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Clinical Trial Results:
Effect of liraglutide for weight management in paediatric subjects with Prader-Willi Syndrome. A randomised, placebo controlled, parallel group, multi-centre, multi-national trial with a 16-week double-blind period and 36-week open-label period

Summary
EudraCT number	2014-004415-37
Trial protocol	IT FR NL
Global end of trial date	19 Nov 2020

Results information
Results version number	v1(current)
This version publication date	02 Jun 2021
First version publication date	02 Jun 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

NN8022-4179

ISRCTN number

US NCT number

NCT02527200

WHO universal trial number (UTN)

U1111-1162-7884

Sponsor organisation name

Novo Nordisk A/S

Sponsor organisation address

Novo Allé, Bagsvaerd, Denmark, 2880

Public contact

Clinical Transparency and Medical Writing Office (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Scientific contact

Clinical Transparency and Medical Writing Office (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000128-PIP02-09

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

25 Mar 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

04 Nov 2020

Global end of trial reached?

Yes

Global end of trial date

19 Nov 2020

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of liraglutide versus placebo on weight loss in paediatric subjects with obesity and PWS at 16 weeks and versus no treatment at 52 weeks.

Protection of trial subjects

The trial was conducted in accordance with the Declaration of Helsinki (64th World Medical Association (WMA) general assembly; October 2013), International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents, 21 US Code of Federal Regulations (CFR) 312.120 and US Food and Drug Administration (FDA) 21 CFR 314.126.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Nov 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

France: 12

Country: Number of subjects enrolled

Italy: 4

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

New Zealand: 5

Country: Number of subjects enrolled

Turkey: 12

Country: Number of subjects enrolled

United States: 13

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The trial was conducted at 20 sites in 8 countries as follows: Australia (2), Canada (1), France (7), Italy (2), Netherlands (1), New Zealand (1), Turkey (3), United States (3).

Screening details

This trial has part A & part B. Part A was conducted in adolescents (≥12-<18 years, Tanner stage 2−5) with Prader-Willi Syndrome (PWS) and obesity. Part B was conducted in children [≥6-˂12 years, Tanner stage below 2 (defined as Tanner stage 1 with or without premature adrenarche)] with PWS and obesity. Entry into part A and part B was sequential.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

The trial was ‘double-blind’ for the first 16 weeks followed by an ‘open-label’ period of 36 weeks.

Are arms mutually exclusive

Yes

Part A+B: Liraglutide 3.0 mg

Arm description

Subjects received once daily subcutaneous (under the skin) injection of liraglutide for 52 weeks (open label for 16 weeks and double-blinded for 36 weeks ) in a dose escalating manner. For both part A and part B (for children with body weight ≥45 kg): dosing was initiated with liraglutide 0.6 mg daily for one week and increased in weekly dosage steps of 0.6 mg until a maximum tolerated dose (MTD) (as judged by the Investigator) or a dose of 3.0 mg liraglutide was reached, i.e., 0.6 mg (week 1), 1.2 mg (week 2), 1.8 mg (week 3), 2.4 mg (week 4) and 3.0 mg (week 5 to week 52). For Part B children with body weight <45 kg: dosing was initiated with liraglutide 0.3 mg daily for one week and increased to 0.6 mg after the first week. Thereafter, the dose was increased in weekly steps of 0.6 mg until an MTD (as judged by the Investigator) or a dose of 2.4 mg liraglutide was reached. i.e., 0.3 mg (week 1), 0.6 mg (week 2), 1.2 mg (week 3), 1.8 mg (week 4), 2.4 mg (week 5 to week 52).

Arm type

Experimental

Investigational medicinal product name

Liraglutide

Investigational medicinal product code

Other name

Saxenda

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received once daily subcutaneous injection of liraglutide (0.3 mg, 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3.0 mg) for 52 weeks either in the abdomen, thigh, or upper arm.

Part A+B: Placebo

Arm description

Subjects received once daily subcutaneous injection of liraglutide matching placebo for 16 weeks (open label).

Arm type

Placebo

Investigational medicinal product name

Liraglutide placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received once daily subcutaneous injection of liraglutide matching placebo (0.3 mg, 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3.0 mg) for 16 weeks either in the abdomen, thigh, or upper arm.

