Clinical Trial Results:
Effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on left ventricular myocardial DYsfunction in patients with type 2 DiAbetes mellitus and concentric left ventricular geometry.
|
Summary
|
|
EudraCT number |
2014-004683-38 |
Trial protocol |
IT |
Global end of trial date |
01 Apr 2019
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
29 Nov 2021
|
First version publication date |
29 Nov 2021
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
G113
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02851745 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Fondazione per il Tuo cuore onlus
|
||
Sponsor organisation address |
Via La Marmora, 36, Florence, Italy, 50121
|
||
Public contact |
Centro Studi ANMCO, Fondazione per il Tuo cuore onlus, 0039 0555101359, centrostudi@anmco.it
|
||
Scientific contact |
Centro Studi ANMCO, Fondazione per il Tuo cuore onlus, 0039 0555101359, centrostudi@anmco.it
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
19 Jul 2019
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
01 Apr 2019
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
01 Apr 2019
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary objective of the study is to evaluate the effect of linagliptin 5 mg daily versus the corresponding placebo on the LV systolic function (measured by midwall shortening analysis) in patients with T2DM and a documented baseline concentric LV geometry and LV systolic dysfunction.
|
||
Protection of trial subjects |
The trial was conducted in accordance with the Helsinki Declaration and the International Council for Harmonisation (ICH) guidelines on Good Clinical Practice (GCP).
During the study were monitored pre-defined safety and tolerability end-points, all serious adverse events, the regular measurements of vital signs and laboratory parameters.
A specific surveillance was adopted on:
- symptomatic or severe hypoglycemia;
- severe pain in upper stomach spreading to back, nausea and vomiting, loss of appetite, fast heart rate (symptoms possibly related to pancreatitis);
- fever, sore throat, "runny nose", and headache with a severe blistering, peeling, and red skin rash
Specific attention was paid to patients at high risk, such as those are receiving insulin secretagogue and those with a history of pancreatitis.
|
||
Background therapy |
None | ||
Evidence for comparator |
None | ||
Actual start date of recruitment |
23 Jul 2015
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Italy: 188
|
||
Worldwide total number of subjects |
188
|
||
EEA total number of subjects |
188
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
57
|
||
From 65 to 84 years |
124
|
||
85 years and over |
7
|
||
|
||||||||||
|
Recruitment
|
||||||||||
Recruitment details |
DYDA 2 enrollment was initiated on 23 July 2015 and terminated on 26 April 2018. A total of 14 Italian centres participated in the project. The patients were followed-up for 48 weeks from random assignment. The follow-up was completed in April 2019 | |||||||||
|
Pre-assignment
|
||||||||||
Screening details |
Patients with LV hypertrophy diagnosed by an ECG and/or a history of concentric LV geometry diagnosed by standard ECHO was asked to give their consent to participate to the study and to perform a complete transthoracic ColorDoppler echocardiographic examination and an ECG in order to verify if they fulfill all the inclusion criteria. | |||||||||
|
Period 1
|
||||||||||
Period 1 title |
overall trial (overall period)
|
|||||||||
Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
|
|||||||||
Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Assessor | |||||||||
Blinding implementation details |
The randomization scheme was accessible only to data analyst in a semi-blinded fashion, until the time of the unblinding for the analysis of results. Within the randomization system, the randomization numbers will be used to link the patient identification number to the correct drug medication number on the treatment packs. Only when the study was completed, the data file verified, and the protocol violations determined the drug codes was broken and made available for data analyses.
|
|||||||||
|
Arms
|
||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||
|
Arm title
|
Linagliptin 5 mg | |||||||||
Arm description |
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Trajenta
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Film-coated tablet
|
|||||||||
Routes of administration |
Oral use
|
|||||||||
Dosage and administration details |
Linagliptin 5 mg was taken orally once daily.
|
|||||||||
|
Arm title
|
Placebo | |||||||||
Arm description |
Matching placebo tablets | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Film-coated tablet
|
|||||||||
Routes of administration |
Oral use
|
|||||||||
Dosage and administration details |
Placebo was taken orally once daily. Placebo tablets was of identical appearance to those of the active drug.
|
|||||||||
|
||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Linagliptin 5 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Matching placebo tablets | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Linagliptin 5 mg
|
||
Reporting group description |
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide. | ||
Reporting group title |
Placebo
|
||
Reporting group description |
Matching placebo tablets | ||
|
|||||||||||||
End point title |
Change in MFS from baseline to 48-weeks | ||||||||||||
End point description |
The primary hypothesis to be investigated is whether linagliptin is superior to placebo in terms of improvement in LV systolic function using the midwall shortening as the primary efficacy variable.
