Clinical Trial Results:
Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-Trial) – a phase III Study
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Summary
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EudraCT number |
2020-002581-14 |
Trial protocol |
AT |
Global end of trial date |
23 Jun 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Dec 2024
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First version publication date |
11 Dec 2024
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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 |
DvL-2020-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Medical University of Graz
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Sponsor organisation address |
Auenbruggerplatz 15, Graz, Austria,
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Public contact |
Dirk von Lewinski, Medical University of Graz, 43 316385 80684, dirk.von-lewinski@medunigraz.at
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Scientific contact |
Dirk von Lewinski, Department of Internal medicine, Division of Cardiology., 43 316385 80684, dirk.von-lewinski@medunigraz.at
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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 |
23 Jun 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 Jun 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Jun 2023
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective is to investigate the impact of ertugliflozin on ventricular arrhythmia burden.
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Protection of trial subjects |
The trial subjects were well informed about the treatment and its common side effects. Adverse reactions were immediately reported and treated according to the local practice. Fungal genital infections are the most common side effect of Ertugliflozin and subjects were informed about this and instructed on preventive measures. Ertugliflozin in combination with sulfonylurea or insulin might cause hypoglycemia, therefore subjects were instructed to reduce concomitant antihyperglycemic medication accordingly.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 Jan 2021
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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: 55
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Worldwide total number of subjects |
55
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EEA total number of subjects |
55
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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) |
27
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From 65 to 84 years |
28
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was conducted between June 24, 2021 (1st visit of 1st patient) and June 23, 2023 (last visit of last patient) and patients were recruited from eight Austrian sites. | ||||||||||||||||||
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Pre-assignment
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Screening details |
The patients with HFrEF/ HFmrEF and ICD and/or CRT therapy with >10 episodes of nsVT within the last 12 months were invited to participate in the study. After obtaining the informed consent, the willing participants were screened for further evaluation for the inclusion and exclusion criteria. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (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 | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ertugliflozin group | ||||||||||||||||||
Arm description |
The participants in this arm received ertugliflozin 5mg orally, once daily for 52 weeks | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Ertugliflozin
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Investigational medicinal product code |
SUB182716
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Other name |
Steglatro
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ertugliflozin is a sodium glucose co-transporter 2 (SGLT-2) inhibitor. The study dose is 5 mg orally, once daily in the morning, with or withour food, for 52 weeks.
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Arm title
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Placebo group | ||||||||||||||||||
Arm description |
The participants in this arm received placebo drug 5 mg orally, once daily for 52 weeks. | ||||||||||||||||||
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 |
Tablet
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Routes of administration |
Buccal use
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Dosage and administration details |
The subjects received 5mg of Placebo drug once daily orally for 52 weeks
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Baseline characteristics reporting groups
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Reporting group title |
Ertugliflozin group
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Reporting group description |
The participants in this arm received ertugliflozin 5mg orally, once daily for 52 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo group
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Reporting group description |
The participants in this arm received placebo drug 5 mg orally, once daily for 52 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Ertugliflozin group
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Reporting group description |
The participants in this arm received ertugliflozin 5mg orally, once daily for 52 weeks | ||
Reporting group title |
Placebo group
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Reporting group description |
The participants in this arm received placebo drug 5 mg orally, once daily for 52 weeks. | ||
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End point title |
Episodes of sustained ventricular tachycardia and ventricular fibrillation (sVT/VF) | |||||||||
End point description |
The primary end point is the difference in number of sVT/VF episodes in the ertugliflozin and placebo group from randomization to week 52.
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End point type |
Primary
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End point timeframe |
From randomization to week 52
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Statistical analysis title |
Negative binomial regression model | |||||||||
Statistical analysis description |
The negative binomial regression model was used to analyze primary outcome. The dependent variable was the number of sVT/VF episodes during the follow up and the independent variable was the treatment category. We adjusted the results for the baseline values of the parameter and the exposure duration. The sample size calculation was based on the formula by Zhu and Lakkis for comparing event rates of two negative binomial distributions.
