Clinical Trial Results:
Multicentric cross-over trial to assess the glycemic profiles on 8 weeks of vildagliptin and sitagliptin treatment, each, in type 2 diabetic patients with a pre-existing cardiovascular disease pre-treated with insulin, using a PROBE design.
Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
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Summary
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EudraCT number |
2011-006118-15 |
Trial protocol |
DE |
Global end of trial date |
08 Sep 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Jul 2018
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First version publication date |
15 Jul 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 |
CLAF237ADE07
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01686932 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
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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 |
08 Sep 2014
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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 |
08 Sep 2014
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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 |
The primary objective of this study was to demonstrate that vildagliptin leads to a more favorable hypoglycemic profile than sitagliptin, after 8 weeks of treatment, each, when used in combination with insulin.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Nov 2012
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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: 51
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Worldwide total number of subjects |
51
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EEA total number of subjects |
51
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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) |
26
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From 65 to 84 years |
25
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||
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Pre-assignment
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Screening details |
Period 1: 8 weeks treatment with vildagliptin 50mg BID or sitagliptin 100mg QD, 1-4 weeks wash-out, followed by Period 2, 8 weeks treatment with sitagliptin 100mg QD or vildagliptin 50mg BID | |||||||||||||||
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Period 1
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Period 1 title |
Period 1
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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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Vildagliptin followed by Sitagliptin | |||||||||||||||
Arm description |
Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
vildagliptin
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Investigational medicinal product code |
LAF237
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Other name |
Galvus
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Vildagliptin 50 mg tablets for oral administration-1 tablet in the morning and in the evening
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Arm title
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Sitagliptin followed by Vildagliptin | |||||||||||||||
Arm description |
Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
sitagliptin
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Investigational medicinal product code |
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Other name |
januvia
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Sitagliptin 100 mg tablets for oral administration -1 tablet in the morning
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Period 2
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Period 2 title |
Period 2
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Is this the baseline period? |
No | |||||||||||||||
Allocation method |
Non-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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Vildagliptin followed by Sitagliptin | |||||||||||||||
Arm description |
Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
vildagliptin
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Investigational medicinal product code |
LAF237
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Other name |
Galvus
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Vildagliptin 50 mg tablets for oral administration-1 tablet in the morning and in the evening
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Arm title
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Sitagliptin followed by Vildagliptin | |||||||||||||||
Arm description |
Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
sitagliptin
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Investigational medicinal product code |
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Other name |
januvia
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Sitagliptin 100 mg tablets for oral administration -1 tablet in the morning
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Baseline characteristics reporting groups
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Reporting group title |
Vildagliptin followed by Sitagliptin
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Reporting group description |
Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sitagliptin followed by Vildagliptin
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Reporting group description |
Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Vitagliptin
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2
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Subject analysis set title |
Sitagliptin
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
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End points reporting groups
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Reporting group title |
Vildagliptin followed by Sitagliptin
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Reporting group description |
Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks | ||
Reporting group title |
Sitagliptin followed by Vildagliptin
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Reporting group description |
Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks | ||
Reporting group title |
Vildagliptin followed by Sitagliptin
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Reporting group description |
Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks | ||
Reporting group title |
Sitagliptin followed by Vildagliptin
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Reporting group description |
Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks | ||
Subject analysis set title |
Vitagliptin
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
For all Vitagliptin 50mg BID for 8 weeks in Period 1 and 8 weeks in Period 2
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Subject analysis set title |
Sitagliptin
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
For all Sitagliptin 100mg QD for 8 weeks in Period 1 and 8 weeks in Period 2
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End point title |
Hypoglycemic profile of vildagliptin compared to sitagliptin over 4 days after 8 weeks of treatment in Period 1 & 2 | ||||||||||||
End point description |
The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC<3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia.