Number of subjects in period 1	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo
Started	37	19
Safety analysis set	37	19
Full analysis set	36	19
Completed	32	16
Not completed	5	3
Unclassified	-	1
Lost to follow-up	1	-
Withdrawal by parent/guardian	4	2

Baseline characteristics

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Reporting group title

Part A+B: Liraglutide 3.0 mg

Reporting group description

Reporting group title

Part A+B: Placebo

Reporting group description

Subjects received once daily subcutaneous injection of liraglutide matching placebo for 16 weeks (open label).

Reporting group values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Total
Number of subjects	37	19	56
Age Categorical
Units: Subjects
Children (2-11 years)	17	7	24
Adolescents (12-17 years)	20	12	32
Gender Categorical
Units: Subjects
Female	22	7	29
Male	15	12	27

End points

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Reporting group title

Part A+B: Liraglutide 3.0 mg

Reporting group description

Reporting group title

Part A+B: Placebo

Reporting group description

Subjects received once daily subcutaneous injection of liraglutide matching placebo for 16 weeks (open label).

Subject analysis set title

Part A: Liraglutide

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received once daily subcutaneous injection of liraglutide for 52 weeks. Dosing was initiated with liraglutide 0.6 mg daily for one week and increased in weekly dosage steps of 0.6 mg until a MTD (as judged by the Investigator) or a dose of 3.0 mg liraglutide was reached, i.e., 0.6 mg (week 1), 1.2 mg (week 2), 1.8 mg (week 3), 2.4 mg (week 4) and 3.0 mg (week 5 to week 52).

Subject analysis set title

Part A: Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received once daily subcutaneous injection of liraglutide matching placebo for 16 weeks.

Subject analysis set title

Part B: Liraglutide

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received once daily subcutaneous injection of liraglutide for 52 weeks. For children with body weight ≥ 45 kg; dosing was initiated with liraglutide 0.6 mg daily for one week and increased in weekly dosage steps of 0.6 mg until a MTD (as judged by the Investigator) or a dose of 3.0 mg liraglutide was reached, i.e., 0.6 mg (week 1), 1.2 mg (week 2), 1.8 mg (week 3), 2.4 mg (week 4) and 3.0 mg (week 5 to week 52). For children with body weight <45 kg: dosing was initiated with liraglutide 0.3 mg daily for one week and increased to 0.6 mg after the first week. Thereafter, the dose was increased in weekly steps of 0.6 mg until an MTD (as judged by the Investigator) or a dose of 2.4 mg liraglutide was reached. i.e., 0.3 mg (week 1), 0.6 mg (week 2), 1.2 mg (week 3), 1.8 mg (week 4), 2.4 mg (week 5 to week 52).

Subject analysis set title

Part B: Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received once daily subcutaneous injection of liraglutide matching placebo for 16 weeks.

Primary: Change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 weeks

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End point title

Change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 weeks

End point description

Change in BMI SDS from baseline to week 16 is presented. BMI SDS also called Z-scores, was calculated using the following formula: Z=[(y / M)^L - 1] / S*L; where L, M and S are median (M), Box-cox power (L) and variation coefficient (S) of children/adolescents', y= individual BMI. 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. Possible values range from -3 to +3, a negative score being beneficial. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis.

End point type

Primary

End point timeframe

From baseline (week 0) to 16 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	34	19	18	12	16	7
Units: SDS score
arithmetic mean (standard deviation)	-0.33 ( 0.49 )	-0.29 ( 0.32 )	-0.18 ( 0.21 )	-0.18 ( 0.23 )	-0.50 ( 0.65 )	-0.48 ( 0.39 )

Part A: Liraglutide 0.3 mg - Placebo

Statistical analysis description

Analysis of in-trial data with missing observations imputed from the placebo arm based on a jump to reference multiple (x1000) imputation approach. Responses at week 16 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.

Comparison groups

Part A: Liraglutide v Part A: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3787

Method

ANCOVA

Parameter type

Treatment difference

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.23

upper limit

0.09

Part B: Liraglutide 0.3 mg - Placebo

Statistical analysis description

Comparison groups

Part B: Liraglutide v Part B: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.9008

Method

ANCOVA

Parameter type

Treatment difference

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-1.06

upper limit

0.93

Notes
[1] - The “number of subjects included in analysis” is being erroneously displayed as 23. It should be read as 'Number of observed subjects with an assessment' = 22.

