Clinical Trial Results:
Investigation of efficacy and safety of semaglutide s.c. once-weekly versus placebo in subjects with non-alcoholic steatohepatitis and compensated liver cirrhosis
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Summary
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EudraCT number |
2018-004484-31 |
Trial protocol |
GB DE FR ES |
Global end of trial date |
10 Jun 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Jun 2022
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First version publication date |
22 Jun 2022
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Other versions |
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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 |
NN9931-4492
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03987451 | ||
WHO universal trial number (UTN) |
U1111-1224-4062 | ||
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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 Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Scientific contact |
Clinical Reporting Office (2834), 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) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Jun 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Apr 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Jun 2021
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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 investigate the effect of semaglutide subcutaneous (s.c.) 2.4 mg once-weekly on liver fibrosis compared with placebo in subjects with Non-alcoholic Steatohepatitis (NASH) and compensated fibrosis stage 4
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (2013) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents, (2016) and 21 US Code of Federal Regulations (CFR) 312.
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Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
18 Jun 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Germany: 5
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Country: Number of subjects enrolled |
Spain: 6
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
United Kingdom: 5
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Country: Number of subjects enrolled |
United States: 51
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Worldwide total number of subjects |
71
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EEA total number of subjects |
15
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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) |
0
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Adults (18-64 years) |
55
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From 65 to 84 years |
16
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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 38 sites in 5 countries as follows (number of sites that screened subjects/ number of sites that randomised subjects): United States (24/19); United Kingdom (4/3); Germany (3/2); France (5/3); Spain (2/2). | ||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects were randomised in a 2:1 ratio to receive once-weekly either semaglutide or placebo subcutaneously as an adjunct to a reduced-calorie diet and increased physical activity. | ||||||||||||||||||
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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 |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Semaglutide 2.4 mg | ||||||||||||||||||
Arm description |
Subjects were to receive once weekly subcutaneous (s.c.) injection of semaglutide for 48 weeks. Subjects initially received 0.24 milligrams (mg) of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 2.4 mg was reached: 0.24 mg (week 1 to week 4), 0.5 mg (week 5 to week 8), 1.0 mg (week 9 to week 12), 1.7 mg (week 13 to week 16), 2.4 mg (week 16 to week 48). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Semaglutide B 3.0 mg/ml PDS290
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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 |
Subjects were to receive once weekly subcutaneous (s.c.) injection of semaglutide for 48 weeks. Subjects initially received 0.24 milligrams (mg) of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 2.4 mg was reached: 0.24 mg (week 1 to week 4), 0.5 mg (week 5 to week 8), 1.0 mg (week 9 to week 12), 1.7 mg (week 13 to week 16), 2.4 mg (week 16 to week 48).
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Subjects were to receive once weekly s.c. injection of placebo matched to semaglutide (0.24 mg, 0.5 mg, 1.0 mg, 1.7 mg or 2.4 mg) for 48 weeks. | ||||||||||||||||||
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 |
Subjects were to receive once weekly s.c. injection of placebo matched to semaglutide (0.24 mg, 0.5 mg, 1.0 mg, 1.7 mg or 2.4 mg) for 48 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Semaglutide 2.4 mg
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Reporting group description |
Subjects were to receive once weekly subcutaneous (s.c.) injection of semaglutide for 48 weeks. Subjects initially received 0.24 milligrams (mg) of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 2.4 mg was reached: 0.24 mg (week 1 to week 4), 0.5 mg (week 5 to week 8), 1.0 mg (week 9 to week 12), 1.7 mg (week 13 to week 16), 2.4 mg (week 16 to week 48). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects were to receive once weekly s.c. injection of placebo matched to semaglutide (0.24 mg, 0.5 mg, 1.0 mg, 1.7 mg or 2.4 mg) for 48 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Semaglutide 2.4 mg
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Reporting group description |
Subjects were to receive once weekly subcutaneous (s.c.) injection of semaglutide for 48 weeks. Subjects initially received 0.24 milligrams (mg) of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 2.4 mg was reached: 0.24 mg (week 1 to week 4), 0.5 mg (week 5 to week 8), 1.0 mg (week 9 to week 12), 1.7 mg (week 13 to week 16), 2.4 mg (week 16 to week 48). | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects were to receive once weekly s.c. injection of placebo matched to semaglutide (0.24 mg, 0.5 mg, 1.0 mg, 1.7 mg or 2.4 mg) for 48 weeks. | ||
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End point title |
At Least One Stage of Liver Fibrosis Improvement With No Worsening of NASH (Yes/No) (worsening defined as an increase of at least one stage of either lobular inflammation, hepatocyte ballooning or steatosis according to the NASH CRN criteria) | ||||||||||||
End point description |
NASH resolution defined by NASH clinical research network (CRN) as lobular inflammation of 0 or 1; hepatocellular ballooning reduced to 0; both criteria were necessary conditions. Hepatocellular ballooning ranges from 0-2; lobular inflammation ranges from 0-3, higher scores indicate more severe hepatocellular ballooning/lobular inflammation. Worsening of NASH defined by increase of at least 1 stage of either lobular inflammation, hepatocyte ballooning or steatosis. Worsening of fibrosis defined by increase in fibrosis at least 1 stage of Kleiner fibrosis classification: fibrosis stages range from 0-4, higher scores indicate greater fibrosis (0=None, 4=Cirrhosis). Endpoint evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive): follow-up visit (week 55); withdrawal of consent; last contact with participant (for participants lost to follow-up); death. Full analysis set: all randomised subjects.