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End point type |
Primary
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End point timeframe |
after 8 weeks (end of period 1 and 2)
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Statistical analysis title |
Hypoglycemic profile | ||||||||||||
Statistical analysis description |
The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 min were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic rangeThese AUC<3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense
hypoglycemia
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Comparison groups |
Vitagliptin v Sitagliptin
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Number of subjects included in analysis |
98
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.1179 | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
6.04
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.6 | ||||||||||||
upper limit |
13.7 | ||||||||||||
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End point title |
Number of hypoglycemic events during vildagliptin treatment compared to sitagliptin treatment. | |||||||||||||||
End point description |
Hypoglycemic events are defined as blood glucose values <70 mg/dL measured by a self-monitored blood glucose (SMBG) or continuous glucose monitoring (CGM) measurement regardless of any symptoms suggestive of low blood glucose.
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End point type |
Secondary
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End point timeframe |
after 8 weeks period 1 and Period 2
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Mean duration of hypoglycemic events (min.) measured with continuous glucose monitoring (CGM) over 4 days after 8 weeks of treatment for Period 1 & Period 2 | ||||||||||||
End point description |
the mean duration of hypoglycemic events is detected by continuous glucose monitoring (CGM)measurement.
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End point type |
Secondary
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End point timeframe |
after 8 weeks for Period 1 & Period 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean amplitudes of hypoglycemic events (mmol/L) measured with continuous glucose monitoring (CGM) over 4 days after 8 weeks of treatment for Period 1 & Period 2 | ||||||||||||
End point description |
To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude over 4 days after 8 weeks of treatment in Period 1 & Period 2
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End point type |
Secondary
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End point timeframe |
after 8 weeks Period 1 & Period 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of severe hypoglycemic events during vildagliptin treatment compared to sitagliptin treatment after 8 weeks of treatment in Period 1 and Period 2 | |||||||||
End point description |
Severe hypoglycemic events are defined as any episode requiring the assistance of another party or measured plasma glucose levels of <40 mg /dL. Assessed by self-monitored blood glucose (SMBG)After 8 weeks of treatment in Period 1 and Period 2
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End point type |
Secondary
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End point timeframe |
after 8 weeks Period 1 & Period 2
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| No statistical analyses for this end point | ||||||||||
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End point title |
Glucose fluctuations during the day under vildagliptin treatment compared to sitagliptin treatment on Day 2 after 8 weeks of treatment Period 1 & Period 2 | ||||||||||||
End point description |
Glucose fluctuations are assessed by the mean amplitude of glycemic excursions (MAGE) and standard deviations (SD) (Service et al., 1970). on day 2 after 8 weeks of treatment Period 1 & Period 2
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End point type |
Secondary
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End point timeframe |
Day 2 after 8 weeks of treatment Period 1 & Period 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of participants with ECG abnormalities depending on hypoglycemic events after 8 weeks of treatment Period 1 & Period 2 | |||||||||||||||
End point description |
ECG abnormalities are defined as either: • Occurrence of >30 ventricular extrasystoles (VES) per hour or • Occurrence of ≥2 consecutive VES (Couplets) or • Occurrence of ≥3 consecutive VES (Triplets) or • QT-time corrected for heart rate (QTc) >440 ms. after 8 weeks of treatment Period 1 & Period 2
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End point type |
Secondary
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End point timeframe |
after 8 weeks of treatment Period 1 & Period 2
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Change from Baseline of inflammatory biomarkers high sensitivity C-reactive protein (hsCRP) after 8 weeks of treatment in Period 1 & Period 2 | ||||||||||||
End point description |
The inflammatory biomarkers hsCRP was assessed at baseline and after 8 weeks of treatment Period 1 & Period 2
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End point type |
Secondary
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End point timeframe |
Baseline, after 8 weeks Period 1 & Period 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline of inflammatory biomarkers Interleukin 6 (IL-6) after 8 weeks of treatment in Period 1 & Period 2 | ||||||||||||
End point description |
The inflammatory biomarkers IL-6 was assessed at baseline and after 8 weeks of treatment Period 1 & Period 2
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End point type |
Secondary
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End point timeframe |
Baseline, after 8 weeks Period 1 & Period 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage Change from baseline of pro-insulin/C-peptide ratios after 8 weeks of treatment Period 1 & Period 2 | ||||||||||||