Part A+B: Liraglutide 0.3 mg - Placebo

Statistical analysis description

Comparison groups

Part A+B: Liraglutide 3.0 mg v Part A+B: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.595

Method

ANCOVA

Parameter type

Treatment difference

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

0.15

Notes
[2] - The “number of subjects included in analysis” is being erroneously displayed as 53. It should be read as 'Number of observed subjects with an assessment' = 52.

Primary: Change in body mass index (BMI) standard deviation score (SDS) from baseline to 52 weeks

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End point title

Change in body mass index (BMI) standard deviation score (SDS) from baseline to 52 weeks

End point description

Change in BMI SDS from baseline to week 52 is presented. BMI SDS also called Z-scores, was calculated using the following formula: Z=[(y / M)^L - 1] / S*L; where L, M and S are median (M), Box-cox power (L) and variation coefficient (S) of children/adolescents', y= individual BMI. 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. Possible values range from -3 to +3, a negative score being beneficial. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis.

End point type

Primary

End point timeframe

From baseline (week 0) to 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	17	11	17	11	14	7
Units: SDS score
arithmetic mean (standard deviation)	-0.27 ( 0.37 )	-0.13 ( 0.25 )	-0.27 ( 0.37 )	-0.13 ( 0.25 )	-0.79 ( 1.21 )	-0.71 ( 0.68 )

Part A: Liraglutide 0.3 mg - Placebo

Statistical analysis description

Analysis of in-trial data with missing observations imputed from the placebo arm based on a jump to reference multiple (x1000) imputation approach. Responses at week 52 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.

Comparison groups

Part A: Liraglutide v Part A: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5665

Method

ANCOVA

Parameter type

Treatment difference

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

0.34

Part B: Liraglutide 0.3 mg - Placebo

Statistical analysis description

Comparison groups

Part B: Liraglutide v Part B: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8761

Method

ANCOVA

Parameter type

Treatment difference

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

0.76

Part A+B: Liraglutide 0.3 mg - Placebo

Statistical analysis description

Comparison groups

Part A+B: Liraglutide 3.0 mg v Part A+B: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.5189

Method

ANCOVA

Parameter type

Treatment difference

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.26

Notes
[3] - The “number of subjects included in analysis” is being erroneously displayed as 28. It should be read as 'Number of observed subjects with an assessment' = 49.

Secondary: Percent of subjects achieving ≥ 5% reduction in baseline BMI

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End point title

Percent of subjects achieving ≥ 5% reduction in baseline BMI

End point description

Percentage of subjects achieving more than or equal to (≥) 5% reduction in their baseline (week 0) BMI at weeks 16 and 52 is presented. In below table, ‘Yes’ infers percentage of subjects who achieved ≥ 5% reduction in their baseline (week 0) BMI at weeks 16 and 52 and ‘No’ infers percentage of subjects who did not achieve ≥ 5% reduction in their baseline (week 0) BMI at weeks 16 and 52. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 34, 19, 18, 12, 16, 7 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 31, 18, 17, 11, 14, 7 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

At weeks 16 and 52

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	34	19	18	12	16	7
Units: Percentage of subjects
number (not applicable)
At Week 16: Yes	32.4	26.3	27.8	8.3	37.5	57.1
At Week 16: No	67.6	73.7	72.2	91.7	62.5	42.9
At Week 52: Yes	32.3	27.8	29.4	18.2	35.7	42.9
At Week 52: No	67.7	72.2	70.6	81.8	64.3	57.1

No statistical analyses for this end point

Secondary: Percent of subjects achieving ≥ 10% reduction in baseline BMI

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End point title

Percent of subjects achieving ≥ 10% reduction in baseline BMI

End point description

Percentage of subjects achieving ≥ 10% reduction in their baseline (week 0) BMI at weeks 16 and 52 is presented. In below table, ‘Yes’ infers percentage of subjects who achieved ≥ 10% reduction in their baseline (week 0) BMI at weeks 16 and 52 and ‘No’ infers percentage of subjects who did not achieve ≥ 10% reduction in their baseline (week 0) BMI at weeks 16 and 52. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 34, 19, 18, 12, 16, 7 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 31, 18, 17, 11, 14, 7 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

