Clinical Trial Results:
Impact of empagliflozin on left ventricular functions: a single center, phase III, randomized, open-label, active treatment-controlled, parallel study in patients with type 2 diabetes and normal left ventricular function
|
Summary
|
|
EudraCT number |
2016-002225-10 |
Trial protocol |
IT |
Global end of trial date |
27 Sep 2021
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
19 Jun 2022
|
First version publication date |
19 Jun 2022
|
Other versions |
|
Summary report(s) |
table 1 table 2 table 3 figure 1 supplemental figure 1 supplemental table 1 supplemental table 2 supplemental table 3 supplemental table 4 complete report |
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 |
EMPA-HEART
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Azienda Ospedaliero Universitaria Pisana
|
||
Sponsor organisation address |
Via Savi, 10, Pisa, Italy, 56100
|
||
Public contact |
andrea.natali@unipi.it, Azienda Ospedaliero Universitaria Pisana, andrea.natali@unipi.it
|
||
Scientific contact |
andrea.natali@unipi.it, Azienda Ospedaliero Universitaria Pisana, +39 3471045488, andrea.natali@unipi.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 |
12 Dec 2021
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
27 Sep 2021
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To verify whether, in type 2 diabetic patients with normal 2-D ejection fraction (>50%) and without inducible myocardial ischemia at the cardiopulmonary test, the treatment with empagliflozin is associated with an improvement in left ventricular systolic function, as measured by global lungitudinal strain (GLS) through speckle tracking echography, in comparison to sitagliptin, an equally effective plasma glucose lowering agent, presumably neutral on cardiac function
|
||
Protection of trial subjects |
The study will be carried out in accordance with the most recent international GCP guidelines (CPMP/ICH/135/1995), EU Directive and guidance and the local legislation on the conduct of clinical trials.
Before enrolment in the study, every participant will receive detailed information about study procedures, risks, and benefits, from the staff of the study and he/she will be given all the necessary time to ask any question about the study. The informed consent form, as well as the form for the general practitioner will be given to the participant (see attached files). The informed consent form will be signed during the screening visit, after having checked the eligibility criteria, and a 6-digit PatientID code will be assigned to each patient by the study staff, as the first two letters of the name + the first two letters of surname + a two-digit progressive number from 01 to 75. The enrolment list, including name and surname of the patients, together with the PatientID code, will be stored in the Clinical trial office of Laboratory of nutrition, diabetes and atherosclerosis of the Department of Clinical and Experimental Medicine (Building 43 - Santa chiara Hospital) under the responsibility of Prof. Andrea Natali.
|
||
Background therapy |
Allowed background therapy is stable hypoglycemic therapy since three months with: 1. Metformin 2. Metformin + basal insulin and assuming stable cardio-active therapies since three months (anti-hypertensive drugs, diuretics, drugs for asthma, drugs for migraine). Patients assuming any other hypoglycemic therapy and those who received any investigational new drug within the last 12 weeks will be excluded from the study. With the exception of those drugs listed among non-permitted medications, participants will be allowed to use any concomitant medication necessary for the treatment of pre-existing concomitant pathologies or intercurrent diseases. However, it is recommended that concomitant chronic medication for underlying diseases are given at constant dose for at least 4 weeks prior to entry in the study and for the entire study duration. All medications taken for any reason (including those taken for intercurrent diseases) must be recorded in the appropriate section of the case report form (CRF). The initiation of treatment or changes in dosage of the following medications is not permitted during the total study period. If this occurs at any time during the study it constitutes a protocol violation and it necessitates the discontinuation of the patient from the study. Any glucose lowering drugs in addition to those included in the present protocol; Any change in metformin or insulin dose greater than 20% with respect to the entry dosage; Any drug able to interfere with cardiac function (i.e. beta blockers, ACE inhibitors, calcium antagonists, alpha blockers, diuretics, theophylline, thyroid hormones) Any drug with potential interference with treatment (cyclosporine, digoxine). The treatment with the following drugs in the 7 days preceding the primary or secondary outcome assessments: Any drug able to interfere with inflammation when assumed systemically (NSAID, steroids, any other immune suppressors-modulator) | ||
Evidence for comparator |
Sitagliptin 100 mg/die was chosen as an active comparator because of its similar potency to empagliflozin in terms of glucose control and, on the bases of large clinical trials, does not influence the risk of developing HF (ref 1). The recent evidence of the PROLOGUE trial (Yamada), showing that sitagliptin is able to prevent the time-related deterioration of diastolic function, raises the possibility that our comparator is not completely neutral on cardiac function. However, this effect was evident after 12, but not after 6 months of treatment and sitagliptin has been shown to be neutral on systolic function in patients with post-ischemic heart failure with mildly reduced ejection fraction [ref 2]. Therefore, there will be, if any, a small risk of type 2 error, which we consider acceptable and eventually would, in case, reinforce any observed positive outcome of empagliflozin. References 1. Green JB, Bethel MA, Armstrong PW, et al. (2015) Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 373: 232-242 2. Yamada H, Tanaka A, Kusunose K, et al. (2017) Effect of sitagliptin on the echocardiographic parameters of left ventricular diastolic function in patients with type 2 diabetes: a subgroup analysis of the PROLOGUE study. Cardiovasc Diabetol 16: 63 | ||
Actual start date of recruitment |
01 Sep 2016
|
||
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: 56
|
||
Worldwide total number of subjects |
56
|
||
EEA total number of subjects |
56
|
||
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) |
28
|
||
From 65 to 84 years |
28
|
||
85 years and over |
0
|
||
|
||||||||||||||||||||||
|
Recruitment
|
||||||||||||||||||||||
Recruitment details |
Volunteers will be recruited among patients attending visits at the Diabetes Outpatient Unit of UO Medicina Interna 1 (AOUP), according to the following inclusion /exclusion criteria: 5.1. Inclusion criteria: Male of female patients affected by type 2 diabetes mellitus (T2DM) Subjects aged >40 and <80 years HbA1c levels ≥53 and ≤ 69 mmol/mo | |||||||||||||||||||||
|
Pre-assignment
|
||||||||||||||||||||||
Screening details |
Male of female patients affected by type 2 diabetes mellitus (T2DM) | |||||||||||||||||||||
|
Period 1
|
||||||||||||||||||||||
Period 1 title |
overall trial (overall period)
|
|||||||||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||
Blinding used |
Not blinded | |||||||||||||||||||||
Blinding implementation details |
In order to prevent any influence of the researcher expectations (type 1 error) we will take care that the cardiologist performing the primary and several of the secondary outcome variables measurements are blind with respect to the treatment allocation.
|
|||||||||||||||||||||
|
Arms
|
||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||
|
Arm title
|
empagliflozin | |||||||||||||||||||||
Arm description |
experimental arm | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Jardiance
|
|||||||||||||||||||||
Investigational medicinal product code |
A10BK03
|
|||||||||||||||||||||
Other name |
Jardiance
|
|||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||
Dosage and administration details |
Empagliflozin 10 mg/die
|
|||||||||||||||||||||
|
Arm title
|
sitagliptin | |||||||||||||||||||||
Arm description |
active comparator | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Januvia
|
|||||||||||||||||||||
Investigational medicinal product code |
A10BH01
|
|||||||||||||||||||||
Other name |
Januvia, Sitagliptin
|
|||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||
Dosage and administration details |
Sitagliptin 100 mg/die
|
|||||||||||||||||||||
|
||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
empagliflozin
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
experimental arm | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
sitagliptin
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
active comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
empagliflozin
|
||
Reporting group description |
experimental arm | ||
Reporting group title |
sitagliptin
|
||
Reporting group description |
active comparator | ||
|
|||||||||||||
End point title |
Primary objective | ||||||||||||
End point description |
The primary aim is to verify whether, in type 2 diabetic patients with normal 2-D ejection fraction (≥50%) and without inducible myocardial ischemia at the cardiopulmonary test, the treatment with empagliflozin is associated with an improvement in left ventricular systolic function, as measured by global lungitudinal strain (GLS) through speckle tracking echography, in comparison to sitagliptin, an equally effective plasma glucose lowering agent, presumably neutral on cardiac function.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
2
|
||||||||||||
|
|||||||||||||
| Notes [1] - 22 [2] - 22 |
|||||||||||||
Statistical analysis title |
Statistical analysis | ||||||||||||
Statistical analysis description |