End point description |
Percentage Change from baseline of pro-insulin/C-peptide ratios after 8 weeks of treatment Period 1 & Period 2 Higher pro-insulin / C-peptide ratios (expressing disproportional hyperproinsulinemia) may be associated with increasing beta cell dysfunction and more inefficient pro-insulin processing
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End point type |
Secondary
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End point timeframe |
Baseline, after 8 weeks Period 1 & Period 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Occurrence of pre-defined ECG findings during 4 days of continuous ECG monitoring at baseline and in the 8th week of Periods 1 and 2 | ||||||||||||||||||||||||||||||
End point description |
Number of Occurrence of pre-defined ECG findings during 4 days of continuous ECG monitoring at baseline and in the 8th week of Periods 1 and 2. ECG data were continuously recorded and analyzed over a period of 4 days simultaneously with continuous glucose monitoring. It assessed number of any Vertical Electric(al) Sounding (VES), number of 2 consecutive VES [couplets], and number of >3 consecutive VES [salves]
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End point type |
Secondary
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End point timeframe |
after 8 weeks Period 1 & Period 2
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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 |
Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
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Adverse event reporting additional description |
Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
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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 |
17.1
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Reporting groups
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Reporting group title |
Vildagliptin
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Reporting group description |
Vildagliptin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Total
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Reporting group description |
Total | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sitagliptin
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Reporting group description |
Sitagliptin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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03 Aug 2012 |
Amendment 1 The protocol was amended to include several clarifications related to the definition of the term "coronarogram", adverse event reporting and test meals. Furthermore, one exclusion criterion was removed due to new findings regarding the use of CGM in patients treated with anticoagulants. These changes were considered substantial and thus required IRB/IEC approval prior to implementation. |
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20 Nov 2012 |
Amendment 2 The protocol was amended to align the exclusion criteria regarding liver function with the current SmPC of vildagliptin, where liver function was determined via AST/ALT-values, but not via bilirubin. Additionally, accepted HbA1c values were lowered to 7.0 % to include patients with a moderate disease status as well. Furthermore, the number of center digits was adapted to be in accordance with the CRF. These changes were considered substantial and thus required IRB/IEC approval prior to implementation. |
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29 Oct 2013 |
Amendment 3 The protocol was amended with changes in inclusion criteria, including the insulin background medication and the patient's history of CV events. The rationale of the amendment was based on new study data showing that patients on an intensified conventional therapy may benefit from an additional DPP-4-inhibitor treatment. Thus, inclusion criterion No. 3 was modified to allow the additional inclusion of patients with stable ICT for at least 12 weeks prior to Visit 1. Moreover, the modification of inclusion criterion No. 6 regarding the CV history was modified to allow also the inclusion of fragile patients with at least 2 risk factors. This modification reflected a very important and relevant patient population, which is prominent in real-life clinical practice. Further, the section on study drug discontinuation was modified to clarify the need for study drug discontinuation, and to avoid unclarity in the study protocol. These changes were considered substantial and thus required IRB/IEC approval prior to implementation. |
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09 Jan 2014 |
Amendment 4 The protocol was amended to adapt the protocol according to the valid approval of the independent EC and health authorities, and to correct inconsistencies that were erroneously introduced with previous amendments. As per Amendment 3, ICT patients were additionally allowed to be enrolled and inclusion criterion No. 3 was modified Novartis accordingly but, erroneously, exclusion criterion No. 2.a was still not adjusted, thereby still precluding the enrollment of ICT patients by excluding the use of rapid- or short-acting insulin except in pre-mixed formulations with intermediate or long-acting insulin, and by excluding insulin administration more frequently than twice-daily. Therefore, also exclusion criterion 2.a was modified accordingly. Further, a typing error was corrected and the row "serum pregnancy test" in the schedule of assessments was corrected in order to reflect assessments defined in the section on pregnancy and assessments of fertility. Overall, the changes introduced with Amendment 4 were regarded as non-substantial. |
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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. | |||
| Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results. | |||
