Clinical Trial Results:
GLUTAmate for Metabolic Intervention in Coronary Surgery II
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Summary
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EudraCT number |
2011-006241-15 |
Trial protocol |
SE |
Global end of trial date |
30 Sep 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Jun 2024
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First version publication date |
06 Jun 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 |
GLUTAMICS2
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02592824 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Region Östergötland
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Sponsor organisation address |
Linköping University Hospital, Linköping, Sweden, SE58185
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Public contact |
Dept Cardiothoracic Surgery, Linköping University Hospital, 46 101034825, rolf.svedjeholm@liu.se
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Scientific contact |
Dept Cardiothoracic Surgery, Linköping University Hospital, 46 101034825, rolf.svedjeholm@liu.se
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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 |
28 May 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Sep 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Sep 2020
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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 aim was to confirm that intravenous glutamate infusion reduces the risk of postoperative heart failure in patients undergoing CABG by demonstrating mitigated increase of NT-proBNP, a biomarker for heart failure, postoperatively.
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Protection of trial subjects |
The Swedish Patient Insurance
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Nov 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 |
Sweden: 314
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Worldwide total number of subjects |
314
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EEA total number of subjects |
314
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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) |
31
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From 65 to 84 years |
283
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were eligible for the study if they had been accepted for on-pump CABG +/- additional procedure, due to at least two vessel disease or left main stenosis. Moreover, patients had to be at moderate- to high risk of postoperative heart failure because of LVEF <= 0.30 or EuroSCORE >=3.0 with a cardiac or procedure-related risk factor. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Screening was done by the clinical investigators at four academic Cardiac Surgery Centers in Sweden. | ||||||||||||||||||
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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, Monitor, Carer | ||||||||||||||||||
Blinding implementation details |
Patients, staff, and investigators were blinded to the infused treatment (clear transparent solutions). Allocation was concealed until the study was terminated by keeping the randomization codes at APL, Sweden. For safety reasons, the sponsor had access to sealed opaque envelopes to permit intervention to be revealed in cases of SUSAR, mortality, or stroke within 24 hours of surgery. The external monitoring team checked all envelopes at the end of the study.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Intravenous Glutamate infusion | ||||||||||||||||||
Arm description |
Intravenous infusion of a 0.125M L-glutamic acid solution or saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After unclamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused. The maximum volume infused to any patient was 500 mL of study solution. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
L-glutamic acid
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Blinded intravenous infusion of either a 0.125M L-glutamic acid solution or saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After declamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused.
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Investigational medicinal product name |
Saline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Blinded intravenous infusion of either a 0.125M L-glutamic acid solution or saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After declamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused.
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Arm title
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Intravenous Saline infusion (Placebo) | ||||||||||||||||||
Arm description |
Intravenous infusion of saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After unclamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused. The maximum volume infused to any patient was 500 mL of study solution. | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Saline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Blinded intravenous infusion of either a 0.125M L-glutamic acid solution or saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After declamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused.
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Baseline characteristics reporting groups
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Reporting group title |
Intravenous Glutamate infusion
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Reporting group description |
Intravenous infusion of a 0.125M L-glutamic acid solution or saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After unclamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused. The maximum volume infused to any patient was 500 mL of study solution. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Intravenous Saline infusion (Placebo)
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Reporting group description |
Intravenous infusion of saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After unclamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused. The maximum volume infused to any patient was 500 mL of study solution. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Intravenous Glutamate infusion
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Reporting group description |
Intravenous infusion of a 0.125M L-glutamic acid solution or saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After unclamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused. The maximum volume infused to any patient was 500 mL of study solution. | ||
Reporting group title |
Intravenous Saline infusion (Placebo)
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Reporting group description |
Intravenous infusion of saline, at a rate of 1.65 mL/ kg body weight /h. The infusion was started 10-20 min before the anticipated release of the aortic cross-clamp. After unclamping the infusion was continued for another 2 h, then the infusion rate was halved, and an additional 50 mL was infused. The maximum volume infused to any patient was 500 mL of study solution. | ||
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End point title |
Postoperative increase of plasma NT-proBNP | ||||||||||||
End point description |
Plasma NT-proBNP reflects the degree of myocardial dysfunction
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End point type |
Primary
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End point timeframe |
Podstoperative increase of plasma NT-proBNP from the preoperative day to postoperative day 3
