Clinical Trial Results:
National, Randomized, Controlled, Open-label, Parallel-Group Study Comparing the Efficacy and Safety of Two Different Titration Algorithm Approaches (Physician Managed Versus Patient Managed) for New Insulin Glargine U300 Therapy in Type 2 Diabetes Patients
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Summary
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EudraCT number |
2015-001167-39 |
Trial protocol |
IT |
Global end of trial date |
05 Oct 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Oct 2018
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First version publication date |
19 Oct 2018
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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 |
GLARGL07537
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Study Name: Italian Titration Approach Study | ||
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Sponsors
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Sponsor organisation name |
Sanofi S.p.A
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Sponsor organisation address |
Viale L. Bodio 37/b, Milano, Italy, 20158
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Public contact |
Sanofi aventis recherche & développement, Trial Transparency Team, contact-US@sanofi.com
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Scientific contact |
Sanofi aventis recherche & développement, Trial Transparency Team, contact-US@sanofi.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 |
06 Feb 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Oct 2017
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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 demonstrate the non-inferiority, in terms of glycemic control, of a subject-managed (nurse assisted) versus a physician-managed algorithm for titrating Insulin glargine 300 U/ml (HOE901-U300) in insulin naïve type 2 diabetes mellitus (T2DM) subjects inadequately controlled with oral antidiabetic agents.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
Subjects received oral anti diabetic drugs (OADs) at a stable dose in accordance to the authorized local labelling for use with insulin. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Aug 2015
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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 |
Italy: 359
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Worldwide total number of subjects |
359
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EEA total number of subjects |
359
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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) |
163
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From 65 to 84 years |
196
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted in 46 centres in Italy. A total of 458 subjects were screened between 28 August 2015 and 23 March 2017, of which 99 subjects were screen failures. Screen failures were mainly due to inclusion criteria not met. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 359 subjects were randomized in 1:1 ratio to either of the 2 titration modality arms. | |||||||||||||||||||||||||||
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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 |
Not blinded | |||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Physician-Managed Titration | |||||||||||||||||||||||||||
Arm description |
Subjects received HOE901-U300 once daily for 24 weeks. The dose was titrated by physician at each study visit according to study design (weekly for the first 12 weeks, bi-weekly until Week 24) to achieve fasting Self-Measured Plasma Glucose (SMPG) in the target range of 80-110 mg/dL. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Insulin glargine
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Investigational medicinal product code |
HOE901-U300
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Other name |
Toujeo
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Pharmaceutical forms |
Solution for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Insulin glargine, 300 U/mL (dose range of 1 unit to 80 units) was self-administered by subcutaneous (SC) injection once in the evening, at approximately the same time every day (i.e., without exceeding +/- 3 hours compared to the usual time) in the abdominal wall, the deltoid or the thigh. Within a given area, location should be changed (rotated) each time to prevent injection-site skin reactions.
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Arm title
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Subject-Managed Titration | |||||||||||||||||||||||||||
Arm description |
Subjects received HOE901-U300 once daily for 24 weeks. The dose was self-titrated every 3-4 days to achieve fasting SMPG in the target range of 80-110 mg/dL. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Insulin glargine
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Investigational medicinal product code |
HOE901-U300
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Other name |
Toujeo
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Pharmaceutical forms |
Solution for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Insulin glargine, 300 U/mL (dose range of 1 unit to 80 units) was self-administered by SC injection once in the evening, at approximately the same time every day (i.e., without exceeding +/- 3 hours compared to the usual time) in the abdominal wall, the deltoid or the thigh. Within a given area, location should be changed (rotated) each time to prevent injection-site skin reactions.