In an MANOVA design for three repeated measures (baseline, 1 month, 6 months) the power of the study to detect a difference between the treatments of 2.5% or 1.7% is 0.98 and 0.80, respectively. In an ANCOVA design with 4 covariates a sample size of 60 subjects will have the power of 0.71 to detect an effect of 0.10 (expressed as of proportion of variance explained by the effect under consideration), which is commonly considered small in biostatistics and a power of 0.99 to detect a medium effec
|
||||||||||||
Comparison groups |
empagliflozin v sitagliptin
|
||||||||||||
Number of subjects included in analysis |
44
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [3] | ||||||||||||
P-value |
< 0.05 [4] | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
90
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
90 | ||||||||||||
upper limit |
100 | ||||||||||||
Variability estimate |
Standard deviation
|
||||||||||||
Dispersion value |
2
|
||||||||||||
| Notes [3] - In an MANOVA design for three repeated measures (baseline, 1 month, 6 months) the power of the study to detect a difference between the treatments of 2.5% or 1.7% is 0.98 and 0.80, respectively. In an ANCOVA design with 4 covariates a sample size of 60 subjects will have the power of 0.71 to detect an effect of 0.10 (expressed as of proportion of variance explained by the effect under consideration), which is commonly considered small in biostatistics and a power of 0.99 to detect a medium effec [4] - significant |
|||||||||||||
|
|||||||||||||
End point title |
Secondary objectives | ||||||||||||
End point description |
To assess the effects of the two treatments on the following parameters:
Changes from baseline at 6 months after treatment initiation in HbA1c;
Changes from baseline at 1 and 6 months after treatment initiation in other well established parameters of cardiac function, such as 3-D ejection fraction, left atrial volume, and E/E'.
Changes from baseline at 6 months after treatment initiation in VO2 max (Cardiopulmonary exercise test), an extremely clinically relevant parameter that will help in appreciating the relevance of the imaging data.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
2
|
||||||||||||
|
|||||||||||||
| Notes [5] - 22 [6] - 22 |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
exploratory objectives | ||||||||||||
End point description |
Given the exploratory nature of the study, we will verify the following hypothesis:
Whether changes from baseline at 6 months after treatment initiation in plasma markers of myocyte strain (BNP, NT-proBNP, proadrenomedullin), inflammation/oxidative stress (hsCRP, TNF-a, myeloperoxydase, uric acid), matrix remodeling (procollagen type III) and myocyte injury (Troponin T) help understanding the mechanisms of action through which the treatments exert their effect/s on the heart.
Whether changes from baseline at 6 months after treatment initiation in cardiac autonomic function score (based on RR changes with Valsalva, deep breathing, standing-to-laying) contribute to the mechanisms of action of the treatments.
Whether the effects of the treatments differ in the subgroup of patients whom at baseline have mild abnormalities in cardiac systolic function or abnormal values of plasma biomarkers or abnormal cardiac autonomic function tests.
Whether the changes in cardiac function a
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
2
|
||||||||||||
|
|||||||||||||
| Notes [7] - 22 [8] - 22 |
|||||||||||||
Statistical analysis title |
Statistical analysis | ||||||||||||
Statistical analysis description |
2-sided, per protocol population (PPP), no interim analysis
|
||||||||||||
Comparison groups |
empagliflozin v sitagliptin
|
||||||||||||
Number of subjects included in analysis |
44
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [9] | ||||||||||||
P-value |
< 0.05 [10] | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
100
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
90 | ||||||||||||
upper limit |
100 | ||||||||||||
Variability estimate |
Standard deviation
|
||||||||||||
Dispersion value |
2
|
||||||||||||
| Notes [9] - 2-sided, per protocol population (PPP), no interim analysis [10] - significant |
|||||||||||||
|
|||||||||||||||||
|
Adverse events information
|
|||||||||||||||||
Timeframe for reporting adverse events |
6 months
|
||||||||||||||||
Adverse event reporting additional description |
No patient developed serious adverse events (SAEs) and/or serious adverse drug reactions (SARs) with either sitagliptin or empagliflozin.
• No patient experienced Unexpected Adverse Reactions (UARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs)
• No death was recorded during the study period and during the 30 days following the end
|
||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||
Dictionary version |
25.0
|
||||||||||||||||
|
Reporting groups
|
|||||||||||||||||
Reporting group title |
Empagliflozin
|
||||||||||||||||
Reporting group description |
Infective balanopostitis | ||||||||||||||||
|
|||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||
|
|||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
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 | |||