The treatment effect on the echocardiographic measurements was tested by one-way ANOVA on the intra-subjects difference between basal and end of treatment response (48 weeks) using treatment group as factor and basal response as covariate.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Changes from baseline to 48-weeks of LV systolic function measured by midwall shortening analysis (MFS).
|
||||||||||||
|
|||||||||||||
Attachments |
Change in MFS |
||||||||||||
Statistical analysis title |
Change in MFS from baseline to 48-weeks | ||||||||||||
Statistical analysis description |
The primary efficacy variable is the modification of midwall shortening (MFS). This was calculated for each surviving patient as the difference between the final echocardiographic measures and those done at randomization. The treatment effect on the echocardiographic measurements was tested by one-way ANOVA on the intra-subjects difference between basal and end of treatment response using treatment group as factor and basal response as covariate.
|
||||||||||||
Comparison groups |
Placebo v Linagliptin 5 mg
|
||||||||||||
Number of subjects included in analysis |
174
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.86 [1] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [1] - Criteria for efficacy: Linagliptin considered superior to placebo if the difference between the treatment arms is statistically significant in favor of linagliptin using a two-sided p level ≤0.05 |
|||||||||||||
|
|||||||||||||
End point title |
Change in mitral annular systolic velocity from baseline to 48-weeks | ||||||||||||
End point description |
The treatment effect on the echocardiographic measurements was tested by one-way ANOVA on the intra-subjects difference between basal and end of treatment response (48 weeks) using treatment group as factor and basal response as covariate.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Changes from baseline to 48 weeks in the longitudinal component of LVSF measured by tissue Doppler technique (peak systolic velocity of S′ wave of mitral annulus).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Change in mitral annular systolic velocity | ||||||||||||
Statistical analysis description |
The change was calculated for each surviving patient as the difference between the final echocardiographic measures and those done at randomization. The treatment effect on the echocardiographic measurements was tested by one-way ANOVA on the intra-subjects difference between basal and end of treatment response using treatment group as factor and basal response as covariate.
|
||||||||||||
Comparison groups |
Linagliptin 5 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
158
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.12 [2] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [2] - Criteria for efficacy: Linagliptin considered superior to placebo if the difference between the treatment arms is statistically significant in favor of linagliptin using a two-sided p level ≤0.05 |
|||||||||||||
|
|||||||||||||
End point title |
Improvement in S' from baseline to 48-weeks | ||||||||||||
End point description |
patients who significantly improved the LV longitudinal component of systolic function (improvement in S' >25% from baseline)
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From baseline to 48-weeks
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
S' improvement >25% | ||||||||||||
Statistical analysis description |
Incidence of patients who had an improvement in S′ > 25% from baseline
|
||||||||||||
Comparison groups |
Linagliptin 5 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
158
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.65 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Diastolic LV function | ||||||||||||
End point description |
Patients with normalization of diastolic LV function at end follow-up (48 weeks).
Diastolic disfunction (DD) was defined as follows:
E/A ratio of transmitral flow <0.75 or E/A>1.50
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From enrollment to 48-weeks
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Normalization of diastolic function | ||||||||||||
Statistical analysis description |
Incidence of patients with normalization of diastolic LV function (patients with diastolic disfunction at baseline and without diastolic disfunction at end of study, 48-weeks).
Diastolic disfunction (DD) was defined as: E/A ratio of transmitral flow <0.75 or E/A>1.50
|
||||||||||||
Comparison groups |
Placebo v Linagliptin 5 mg
|
||||||||||||
Number of subjects included in analysis |
174
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.89 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the randomization to 4 weeks after the study treatment (lingliptin/placebo) discontinuation at the final visit (48 weeks).
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All SAEs was monitored through the data collected in the CRFs based on information provided by the patient at each visit. Other AEs not considered serious was only recorded if they are suspected to be related to study treatment (ADRs) or leading to drug discontinuation.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14.1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Linagliptin 5mg
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
06 Mar 2015 |
The amendment has been prepared following a note from AIFA requiring to detail in the protocol the contexts in which the researcher should have evaluated the discontinuation of the treatment |
||
03 Mar 2017 |
This is a substantial amendment made necessary by a modification of the originally submitted CTA form. The clinical trial medicinal product undergoes a change in primary packaging (from blister to vial). |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/33755143 |
|||