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Baseline characteristics reporting groups
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Reporting group title |
Physician-Managed Titration
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Reporting group description |
Subjects received HOE901-U300 once daily for 24 weeks. The dose was titrated by physician at each study visit according to study design (weekly for the first 12 weeks, bi-weekly until Week 24) to achieve fasting Self-Measured Plasma Glucose (SMPG) in the target range of 80-110 mg/dL. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Subject-Managed Titration
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Reporting group description |
Subjects received HOE901-U300 once daily for 24 weeks. The dose was self-titrated every 3-4 days to achieve fasting SMPG in the target range of 80-110 mg/dL. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Physician-Managed Titration
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Reporting group description |
Subjects received HOE901-U300 once daily for 24 weeks. The dose was titrated by physician at each study visit according to study design (weekly for the first 12 weeks, bi-weekly until Week 24) to achieve fasting Self-Measured Plasma Glucose (SMPG) in the target range of 80-110 mg/dL. | ||
Reporting group title |
Subject-Managed Titration
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Reporting group description |
Subjects received HOE901-U300 once daily for 24 weeks. The dose was self-titrated every 3-4 days to achieve fasting SMPG in the target range of 80-110 mg/dL. | ||
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End point title |
Change From Baseline in HbA1c to Week 24 | ||||||||||||
End point description |
Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Adjusted least square means and standard errors were obtained from a mixed-effect model. Analysis was performed on ITT population that included all randomized subjects who received at least one dose of study drug and had a baseline assessment of primary efficacy variable. Subjects were analysed as per allocated treatment group.
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End point type |
Primary
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End point timeframe |
Baseline, Week 24
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Statistical analysis title |
Subject-Managed Titration vs Physician-Managed | ||||||||||||
Statistical analysis description |
Analysis was performed using a linear mixed-effect model approach with titration approach and center as fixed effects and the HbA1c baseline value as covariate.
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Comparison groups |
Subject-Managed Titration v Physician-Managed Titration
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Number of subjects included in analysis |
355
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
Method |
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Parameter type |
Least Square (LS) Mean Difference | ||||||||||||
Point estimate |
-0.11
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.26 | ||||||||||||
upper limit |
0.04 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.08
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| Notes [1] - Non-inferiority of subject-managed titration versus physician-managed titration was demonstrated if the upper bound of the two-sided 95% confidence interval (CI) for the difference between groups was <0.3%. |
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End point title |
Percentage of Subjects With At Least One Confirmed and/or Severe Nocturnal Hypoglycemic Events (Hypoglycemia <=70 mg/dL [3.9 mmol/L]) From Baseline to Week 24 | ||||||||||||
End point description |
Severe hypoglycemia is an event requiring assistance of another person to actively administer carbohydrate, glucagon, or perform other resuscitative actions. Severe and/or confirmed hypoglycaemia event was a severe event or an event confirmed with plasma glucose =<70 mg/dL (=<3.9 mmol/L). Nocturnal hypoglycemia was hypoglycemia that occurred between 00:00 and 05:59 hours (clock time). Analysis was performed on ITT population.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 24
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Fasting Plasma Glucose (FPG) to Week 24 | ||||||||||||
End point description |
Change in FPG was calculated by subtracting baseline value from Week 24 value. Analysis was performed on ITT population.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Insulin Dose (U/kg Body Weight) to Week 24 | ||||||||||||
End point description |
Changes in insulin dose were based on the median of the fasting SMPG values measured on 3 consecutive days, the last being the day of titration. Change in daily insulin dose was calculated by subtracting baseline value from Week 24 value. Analysis was performed on ITT population. Here, number of subjects analysed=subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Week 24) regardless of seriousness or relationship to investigational product.
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Adverse event reporting additional description |
Reported AEs are treatment-emergent AEs that developed/worsened or became serious during on-treatment period from first dose of the study drug up to two days after the last dose of study drug for both titration groups. Analysis was performed on safety population that included all randomized subjects who have taken at least one dose of study drug.
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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 |
20.1
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Reporting groups
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Reporting group title |
Physician managed titration
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Reporting group description |
Subjects received HOE901-U300 once daily for 24 weeks. The dose was titrated by physician at each study visit according to study design (weekly for the first 12 weeks, bi-weekly until Week 24 to achieve fasting SMPG in the target range of 80-110 mg/dL. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Subject managed titration
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Reporting group description |
Subjects received HOE901-U300 once daily for 24 weeks. The dose was self-titrated every 3-4 days to achieve fasting self-measured plasma glucose (SMPG) in the target range of 80-110 mg/dL. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: There were no non-serious adverse events at 5% frequency threshold. |
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Dec 2016 |
Following amendment changes were made: The sample size was changed to 354 randomized subjects. Per protocol population was added to the analysis populations in order to provide supportive information for the analysis of the primary variable. |
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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 | |||