At weeks 16 and 52

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	34	19	18	12	16	7
Units: Percent of subjects
number (not applicable)
At Week 16: Yes	2.9	5.3	0	0	6.3	14.3
At Week 16: No	97.1	94.7	100	100	93.8	85.7
At Week 52: Yes	12.9	11.1	11.8	0	14.3	28.6
At Week 52: No	87.1	88.9	88.2	100	85.7	71.4

No statistical analyses for this end point

Secondary: Change in BMI

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End point title

Change in BMI

End point description

Change in body mass index (BMI) from baseline to week 16 and week 52 is presented. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 34, 19, 18, 12, 16, 7 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 31, 18, 17, 11, 14, 7 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

From baseline (week 0) to 16 and 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	34	19	18	12	16	7
Units: kilogram per metre square (kg/m^2)
arithmetic mean (standard deviation)
Week 16	-1.0 ( 1.4 )	-1.1 ( 1.6 )	-0.9 ( 1.4 )	-0.8 ( 1.6 )	-1.1 ( 1.5 )	-1.5 ( 1.7 )
Week 52	-0.7 ( 2.7 )	-0.4 ( 2.3 )	-0.8 ( 2.2 )	-0.1 ( 2.1 )	-0.6 ( 3.3 )	-0.7 ( 2.7 )

No statistical analyses for this end point

Secondary: Change in Body weight (kilogram (kg)

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End point title

Change in Body weight (kilogram (kg)

End point description

Change in body weight (kg) from baseline to week 16 and week 52 is presented. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 34, 19, 18, 12, 16, 7 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 31, 18, 17, 11, 14, 7 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

From baseline (week 0) to 16 and 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	34	19	18	12	16	7
Units: kilograms (kg)
arithmetic mean (standard deviation)
Week 16	-1.2 ( 3.0 )	-1.0 ( 4.2 )	-1.7 ( 3.6 )	-1.1 ( 5.0 )	-0.6 ( 2.2 )	-1.0 ( 2.7 )
Week 52	1.1 ( 6.5 )	2.3 ( 5.6 )	-0.4 ( 6.3 )	1.9 ( 6.0 )	3.0 ( 6.6 )	2.8 ( 5.2 )

No statistical analyses for this end point

Secondary: Change in Body weight (pounds (lb))

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End point title

Change in Body weight (pounds (lb))

End point description

Change in body weight (lb) from baseline to week 16 and week 52 is presented. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 34, 19, 18, 12, 16, 7 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 31, 18, 17, 11, 14, 7 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

From baseline (week 0) to 16 and 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	34	19	18	12	16	7
Units: pounds (lb)
arithmetic mean (standard deviation)
Week 16	-2.6 ( 6.6 )	-2.3 ( 9.2 )	-3.7 ( 7.8 )	-2.4 ( 11.0 )	-1.4 ( 4.8 )	-2.1 ( 5.9 )
Week 52	2.5 ( 14.4 )	5.0 ( 12.3 )	-0.9 ( 13.9 )	4.3 ( 13.2 )	6.7 ( 14.4 )	6.2 ( 11.5 )

No statistical analyses for this end point

Secondary: Change in Body weight (percentage (%))

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End point title

Change in Body weight (percentage (%))

End point description

Change in body weight (percentage (%)) from baseline to week 16 and week 52 is presented. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 34, 19, 18, 12, 16, 7 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 31, 18, 17, 11, 14, 7 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

From baseline (week 0) to 16 and 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	34	19	18	12	16	7
Units: percentage of body weight
arithmetic mean (standard deviation)
Week 16	-1.4 ( 3.9 )	-1.2 ( 4.3 )	-1.7 ( 3.8 )	-0.7 ( 3.7 )	-1.1 ( 4.1 )	-2.2 ( 5.5 )
Week 52	2.6 ( 9.9 )	3.3 ( 6.9 )	-0.4 ( 6.5 )	2.3 ( 5.7 )	6.3 ( 12.1 )	4.9 ( 8.6 )

No statistical analyses for this end point

Secondary: Change in hyperphagia score: total score and hyperphagic behaviour, drive and severity score

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End point title

Change in hyperphagia score: total score and hyperphagic behaviour, drive and severity score

End point description

Change in hyperphagia score (hyperphagia total score and hyperphagic behaviour, drive and severity score respectively), from baseline to week 16 and week 52 is presented. Hyperphagia, is assessed using the hyperphagia questionnaire. It contains 13 questions. Out of 13 questions 11 questions are categorised into 3 domains (behaviour, drive and severity) scores. 2 questions are considered as additional questions. The total score is the sum of all the 3 domain scores. Total score ranges from 0 to 36, with higher score indicating a worse outcome. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis.

