Clinical Trial Results:
Efficacy and safety of semaglutide once-weekly versus placebo as add on to SGLT-2i in subjects with type 2 diabetes mellitus. A 30-week randomised, double-blind, placebo-controlled trial
Summary
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EudraCT number |
2016-000904-27 |
Trial protocol |
NO AT |
Global end of trial date |
06 Aug 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Aug 2019
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First version publication date |
22 Aug 2019
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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 |
NN9535-4269
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03086330 | ||
WHO universal trial number (UTN) |
U1111-1180-1213 | ||
Other trial identifiers |
JapicCTI: 173542 | ||
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) |
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 |
18 Feb 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Jul 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Aug 2018
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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 effect of semaglutide s.c. 1.0 mg once-weekly versus placebo as add-on to SGLT-2 inhibitor monotherapy or in combination with either metformin or SU on glycaemic control after 30 weeks of treatment in subjects with T2D.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (2013) and ICH Good Clinical Practice, including archiving of essential documents, (1996) and 21 CFR 312.120.
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Background therapy |
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors, metformin and sulphonylurea (SU) were considered as background medications. All participants were to be on a SGLT-2 inhibitor treatment. Subjects were to continue their anti-diabetic background medication throughout the trial at the same dose level with the same frequency as at the trial entry unless rescue criteria were met, or a safety concern related to acute renal impairment or hospitalization for major surgical procedures or acute serious medical illnesses occurred. All background medications were to be used in accordance with standard of care in the individual country and were not to exceed the maximum approved dose in the individual country. | ||
Evidence for comparator |
Not applicable. | ||
Actual start date of recruitment |
15 Mar 2017
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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 |
Austria: 39
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Country: Number of subjects enrolled |
Canada: 47
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Country: Number of subjects enrolled |
Japan: 50
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Country: Number of subjects enrolled |
Norway: 27
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Country: Number of subjects enrolled |
Russian Federation: 40
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Country: Number of subjects enrolled |
United States: 99
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Worldwide total number of subjects |
302
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EEA total number of subjects |
66
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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) |
244
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From 65 to 84 years |
58
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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 61 sites in 6 countries as follows: Austria (4 sites), Canada (8 sites), Japan (4 sites), Norway (4 sites), Russian Federation (5 sites), United States of America (USA) (36 sites). In addition, 1 site in Norway and 3 sites in the USA screened, but didn’t randomise any participant. | ||||||||||||||||||
Pre-assignment
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Screening details |
Not applicable. | ||||||||||||||||||
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 | ||||||||||||||||||
Blinding implementation details |
According to standard pharmacovigilance procedures, specific members of the Novo Nordisk A/S Global Safety department were not blinded to suspected unexpected serious adverse reaction (SUSARs; for reporting purpose), whereas the clinical study group and the investigator remained blinded throughout the trial.
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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 1.0 mg | ||||||||||||||||||
Arm description |
Participants received semaglutide in a dose escalation manner for 30 weeks: 0.25 mg (weeks 1 to 4), 0.50 mg (weeks 5 to 8) and 1.0 mg (weeks 9 to 30). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Semaglutide B 1.34 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 |
Semaglutide was taken once weekly as subcutaneous (s.c.) injections.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Participants received matching placebo (for semaglutide) in a dose escalation manner for 30 weeks. Dose escalation for placebo matched that for semaglutide with regards to volume. | ||||||||||||||||||
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 was taken once weekly as s.c. injections.
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Baseline characteristics reporting groups
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Reporting group title |
Semaglutide 1.0 mg
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Reporting group description |
Participants received semaglutide in a dose escalation manner for 30 weeks: 0.25 mg (weeks 1 to 4), 0.50 mg (weeks 5 to 8) and 1.0 mg (weeks 9 to 30). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received matching placebo (for semaglutide) in a dose escalation manner for 30 weeks. Dose escalation for placebo matched that for semaglutide with regards to volume. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Semaglutide 1.0 mg
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Reporting group description |
Participants received semaglutide in a dose escalation manner for 30 weeks: 0.25 mg (weeks 1 to 4), 0.50 mg (weeks 5 to 8) and 1.0 mg (weeks 9 to 30). | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received matching placebo (for semaglutide) in a dose escalation manner for 30 weeks. Dose escalation for placebo matched that for semaglutide with regards to volume. |
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End point title |
Change in HbA1c | ||||||||||||
End point description |
Change from baseline (week 0) in HbA1c was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product and ended at the first date of any of the following: 1) the last dose of trial product + 7 days or 2) initiation of rescue medication. Population description: 'Full analysis set (FAS)' included all randomised participants. Number of subjects analysed = number of participants with available data.
