Clinical Trial Results:
Effect of liraglutide for weight management in pubertal adolescent subjects with obesity. 56-week, double-blind, randomised, parallel-group, placebo-controlled multi-national trial followed by a 26-week period off study-drug
Summary
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EudraCT number |
2014-004353-14 |
Trial protocol |
SE BE |
Global end of trial date |
08 Aug 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Feb 2020
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First version publication date |
21 Feb 2020
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Other versions |
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 |
NN8022-4180
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02918279 | ||
WHO universal trial number (UTN) |
U1111-1162-7101 | ||
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-PIP02-09 | ||
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 |
23 Dec 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Feb 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Aug 2019
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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 compare the efficacy of liraglutide versus placebo on weight loss in adolescent subjects with obesity after 56 weeks of treatment
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (Last amended by the 64th World Medical Association General Assembly, Fortaleza, Brazil. October 2013) and ICH Good Clinical Practice, including archiving of essential documents (E6(R1), Step 4. 10 June 1996) and 21 CFR 312.120.
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Background therapy |
Not applicable. | ||
Evidence for comparator |
Not applicable. | ||
Actual start date of recruitment |
29 Sep 2016
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Long term follow-up planned |
No
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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 |
Belgium: 33
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Country: Number of subjects enrolled |
Mexico: 46
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Country: Number of subjects enrolled |
Russian Federation: 68
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Country: Number of subjects enrolled |
Sweden: 44
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Country: Number of subjects enrolled |
United States: 60
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Worldwide total number of subjects |
251
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EEA total number of subjects |
77
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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) |
0
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Adolescents (12-17 years) |
251
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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 |
This trial was conducted at 32 sites in 5 countries: Belgium (6 sites), Sweden (4 sites), Russia (8 sites), Mexico (2 sites) and the United States of America (USA - 12 sites). Additionally, 1 site in the USA was approved by the independent review board, but did not randomise any subject. | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
This trial consisted of a 12-week run-in period, during which participants received counselling on healthy nutrition and physical activity. Completed numbers include participants who completed the trial without prematurely discontinuing the trial product and participants who discontinued the trial product but came for the week 82 follow-up visit. | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Subject | ||||||||||||||||||||||||||||||
Blinding implementation details |
Liraglutide and placebo injections were visually identical.
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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 3.0 mg | ||||||||||||||||||||||||||||||
Arm description |
Subjects received liraglutide in a dose escalation manner for 56 weeks: 0.6 mg during week 1, 1.2 mg during week 2, 1.8 mg during week 3, 2.4 mg during week 4 and 3.0 mg from week 5 to week 56. There was a 26-week off-study-drug follow-up period (week 57–82). | ||||||||||||||||||||||||||||||
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 was administered once daily by subcutaneous (s.c.; under the skin) injection in the abdomen, thigh or upper arm irrespective of the timing of meals.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Subjects received liraglutide matching placebo for 56 weeks. There was a 26-week off-study-drug follow-up period (week 57–82). | ||||||||||||||||||||||||||||||
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 |
Placebo for liraglutide was administered once daily by s.c. injection in the abdomen, thigh or upper arm irrespective of the timing of meals.
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Baseline characteristics reporting groups
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Reporting group title |
Liraglutide 3.0 mg
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Reporting group description |
Subjects received liraglutide in a dose escalation manner for 56 weeks: 0.6 mg during week 1, 1.2 mg during week 2, 1.8 mg during week 3, 2.4 mg during week 4 and 3.0 mg from week 5 to week 56. There was a 26-week off-study-drug follow-up period (week 57–82). | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received liraglutide matching placebo for 56 weeks. There was a 26-week off-study-drug follow-up period (week 57–82). | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Liraglutide 3.0 mg
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Reporting group description |
Subjects received liraglutide in a dose escalation manner for 56 weeks: 0.6 mg during week 1, 1.2 mg during week 2, 1.8 mg during week 3, 2.4 mg during week 4 and 3.0 mg from week 5 to week 56. There was a 26-week off-study-drug follow-up period (week 57–82). | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received liraglutide matching placebo for 56 weeks. There was a 26-week off-study-drug follow-up period (week 57–82). |
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End point title |
Change in body mass index (BMI) standard deviation score (SDS) | ||||||||||||
End point description |
Change from baseline (Wk 0) in BMI SDS was evaluated at Wk 56. 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 SDS Z 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. Results are based on the FAS and included both the participants who completed treatment for 56 weeks and participants who could not complete treatment for 56 weeks, but attended the follow-up visit at week 56.
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End point type |
Primary
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End point timeframe |
From baseline (randomisation) to 56 weeks
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Statistical analysis title |
Liraglutide 3.0 mg – Placebo | ||||||||||||
Statistical analysis description |
Analysis of in-trial data with missing observations was imputed from the placebo arm based on a jump to reference multiple (x100) imputation approach. Responses at week 56 were analysed using an analysis of covariance model with treatment, sex, region, baseline glycaemic category, stratification factor for Tanner stage and interaction between baseline glycaemic category and stratification factor for Tanner stage as fixed effects, baseline BMI SDS, age as covariates.
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Comparison groups |
Placebo v Liraglutide 3.0 mg
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Number of subjects included in analysis |
218
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.0022 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-0.22
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.37 | ||||||||||||
upper limit |
-0.08 | ||||||||||||
Notes [1] - The “number of subjects included in analysis” is being erroneously displayed as 218. Actual “number of subjects included in analysis” is 251. |
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End point title |
Percent of subjects achieving ≥5% reduction in baseline BMI | ||||||||||||||||||
End point description |
Participants achieving more than or equal to 5% reduction in their baseline (week 0) body mass index (BMI) was evaluated at weeks 56. Results are based on the FAS and included both participants who completed the 56-week trial period and participants who could not complete the 56-week trial period, but attended the follow-up visit at week 56. The FAS included all randomised participants who had received at least one dose of trial product and had any post-randomisation data (according to the intention-to-treat [ITT] principle).
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End point type |
Secondary
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End point timeframe |
At week 56
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No statistical analyses for this end point |
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End point title |
Percent of subjects achieving ≥10% reduction in baseline BMI | ||||||||||||||||||
End point description |
Participants achieving more than or equal to 10% reduction in their baseline (week 0) BMI was evaluated at weeks 56. Results are based on the FAS and included both participants who completed the 56-week trial period and participants who could not complete the 56-week trial period, but attended the follow-up visit at week 56. The FAS included all randomised participants who had received at least one dose of trial product and had any post-randomisation data (according to the ITT principle).
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End point type |
Secondary
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End point timeframe |
At week 56
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No statistical analyses for this end point |
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End point title |
Change in BMI from baseline to 56 weeks | ||||||||||||
End point description |
Change in BMI was evaluated from baseline (week 0) to weeks 56. Results are based on the FAS and included both participants who completed the 56-week trial period and participants who could not complete the 56-week trial period, but attended the follow-up visit at week 56. The FAS included all randomised participants who had received at least one dose of trial product and had any post-randomisation data (according to the ITT principle).
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End point type |
Secondary
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End point timeframe |
From baseline to 56 weeks
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No statistical analyses for this end point |
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End point title |
Change in body weight (kilogram [kg]) from baseline to 56 weeks | ||||||||||||
End point description |
Change in body weight (kg) was evaluated from baseline (week 0) to weeks 56. Results are based on the FAS and included both participants who completed the 56-week trial period and participants who could not complete the 56-week trial period, but attended the follow-up visit at week 56. The FAS included all randomised participants who had received at least one dose of trial product and had any post-randomisation data (according to the ITT principle).