End point type

Secondary

End point timeframe

From baseline (week 0) to 16 and 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	36	19	19	12	17	7
Units: score on a scale
arithmetic mean (standard deviation)
Week 16:Hyperphagia behaviour score	-1.0 ( 2.97 )	-2.0 ( 3.48 )	-0.8 ( 2.01 )	-1.7 ( 4.14 )	-1.2 ( 3.83 )	-2.6 ( 2.07 )
Week 16:Hyperphagia drive score	-1.3 ( 2.87 )	-1.3 ( 2.69 )	-0.9 ( 2.80 )	-0.9 ( 2.61 )	-1.8 ( 2.97 )	-2.0 ( 2.89 )
Week 16:Hyperphagia severity score	-0.4 ( 1.59 )	-0.2 ( 2.12 )	-0.6 ( 1.54 )	-0.3 ( 2.46 )	-0.1 ( 1.65 )	0.1 ( 1.46 )
Week 16:Hyperphagia total score	-2.7 ( 6.34 )	-3.5 ( 5.63 )	-2.4 ( 5.55 )	-2.9 ( 5.79 )	-3.1 ( 7.28 )	-4.4 ( 5.65 )
Week 52:Hyperphagia behaviour score	-0.8 ( 3.82 )	-1.3 ( 3.00 )	-0.9 ( 3.20 )	-0.6 ( 2.62 )	-0.7 ( 4.63 )	-2.6 ( 3.65 )
Week 52:Hyperphagia drive score	-1.7 ( 3.41 )	-0.8 ( 3.06 )	-2.2 ( 2.90 )	-0.5 ( 2.42 )	-1.1 ( 3.99 )	-1.4 ( 4.45 )
Week 52:Hyperphagia severity score	-0.9 ( 2.27 )	-1.1 ( 2.26 )	-1.3 ( 1.81 )	-0.9 ( 2.51 )	-0.4 ( 2.73 )	-1.4 ( 1.82 )
Week 52:Hyperphagia total score	-3.4 ( 8.23 )	-3.1 ( 6.77 )	-4.4 ( 6.57 )	-2.1 ( 6.11 )	-2.1 ( 10.11 )	-5.4 ( 8.32 )

No statistical analyses for this end point

Secondary: Change in systolic and diastolic blood pressure

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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) from baseline to week 16 and week 52 is presented. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 33, 19, 18, 12, 15, 7 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 30, 16, 17, 11, 13, 5 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

From baseline (week 0) to 16 and 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	33	19	18	12	15	7
Units: millimeters of mercury (mmHg)
arithmetic mean (standard deviation)
Week 16: SBP	-1 ( 13 )	-1 ( 11 )	-5 ( 15 )	-2 ( 13 )	2 ( 9 )	2 ( 6 )
Week 16: DBP	0 ( 9 )	0 ( 11 )	-1 ( 10 )	0 ( 7 )	1 ( 8 )	-1 ( 17 )
Week 52: SBP	-1 ( 11 )	5 ( 11 )	-5 ( 6 )	4 ( 12 )	4 ( 15 )	7 ( 8 )
Week 52: DBP	0 ( 11 )	4 ( 12 )	-3 ( 9 )	5 ( 13 )	4 ( 13 )	1 ( 7 )

No statistical analyses for this end point

Secondary: Change in glucose metabolism: glycosylated haemoglobin (HbA1c)

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End point title

Change in glucose metabolism: glycosylated haemoglobin (HbA1c)

End point description

Change in HbA1c from baseline to week 16 and week 52 is presented. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 29, 19, 16, 12, 13, 7 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 28, 14, 16, 9, 12, 5 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