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End point type |
Primary
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End point timeframe |
From baseline to week 30
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Statistical analysis title |
Semaglutide 1.0 mg versus Placebo | ||||||||||||
Statistical analysis description |
The responses were analysed using an analysis of covariance (ANCOVA) with treatment, stratification factor and region as fixed factors and baseline value as covariate. Before analysis, missing data were multiple imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including stratification factor and region as categorical effects and data from baseline and all previous visits as covariates.
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Comparison groups |
Semaglutide 1.0 mg v Placebo
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Number of subjects included in analysis |
247
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-1.42
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.61 | ||||||||||||
upper limit |
-1.24 |
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End point title |
Change in body weight (kg) | ||||||||||||
End point description |
Change from baseline (week 0) in body weight was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. Population description: 'FAS' included all randomised participants. Number of subjects analysed = number of participants with available data.
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End point type |
Secondary
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End point timeframe |
From baseline to week 30
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Statistical analysis title |
Semaglutide 1.0 mg versus placebo | ||||||||||||
Statistical analysis description |
The responses were analysed using an ANCOVA with treatment, stratification factor and region as fixed factors and baseline value as covariate. Before analysis, missing data were multiple imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including stratification factor and region as categorical effects and data from baseline and all previous visits as covariates.
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Comparison groups |
Semaglutide 1.0 mg v Placebo
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Number of subjects included in analysis |
249
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-3.81
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-4.7 | ||||||||||||
upper limit |
-2.93 |
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End point title |
Change in fasting plasma glucose | ||||||||||||
End point description |
Change from baseline (week 0) in fasting plasma glucose (FPG) was evaluated at week 30. Results are based on the ‘on-treatment without rescue medication’ observation period. Population description: 'FAS' included all randomised participants. Number of subjects analysed = number of participants with available data.
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End point type |
Secondary
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End point timeframe |
From baseline to week 30
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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 from baseline (week 0) in systolic and diastolic blood pressure was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. Population description: 'FAS' included all randomised participants. Number of subjects analysed = number of participants with available data.
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End point type |
Secondary
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End point timeframe |
From baseline to week 30
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No statistical analyses for this end point |
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End point title |
Change in scores for selected patient reported outcomes (PRO): Diabetes Treatment Satisfaction Questionnaire (DTSQ) | |||||||||||||||||||||||||||||||||||||||
End point description |
Change from baseline (week 0) in PRO questionnaire, DTSQ was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. The DTSQ measures satisfaction with diabetes treatment. The DTSQ consists of 8 items evaluating 6 aspects of treatment satisfaction and 2 perceived recent event rates of hyperglycemia/hypoglycemia. Each item is scored on a 7- point Likert scale ranging from 0 (very dissatisfied) to 6 (very satisfied). Items evaluating 6 aspects (items 3-8) of treatment satisfaction are summed to produce a total treatment satisfaction score; DTSQ status total scores range from 0-36, with higher scores indicating greater satisfaction; the perceived frequency of hyperglycemia/hypoglycemia items are scored separately, with lower scores indicating better perceived blood glucose control. Population description: ‘FAS’ included all randomised participants. Number of subjects analysed = number of participants with available data.
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End point type |
Secondary
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End point timeframe |
From baseline to week 30
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No statistical analyses for this end point |
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End point title |
Subjects who achieve HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists target (yes/no) | ||||||||||||
End point description |
Percentage of participants with HbA1c equal to or below 6.5% (48 mmol/mol) was evaluated at week 30. Results are based on the 'on-treatment without rescue medication' observation period. Population description: 'FAS' included all randomised participants. Number of subjects analysed = number of participants with available data.
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End point type |
Secondary
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End point timeframe |
After 30 weeks' treatment
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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 to week 30 (treatment period) + 42 days (follow-up period).
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Adverse event reporting additional description |
Results are based on the safety analysis set (SAS), which included all participants exposed to at least one dose of trial product (semaglutide or placebo). 'Number of deaths causally related to treatment’ is the data considered to present under ‘total number of deaths resulting from adverse events'.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
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Reporting groups
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Reporting group title |
Semaglutide 1.0 mg
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Reporting group description |
Participants received semaglutide in a dose escalation manner for 30 weeks: 0.25 mg (weeks 1 to 4), 0.50 mg (weeks 5 to 8) and 1.0 mg (weeks 9 to 30). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received matching placebo (for semaglutide) in a dose escalation manner for 30 weeks. Dose escalation for placebo matched that for semaglutide with regards to volume. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |