition, a number of protocol clarifications were implemented. The key changes included:
1. addition of a fasting blood sample at visit 22 (week 42)
2. clarification of age definition of ≤14 years
3. new reporting timelines for MESI |
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19 Mar 2015 |
Significant delays in subject recruitment led to this protocol amendment implemented in order to facilitate recruitment. The key changes included:
1. reducing the required duration of diabetes at screening from 90 to 30 days
2. inclusion of children and adolescents currently treated with basal insulin
3. change in method to evaluate randomisation criterion #1 (FPG measured prior to the randomisation visit (visit 7), must be ≥126 mg/dL (7.0 mmol/L) and ≤220 mg/dL (12.2 mmol/L). The measurement must be based on an average of fasting SMPG values taken on the 3 consecutive days leading up to the randomisation visit (visit 7))
4. use of basal insulin as initial rescue therapy in both liraglutide and placebo treatment arms
5. elimination of the requirement for randomised treatment unblinding prior to rescue treatment initiation, since subjects
in both treatment arms were to receive the same initial rescue treatment (basal insulin)
6. changes to trial completion timeline
7. reduction of sample size from 172 to 150 randomised subjects |
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18 Apr 2017 |
Due to recruitment difficulties, the planned sample size was reduced from 150 to 94 randomised subjects. The primary analysis was changed to a PMM analysis using a multiple imputations approach to account for missing data. Additional revisions and clarifications were also made to the “Statistical Considerations” section of the protocol. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/31034184 http://www.ncbi.nlm.nih.gov/pubmed/33634589 |