From baseline (week 0) to 16 and 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	29	19	16	12	13	7
Units: Percentage point of HbA1c
arithmetic mean (standard deviation)
Week 16	-0.2 ( 0.2 )	-0.1 ( 0.3 )	-0.2 ( 0.1 )	0 ( 0.3 )	-0.2 ( 0.3 )	-0.2 ( 0.3 )
Week 52	-0.2 ( 0.3 )	0.1 ( 0.3 )	-0.2 ( 0.2 )	0.1 ( 0.3 )	-0.2 ( 0.4 )	-0.1 ( 0.3 )

No statistical analyses for this end point

Secondary: Change in glucose metabolism: fasting plasma glucose (FPG)

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End point title

Change in glucose metabolism: fasting plasma glucose (FPG)

End point description

Change in FPG from baseline to week 16 and week 52 is presented. Results are based on the FAS which included all randomised subjects who received at least one dose of trial product and had any post-randomisation data. Number of subjects analysed = Number of subjects who contributed to the analysis. n = number of subjects from the respective arms analysed for specific timepoints. At week 16: n= 31, 16, 18, 11, 13, 5 are the number of subjects from the respective arms analysed for week 16. At week 52: n= 27, 14, 15, 9, 12, 5 are the number of subjects from the respective arms analysed for week 52.

End point type

Secondary

End point timeframe

From baseline (week 0) to 16 and 52 weeks

End point values	Part A+B: Liraglutide 3.0 mg	Part A+B: Placebo	Part A: Liraglutide	Part A: Placebo	Part B: Liraglutide	Part B: Placebo
Number of subjects analysed	31	16	18	11	13	5
Units: Millimoles per litre (mmol/L)
arithmetic mean (standard deviation)
Week 16	-0.2 ( 0.5 )	0.1 ( 0.4 )	-0.2 ( 0.5 )	0.1 ( 0.5 )	-0.1 ( 0.5 )	0.2 ( 0.4 )
Week 52	0 ( 0.6 )	0.2 ( 0.7 )	0 ( 0.7 )	0.3 ( 0.8 )	0 ( 0.4 )	0 ( 0.4 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Weeks 0-54. Results are based on SAS which included all subjects exposed to at least one dose of trial product. All presented adverse events (AEs) are treatment emergent adverse events (TEAEs). TEAE was an event that occurred during on-treatment period.

Adverse event reporting additional description

On treatment period: AEs are included with an onset date on or after first day of trial product administration and any of following dates, whichever came first: 14 days after last day on trial product, or Follow-up visit (week 54) for subjects with trial product discontinuation, or Last study visit (subjects withdrawn without follow-up visit).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Part A+B: Liraglutide 3.0 mg

Reporting group description

Subjects received once daily subcutaneous injection of liraglutide for 52 weeks (open label for 16 weeks and double-blinded for 36 weeks) in a dose escalating manner. For both part A and part B (for children with body weight ≥45 kg): dosing was initiated with liraglutide 0.6 mg daily for one week and increased in weekly dosage steps of 0.6 mg until a MTD (as judged by the Investigator) or a dose of 3.0 mg liraglutide was reached, i.e., 0.6 mg (week 1), 1.2 mg (week 2), 1.8 mg (week 3), 2.4 mg (week 4) and 3.0 mg (week 5 to week 52). For Part B children with body weight <45 kg: dosing was initiated with liraglutide 0.3 mg daily for one week and increased to 0.6 mg after the first week. Thereafter, the dose was increased in weekly steps of 0.6 mg until an MTD (as judged by the Investigator) or a dose of 2.4 mg liraglutide was reached. i.e., 0.3 mg (week 1), 0.6 mg (week 2), 1.2 mg (week 3), 1.8 mg (week 4), 2.4 mg (week 5 to week 52).

Reporting group title

Placebo

Reporting group description

Subjects received once daily subcutaneous injection of liraglutide matching placebo for 16 weeks (open label).