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End point type |
Primary
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End point timeframe |
From baseline (week 0) to visit 12 (week 48)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The common odds ratio between semaglutide and placebo adjusting for baseline diabetes was estimated along with exact 95% confidence interval based on conditioning on the marginal 2×2 tables.
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Comparison groups |
Semaglutide 2.4 mg v Placebo
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Number of subjects included in analysis |
71
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0867 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
0.28
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
0.06 | ||||||||||||
upper limit |
1.24 | ||||||||||||
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End point title |
Relative Change in Liver Fat Content (%) Measured by MRI-PDFF | ||||||||||||
End point description |
Relative change in liver fat content (measured in %) is presented as ratio to baseline. It was assessed by Magnetic Resonance Imaging–Proton Density Fat Fraction (MRI-PDFF) that utilized a gradient echo sequence with low flip angle to minimize T1 bias, corrected T2* decay (due to iron overload) via modeling of fat signal as a superposition of multiple frequency components from 5 different lipid types, was applied in each of 9 Couinaud segments. Technique improved fat quantification accuracy for entire liver permitting quantification of small changes following pharmacological intervention. Endpoint evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive): follow-up visit (week 55); withdrawal of consent; last contact with subject (for subjects lost to follow-up); death. Full analysis set (FAS): all randomised subjects. Number of subjects analysed = Number of subjects who contributed to the analysis
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End point type |
Secondary
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End point timeframe |
From baseline (week 0) to visit 12 (week 48)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Relative Change in Liver Stiffness Measured by MRE | ||||||||||||
End point description |
Relative change in Liver Stiffness from baseline to week 48 is presented as ratio to baseline. Liver stiffness was measured by MRI using a Magnetic Resonance Elastography (MRE) technique and measured in kilopascal. MRE is a technology that uses MRI imaging with low-frequency vibrations to create a visual map (elastogram) that shows stiffness of the liver. Endpoint was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. FAS included all randomised subjects. Number of subjects analysed = Number of subjects who contributed to the analysis
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End point type |
Secondary
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End point timeframe |
From baseline (week 0) to visit 12 (week 48)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
NASH Resolution (Yes/No) (defined by the NASH CRN as lobular inflammation 0 – 1 and ballooning 0) | ||||||||||||
End point description |
NASH resolution defined by NASH clinical research network as lobular inflammation of 0 or 1 and hepatocellular ballooning reduced to 0; both criteria were necessary conditions. Hepatocellular ballooning ranges from 0-2; lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Worsening of fibrosis defined by an increase in fibrosis at least one stage of Kleiner fibrosis classification: fibrosis stages range from 0-4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Endpoint was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. FAS included all randomised subjects.