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Comparison groups |
Ertugliflozin group v Placebo group
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||
P-value |
< 0.001 [2] | |||||||||
Method |
Negative binomial reression model | |||||||||
Parameter type |
Rate Ratio | |||||||||
Point estimate |
0.16
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.04 | |||||||||
upper limit |
0.61 | |||||||||
| Notes [1] - To mitigate the effect of few extreme values we performed prespecified sensitivity analysis using robust estimation approaches for the negative binomial model. The robust methods applied weights on the response variable by applying Tukeys biweight function on the Pearson residuals and/or using the robust Mahalanobis distance for co-variate weighting. Due to early termination of the trial we had a small sample size and a complete-case analysis was used. [2] - The yearly rate ratio, estimated from the negative binomial model, after adjusting for baseline sVT/VF episodes in the ertugliflozin group was less compared to placebo and this effect remained after adjustment for baseline NTproBNP levels. |
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End point title |
Number of nonsustained ventricular tachycardia episodes | |||||||||
End point description |
The difference in the number of non-sustained ventricular tachycardia episodes between the two groups from randomization to week 52.
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End point type |
Secondary
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End point timeframe |
Randomization to week 52
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of episodes of appropriate ICD therapies | |||||||||
End point description |
This represents the difference in the number of Implantable cardioverter-defibrillator therapies between the ertugliflozin and placebo group from randomization to week 52.
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End point type |
Secondary
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End point timeframe |
randomization to week 52
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change in NTproBNP levels | ||||||||||||
End point description |
The change in NTproBNP levels from randomization to week 52 in ertugliflozin and placebo groups.
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End point type |
Secondary
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End point timeframe |
randomization to week 52
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Statistical analysis title |
Multiple linear regression | ||||||||||||
Statistical analysis description |
The confidence interval was not adjusted for multiple comparisons as no plan to control for multiple comparisons was prespecified.
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Comparison groups |
Placebo group v Ertugliflozin group
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
> 0.05 [3] | ||||||||||||
Method |
Multiple linear regression model | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.17
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.35 | ||||||||||||
upper limit |
0.69 | ||||||||||||
| Notes [3] - Multiple linear regression for the change in level from baseline to week 52 in log-NTproBNP levels, adjusting for baseline level, was similar between the ertugliflozin and placebo groups. |
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End point title |
Change in HbA1c levels | ||||||||||||
End point description |
This represents the change in HbA1c levels from randomization to week 52 in the ertugliflozin and placebo groups.
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End point type |
Secondary
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End point timeframe |
Randomization to week 52.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of hospitalizations | ||||||||||||
End point description |
This variable represents the mean number of all-cause hospitalizations in each group.
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End point type |
Secondary
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End point timeframe |
Randomization to week 56
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Aleast one hospitalization due to heart failure | |||||||||
End point description |
This represents atleast one hospitalization due to heart failure in ertugliflozin and placebo groups.
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End point type |
Secondary
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End point timeframe |
Randomization to week 56
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of hospitalizations due to heart failure | |||||||||
End point description |
This represents the number of hospitalizations due to heart failure in the ertugliflozin and the placebo group.
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End point type |
Secondary
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End point timeframe |
Randomization to week 56
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| No statistical analyses for this end point | ||||||||||
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End point title |
Duration of hospital stay | ||||||||||||
End point description |
The average number of days of hospitalization in ertugliflozin and placebo group.
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End point type |
Secondary
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End point timeframe |
Randomization to week 56
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Cardiovascular death | |||||||||
End point description |
The total number of cardiovascular deaths in ertugliflozin and placebo group.
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End point type |
Secondary
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End point timeframe |
Randomization to week 56
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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 |
This study reported all serious (SAE) and non-serious adverse events (relevant for a reported SAE) and adverse events of special interest from randomization to week 56.
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Adverse event reporting additional description |
The study sites reported all SAE and non-serious AEs and adverse events of special interest by fax or other secure method using the FDA Safety information Form to the MSD Unique entry point immediately.
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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 |
21.0
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Reporting groups
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Reporting group title |
Ertugliflozin group
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Reporting group description |
This is the intervention group and 25 patients were initially enrolled in this group. They Received 5 mg of Ertugliflozin once daily orally from randomization to week 52. Among them, 3 withdrew their consent and 3 died with sufficient telemetric data. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo group
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Reporting group description |
This is the control group. They received 5 mg of Placebo drug once daily orally from randomization to week 52. Initially 30 patients were randomized to this group. Among them, 5 withdrew their consent and 3 died. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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11 Nov 2020 |
Addition of study sites (Wiener Neustadt and Medical University of Vienna) |
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11 Aug 2021 |
change of inclusion criterion ( at least 10 documented VT episodes (either nsVT or sVT +/- ICD treatment within the last 12 months |
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22 Dec 2021 |
Addition of new study site (St.Pölten) |
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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 early termination of the trial, we could not achieve the planned power. There is lack of generalizability as our study predominantly included White men. Additionally, 7 patients withdrew their consent. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/35045327 http://www.ncbi.nlm.nih.gov/pubmed/39217453 |
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