Serious adverse events	Part A+B: Liraglutide 3.0 mg	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 37 (8.11%)	1 / 19 (5.26%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Surgical and medical procedures
Arthrodesis
subjects affected / exposed	1 / 37 (2.70%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal operation
subjects affected / exposed	1 / 37 (2.70%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Hyperthermia
subjects affected / exposed	1 / 37 (2.70%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 37 (2.70%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Staphylococcal infection
subjects affected / exposed	1 / 37 (2.70%)	0 / 19 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part A+B: Liraglutide 3.0 mg	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 37 (81.08%)	14 / 19 (73.68%)
Surgical and medical procedures
Pain prophylaxis
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	3 / 37 (8.11%)	0 / 19 (0.00%)
occurrences all number	3	0
Injection site bruising
subjects affected / exposed	2 / 37 (5.41%)	1 / 19 (5.26%)
occurrences all number	2	1
Injection site haematoma
subjects affected / exposed	3 / 37 (8.11%)	1 / 19 (5.26%)
occurrences all number	4	1
Malaise
subjects affected / exposed	1 / 37 (2.70%)	2 / 19 (10.53%)
occurrences all number	1	2
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 37 (5.41%)	0 / 19 (0.00%)
occurrences all number	2	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 37 (8.11%)	1 / 19 (5.26%)
occurrences all number	3	1
Oropharyngeal pain
subjects affected / exposed	4 / 37 (10.81%)	1 / 19 (5.26%)
occurrences all number	5	1
Sleep apnoea syndrome
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Psychiatric disorders
Aggression
subjects affected / exposed	2 / 37 (5.41%)	0 / 19 (0.00%)
occurrences all number	2	0
Investigations
C-reactive protein increased
subjects affected / exposed	1 / 37 (2.70%)	1 / 19 (5.26%)
occurrences all number	1	1
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Insulin-like growth factor decreased
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Thyroxine free decreased
subjects affected / exposed	2 / 37 (5.41%)	0 / 19 (0.00%)
occurrences all number	3	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	2 / 37 (5.41%)	0 / 19 (0.00%)
occurrences all number	2	0
Fall
subjects affected / exposed	3 / 37 (8.11%)	0 / 19 (0.00%)
occurrences all number	4	0
Hip fracture
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Ligament sprain
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Nervous system disorders
Headache
subjects affected / exposed	4 / 37 (10.81%)	3 / 19 (15.79%)
occurrences all number	11	6
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	9 / 37 (24.32%)	3 / 19 (15.79%)
occurrences all number	20	3
Abdominal pain upper
subjects affected / exposed	4 / 37 (10.81%)	0 / 19 (0.00%)
occurrences all number	8	0
Abdominal rigidity
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Constipation
subjects affected / exposed	3 / 37 (8.11%)	0 / 19 (0.00%)
occurrences all number	4	0
Diarrhoea
subjects affected / exposed	17 / 37 (45.95%)	2 / 19 (10.53%)
occurrences all number	92	4
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 37 (5.41%)	0 / 19 (0.00%)
occurrences all number	2	0
Nausea
subjects affected / exposed	2 / 37 (5.41%)	0 / 19 (0.00%)
occurrences all number	3	0
Vomiting
subjects affected / exposed	5 / 37 (13.51%)	0 / 19 (0.00%)
occurrences all number	7	0
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Precocious puberty
subjects affected / exposed	2 / 37 (5.41%)	0 / 19 (0.00%)
occurrences all number	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 37 (2.70%)	1 / 19 (5.26%)
occurrences all number	1	1
Pain in extremity
subjects affected / exposed	2 / 37 (5.41%)	0 / 19 (0.00%)
occurrences all number	2	0
Infections and infestations
Ear infection viral
subjects affected / exposed	1 / 37 (2.70%)	1 / 19 (5.26%)
occurrences all number	3	1
Gastroenteritis
subjects affected / exposed	4 / 37 (10.81%)	0 / 19 (0.00%)
occurrences all number	6	0
Influenza
subjects affected / exposed	4 / 37 (10.81%)	3 / 19 (15.79%)
occurrences all number	6	5
Nasopharyngitis
subjects affected / exposed	5 / 37 (13.51%)	1 / 19 (5.26%)
occurrences all number	8	1
Pharyngitis
subjects affected / exposed	1 / 37 (2.70%)	1 / 19 (5.26%)
occurrences all number	1	1
Rhinitis
subjects affected / exposed	3 / 37 (8.11%)	0 / 19 (0.00%)
occurrences all number	3	0
Upper respiratory tract infection
subjects affected / exposed	3 / 37 (8.11%)	2 / 19 (10.53%)
occurrences all number	3	2
Metabolism and nutrition disorders
Hyperlipidaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1
Hypernatraemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 19 (5.26%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