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| Notes [1] - Seven patients excluded. Sampling for NT-proBNP missed in 3 patients on postop day 3 [2] - Four patients excluded. Sampling for BT-proBNP missed in 5 patients on postop day 3. |
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Statistical analysis title |
Primary endpoint | ||||||||||||
Statistical analysis description |
Two-sided Student’s t-test was used. Levene’s test was used for this analysis
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Comparison groups |
Intravenous Glutamate infusion v Intravenous Saline infusion (Placebo)
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Number of subjects included in analysis |
295
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.09 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Postoperative mortality | |||||||||
End point description |
Safety endpoint
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End point type |
Other pre-specified
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End point timeframe |
Postoperative mortality within 30 days of surgery
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Statistical analysis title |
Postoperative mortality | |||||||||
Statistical analysis description |
Postoperative mortality within 30 days
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Comparison groups |
Intravenous Glutamate infusion v Intravenous Saline infusion (Placebo)
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Number of subjects included in analysis |
306
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | |||||||||
P-value |
= 0.12 [4] | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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| Notes [3] - Safety endpoint [4] - Fisher exact test, two-tailed |
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End point title |
Postoperative stroke < 24 hours | |||||||||
End point description |
Safety endpoint
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End point type |
Other pre-specified
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End point timeframe |
Postoperative stroke < 24 hours of surgery
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| Notes [5] - 5 patients did not receive the infusion because of intraoperative exclusion criteria [6] - 3 patients did not receive the infusion because of intraoperative exclusion criteria |
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Statistical analysis title |
Posotperative stroke < 24 hours of surgery | |||||||||
Statistical analysis description |
Fisher exact test, two-tailed
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Comparison groups |
Intravenous Glutamate infusion v Intravenous Saline infusion (Placebo)
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Number of subjects included in analysis |
306
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Analysis specification |
Pre-specified
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Analysis type |
other [7] | |||||||||
P-value |
= 0.12 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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| Notes [7] - Safety analysis |
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End point title |
SUSAR | |||||||||
End point description |
Safety endpoint
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End point type |
Other pre-specified
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End point timeframe |
SUSAR during the first postoperative day
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| Notes [8] - 5 patients did not receive the infusion because of intraoperative exclusion criteria [9] - 3 patients did not receive the infusion because of intraoperative exclusion criteria |
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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 were recorded within 30 days after cardiac surgery
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Adverse event reporting additional description |
Safety endpoints postop mortality, stroke < 24 h of surgery, and SUSAR are presented in the endpoints section.
Adverse events directly related to glutamate infusion were not detected. Adverse events typical to cardiac surgery did not differ significantly between study groups. DOI 10.1371/journal.pmed.1003997
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
according to GCP | |||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Intravenous Glutamate infusion
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Reporting group description |
SAE includes postoperative mortality, stroke, postoperative heart failure, acute kidney injury, reoperation for bleeding or infection, and all other AE resulting in hospital stay longer than 7 days. Atrial fibrillation for instance can be both SAE and AE. | |||||||||||||||||||||||||||||||||
Reporting group title |
Intravenous Saline infusion (Placebo)
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Reporting group description |
SAE includes postoperative mortality, stroke, postoperative heart failure, acute kidney injury, reoperation for bleeding or infection, and all other AE resulting in hospital stay longer than 7 days. Atrial fibrillation for instance can be both SAE and AE. | |||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||
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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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10 Sep 2015 |
The planned sample size was reduced from 1400 patients to 310 patients. The initial protocol was based on clinical endpoints for postoperative heart failure, which required a larger sample size. Due to insufficient funding, the clinical endpoints were replaced by NT-proBNP, a biomarker of myocardial dysfunction*. Sample size estimation suggested a total of 310 patients to be sufficient.
*The rise in postoperative NT-proBNP is reported to be associated with postoperative heart failure, morbidity, and mortality. In addition, a good agreement was found between the hemodynamic and clinical criteria used for postoperative heart failure in the first GLUTAMICS trial and postoperative NT-proBNP levels.
Two sites and three new investigators were added. |
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20 Nov 2015 |
Cardiac and procedure-related risk factors required for EuroSCORE II >= 3.0 were specified. Left ventricular ejection fraction <= 0.30 added to inclusion criteria. A new center and a new investigator were added. |
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05 Sep 2016 |
Exclusion criteria were modified. Inotropic treatment before surgery is not an exclusion criterion if given preemptively.
A new site and two new investigators were added. |
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21 Sep 2017 |
The shelf life of study solutions was extended and the infusion bottles were relabeled following pharmaceutical quality control as required by the Swedish MPA. |
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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. | |||
| The proportion of patients with diabetes had almost doubled to 47% compared with the first GLUTAMICS trial. Gutamate does not benefit diabetic hearts, due to downregulation of mitochondrial glutamate transporter EAAT1. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/35533197 http://www.ncbi.nlm.nih.gov/pubmed/37657522 http://www.ncbi.nlm.nih.gov/pubmed/38252440 http://www.ncbi.nlm.nih.gov/pubmed/37365871 |
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