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End point type |
Secondary
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End point timeframe |
From baseline to 56 weeks
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No statistical analyses for this end point |
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End point title |
Change in body weight (pounds [lb]) from baseline to 56 weeks | ||||||||||||
End point description |
Body weight was not analysed in pounds (lb). It was analysed for standard unit, ‘kg’ only.
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End point type |
Secondary
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End point timeframe |
From baseline to 56 weeks
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Notes [2] - Body weight was not analysed in pounds (lb). It was analysed for standard unit, ‘kg’ only. [3] - Body weight was not analysed in pounds (lb). It was analysed for standard unit, ‘kg’ only. |
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No statistical analyses for this end point |
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End point title |
Change in body weight (percent [%]) from baseline to 56 weeks | ||||||||||||
End point description |
Relative change in body weight (kg) was evaluated from baseline (week 0) to weeks 56. Results are based on the FAS and included both participants who completed the 56-week trial period and participants who could not complete the 56-week trial period, but attended the follow-up visit at week 56. The FAS included all randomised participants who had received at least one dose of trial product and had any post-randomisation data (according to the ITT principle).
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End point type |
Secondary
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End point timeframe |
From baseline to 56 weeks
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No statistical analyses for this end point |
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End point title |
Change in systolic and diastolic blood pressure | ||||||||||||||||||
End point description |
Change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was evaluated from baseline (week 0) to weeks 56. Results are based on the FAS and included participants who completed the 56-week trial period. The FAS included all randomised participants who had received at least one dose of trial product and had any post-randomisation data (according to the ITT principle).
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End point type |
Secondary
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End point timeframe |
From baseline to 56 weeks
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No statistical analyses for this end point |
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End point title |
Change in glycosylated haemoglobin (HbA1c) | ||||||||||||
End point description |
Change in HbA1c was evaluated from baseline (week 0) to weeks 56. Results are based on the FAS and included participants who completed the 56-week trial period. The FAS included all randomised participants who had received at least one dose of trial product and had any post-randomisation data (according to the ITT principle).
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End point type |
Secondary
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End point timeframe |
From baseline to 56 weeks
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No statistical analyses for this end point |
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End point title |
Change in fasting plasma glucose | ||||||||||||
End point description |
Change in fasting plasma glucose (FPG) was evaluated from baseline (week 0) to weeks 56. Results are based on the FAS and included participants who completed the 56-week trial period. The FAS included all randomised participants who had received at least one dose of trial product and had any post-randomisation data (according to the ITT principle).
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End point type |
Secondary
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End point timeframe |
From baseline to 56 weeks
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No statistical analyses for this end point |
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End point title |
Number of treatment emergent adverse events | |||||||||
End point description |
A treatment emergent adverse event (TEAE) was defined as an event that occurred in the “on-treatment” period. ‘On-treatment’ period: Events with onset date between the first day of trial product administration and any of the following date, whichever came first: 1) 14 days after the last day on trial product, or 2) follow-up visit (week 58) for participants who discontinued trial product, or 3) last study visit (participants withdrawn without follow-up visit). Results are based on the SAS which included all randomised participants exposed to at least one dose of trial product.
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End point type |
Secondary
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End point timeframe |
Week 0–56 + 14 days
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Week 0–56 + 14 days.
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Adverse event reporting additional description |
Results are based on the SAS which included all randomised participants exposed to at least one dose of trial product. All presented adverse events are TEAEs.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22
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Reporting groups
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Reporting group title |
Liraglutide 3.0 mg
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Reporting group description |
Subjects received liraglutide in a dose escalation manner for 56 weeks: 0.6 mg during week 1, 1.2 mg during week 2, 1.8 mg during week 3, 2.4 mg during week 4 and 3.0 mg from week 5 to week 56. There was a 26-week off-study-drug follow-up period (week 57–82). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received liraglutide matching placebo for 56 weeks. There was a 26-week off-study-drug follow-up period (week 57–82). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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 |