01 Oct 2015

Following changes were made in this amendment: • A new exclusion criterion of “Suggestive history of, or significant risk of gastroparesis (e.g. marked abdominal bloating post meal, history of vomiting, severe constipation), as judged by the Investigators” was included. • The order of definitions for hip and waist circumference in Section 8.4.1.2 was changed to align with electronic data capture (EDC) standards. • Systolic and diastolic blood pressure text specifying cuff size when measuring blood pressure was deleted, as it referred to an adult population. • The text for calcium measurement in Section 8.5.7 was corrected due to an error in writing. Albumin corrected calcium was collected instead of the ionised form.

24 Jan 2018

Following changes were made in this amendment: • The starting dose and dose escalation for part B were adjusted based on the results of the safety and PK data from the NN8022-4181 trial and part A of NN8022-4179. Dosing was changed for part B such that: a) Children with a body weight < 45 kilograms (kg), initiated dose titration with 0.3 milligrams per day (mg/day) and had a maximum dose of 2.4 mg/day or maximum tolerated dose (MTD). b) Children with body weight ≥ 45 kg, initiated dose titration at 0.6 mg/day, with a maximum dose of 3.0 mg/day or MTD • Clarification and alignment with the Paediatric Investigational Plan of inclusion criterion 4 and related text regarding Tanner staging throughout the protocol • Alignment of number of subjects completing the trial and definition of evaluable subjects with wording from the Paediatric Investigational Plan (Sections 6.1 and 6.6) • To be in alignment with the Novo Nordisk recommendation to use patient centric language, “obese children” was changed to “children with obesity” throughout the protocol. • The option of local testing for adrenal insufficiency was added to facilitate the inclusion of subjects with missing documentation of test results

09 Apr 2020

Following changes were made in this amendment: Section 6.1 related to number of subjects and Section 12.6 related to product overdose were updated

20 Jul 2020

Following sections were updated for number of subjects in this amendment: • Section 1 (Summary); • Section 6.1 (Number of subjects); • Section 6.6 (Subject replacement); • Section 17.1 (Sample size calculation).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Effect of liraglutide for weight management in paediatric subjects with Prader-Willi Syndrome. A randomised, placebo controlled, parallel group, multi-centre, multi-national trial with a 16-week double-blind period and 36-week open-label period

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 weeks

Primary: Change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 weeks

Primary: Change in body mass index (BMI) standard deviation score (SDS) from baseline to 52 weeks

Primary: Change in body mass index (BMI) standard deviation score (SDS) from baseline to 52 weeks

Secondary: Percent of subjects achieving ≥ 5% reduction in baseline BMI

Secondary: Percent of subjects achieving ≥ 5% reduction in baseline BMI

Secondary: Percent of subjects achieving ≥ 10% reduction in baseline BMI

Secondary: Percent of subjects achieving ≥ 10% reduction in baseline BMI

Secondary: Change in BMI

Secondary: Change in BMI

Secondary: Change in Body weight (kilogram (kg)

Secondary: Change in Body weight (kilogram (kg)

Secondary: Change in Body weight (pounds (lb))

Secondary: Change in Body weight (pounds (lb))

Secondary: Change in Body weight (percentage (%))

Secondary: Change in Body weight (percentage (%))

Secondary: Change in hyperphagia score: total score and hyperphagic behaviour, drive and severity score

Secondary: Change in hyperphagia score: total score and hyperphagic behaviour, drive and severity score

Secondary: Change in systolic and diastolic blood pressure

Secondary: Change in systolic and diastolic blood pressure

Secondary: Change in glucose metabolism: glycosylated haemoglobin (HbA1c)

Secondary: Change in glucose metabolism: glycosylated haemoglobin (HbA1c)

Secondary: Change in glucose metabolism: fasting plasma glucose (FPG)

Secondary: Change in glucose metabolism: fasting plasma glucose (FPG)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Effect of liraglutide for weight management in paediatric subjects with Prader-Willi Syndrome. A randomised, placebo controlled, parallel group, multi-centre, multi-national trial with a 16-week double-blind period and 36-week open-label period