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End point type |
Secondary
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End point timeframe |
From baseline (week 0) to visit 12 (week 48)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in Stage of Fibrosis According to the NASH CRN Fibrosis Score | ||||||||||||||||||||||||
End point description |
Percentage of subjects who had improved, worsened, had no change in fibrosis stage from baseline to week 48 or missing data is presented. Degree of fibrosis defined by Kleiner fibrosis staging system, range from 0-4: F0 (absence of fibrosis), F1 (portal/perisinusoidal fibrosis), F2 (perisinusoidal & portal/periportal fibrosis), F3 (septal/bridging fibrosis) through F4 (cirrhosis); higher scores indicate greater fibrosis. Improvement defined as at least 1 stage decrease; Worsening by at least 1 stage increase; No change is no change in fibrosis stage and missing refers to subjects with missing outcomes. Endpoint evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive): follow-up visit (week 55); withdrawal of consent; last contact with subject (subjects lost to follow-up); death. FAS: all randomised subjects. Number of subjects analysed = Number of subjects who contributed to the analysis
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End point type |
Secondary
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End point timeframe |
From baseline (week 0) to visit 12 (week 48)
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change in NAFLD Activity Score (NAS) According to the NASH CRN Criteria | ||||||||||||||||||||||||
End point description |
Percentage of subjects who had worsened, improved or had no change in total Non-Alcoholic Fatty Liver Disease (NAFLD) activity score from baseline to week 48 or missing data is presented. Worsening defined as an increase of at least 1 in the NAS; Improvement was defined as a decrease of at least 1 in the NAS; while no change corresponds to no change in NAS and missing refers to subjects with missing outcomes for NAS from baseline to week 48. NAS was calculated as the sum of scores for steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocyte ballooning (0 to 2). Therefore, it is assessed on a scale of 0-8, with higher scores indicating more severe disease. Endpoint was evaluated based on data from in-trial period which started on date of randomisation visit and ended on first of following dates (both inclusive):1) follow-up visit (week 55); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. FAS included all randomised subjects.
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End point type |
Secondary
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End point timeframe |
From baseline (week 0) to visit 12 (week 48)
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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 |
An adverse event (AE) was any untoward medical occurrence in a clinical trial subject administered or using a medicinal product, whether or not considered related to the medicinal product or usage. All AEs reported here are Treatment Emergent Adverse Events (TEAEs). TEAE is defined as an event that had onset date during the on-treatment period. Endpoint was evaluated based on data from on-treatment period which started on the date of first administration of trial product and ended on the date of whatever comes first of: a) last dose of trial product + 49 days (7 half-lives of semaglutide), b) follow-up visit (week 55), or c) end of the in-trial period. Safety analysis set included all subjects receiving at least one dose of randomised treatment.
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End point type |
Secondary
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End point timeframe |
From baseline (week 0) to week 55
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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 |
From week 0 to week 55. Results are based on the safety analysis set which included all subjects who received at least one dose of randomised treatment.
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Adverse event reporting additional description |
All AEs here are TEAEs, defined as an event that had onset date during on-treatment period. On-treatment period started on the date of first administration of trial product and ended on the date of whatever comes first of: last dose of trial product + 49 days (7 half-lives of semaglutide); follow-up visit (week 55), or end of the in-trial period.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects were to receive once weekly s.c. injection of placebo matched to semaglutide (0.24 mg, 0.5 mg, 1.0 mg, 1.7 mg or 2.4 mg) for 48 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Semaglutide 2.4 mg
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Reporting group description |
Subjects were to receive once weekly subcutaneous (s.c.) injection of semaglutide for 48 weeks. Subjects initially received 0.24 milligrams (mg) of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 2.4 mg was reached: 0.24 mg (week 1 to week 4), 0.5 mg (week 5 to week 8), 1.0 mg (week 9 to week 12), 1.7 mg (week 13 to week 16), 2.4 mg (week 16 to week 48). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Apr 2020 |
Following changes were made in this amendment: • To align with requirements as per regulatory guidance regarding primary endpoint in NASH trials, the former secondary endpoint was changed to the primary endpoint: “At least one
stage of liver fibrosis improvement with no
worsening of NASH after 48 weeks (yes/no)
(worsening defined as an increase of at least
one stage of either lobular inflammation,
hepatocyte ballooning or steatosis according to
the NASH CRN criteria).” • As a consequence of the above, the former primary endpoint was changed to the secondary
endpoint: "Relative change from baseline (week 0) to week 48 in liver stiffness measured by MRE." • To ensure complete follow-up of primary endpoint assessment, liver biopsies were
needed at week 48 for subjects who discontinued treatment during the trial (visit 12 A). • To reflect the change in primary endpoint, the primary estimand was changed accordingly. • Clarification of various procedures and assessments |
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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 | |||
