Dexamethasone, olanzapine, hemodynamics, and ventilation in cardiac surgery (GLORIOUSII)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

10 Nov 2022 → ongoing

Decision date (initial)

2024-10-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Snedkermester Sophus Jacobsen og hustru Astrid Jacobsens Fond’ through The Danish Heart Foundation · The Danish Heart Foundation · Else og Svend Madsens legat · Grosserer L. F. Foghts Fond

External identifiers

EU CT number

2024-515998-94-00

EudraCT number

2021-005618-32

ClinicalTrials.gov

NCT05635227

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective of this trial is to determine the efficacy of dexamethasone compared with placebo on the primary endpoint days alive outside hospital within 90 days in adult subjects undergoing elective or subacute isolated CABG, isolated AVR, or CABG plus any concomitant valve surgery. The coprimary objectives are to determine the efficacy of olanzapine versus placebo administered preoperatively, the efficacy of flow-targeted versus pressure-targeted hemodynamic management during CPB, and the efficacy of low tidal volume ventilation versus no ventilation during CPB, on the endpoint days alive outside hospital within 90 days in adult subjects undergoing elective or subacute isolated CABG, isolated AVR, or CABG plus any concomitant valve surgery.

Secondary objectives 2

1. The secondary objectives of this trial are to determine the efficacy of the interventions on mortality as well as morbidity assessed by either manifest organ damage or by surrogate markers (ex. biomarkers) of organ damage.
2. A pre-defined substudy is planned. All trial participants from one site (Rigshospitalet) will participate in the substudy. All relevant data will be collected as part of the primary trial eCRF, and accordingly, the substudy will not include any other investigations or interventions than the primary trial. Cardiac CT is a relatively new modality, and at present it is XML File Identifier: QeeuDx53gYvIO861uX0Tfm6VnPo= Page 14/25 not routinely being applied after open heart surgery. Standardized cardiac CT images will enable us to investigate a number of unanswered research questions involving graft patency, myocardial resting perfusion, and ventricular function. Specifically, this substudy will use the cardiac CT images to investigate the following: 1. Graft patency after three months, assessed by cardiac CT. 2. Predictors of graft patency after three months, assessed by cardiac CT 3. Associations between myocardial resting perfusion, graft patency and outcomes 4. Predictors of left and right ventricular function three months after surgery, assessed by cardiac CT Descriptive statistics as well as generalized linear models will be applied to investigate predictors of graft patency, ventricular function and associations between myocardial resting perfusion, graft patency, and outcomes.

Conditions and MedDRA coding

We investigate the efficacy of two pharmaceutical interventions for reducing mortality and organ damage, and shortening length of hospital stay in patients undergoing heart surgery (i.e. coronary artery bypass grafting and/or heart valve replacement).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Adult, i.e., above 18 years of age
2. Scheduled for CABG and/or AVR, irrespective of other concomitant valve surgery.

Exclusion criteria 20

1. Acute surgery (i.e. off hours surgery)
2. Recipient of any major organ transplant
3. Obstructive hypertrophic cardiomyopathy, active myocarditis, constrictive pericarditis, untreated hypothyroidism or hyperthyroidism
4. Having received cytotoxic/cytostatic chemotherapy or radiation therapy for treatment of malignancy within the last 6 months
5. Clinical evidence of current malignancy except for basal or localized squamous cell carcinoma, cervical intraepithelial neoplasia or stable prostate cancer.
6. Known narrow-angle glaucoma
7. Known phenylketonuria
8. Pregnancy or currently breastfeeding
9. Known endocarditis at time of screening
10. Previous participation in the trial
11. Active infection, including bacterial, viral, and/or fungal infection
12. Known hepatic cirrhosis
13. Known severe thrombocytopenia with thrombocyte levels < 50 x 109/L
14. Known severe neutropenia with neutrocyte levels < 2 x 109/L
15. On the waiting list for a heart transplant
16. Type I diabetes
17. Known long QT syndrome
18. Known allergy for any of the included study drugs
19. Any condition, where participation in the study, in the investigator's opinion could put the subject at risk, confound the study results or interfere significantly with participation in the study
20. Patients with extracardiac arteriopathy (assessed as part of the preoperative EuroSCORE) will be excluded from the intervention 'flowtargeted vs. pressure-targeted hemodynamic management during CPB'.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be number of days alive and outside hospital within 90 days after surgery.

Secondary endpoints 6

1. Time in days to occurrence of any component in a composite secondary endpoint during follow-up: a) Death from any cause, b) Stroke, c) Acute kidney injury or d) New onset or worsening heart failure
2. Severe post-operative complications during index admission, defined as a Clavien-Dindo class of 3 to 5.
3. Delirium during the first 7 days after surgery, defined as a positive Confusion Assessment Method for the ICU (CAM-ICU) score or a positive Confusion Assessment Method (CAM) score for the general wards
4. Quality of Recovery-15 (QoR-15) score 3 days, or as soon as possible, after surgery
5. 90-day outcomes: Survival, Change in modified Rankin Scale (mRS) from baseline, Health-related quality of life (EQ-5D-5L), Change in self-perceived function "two simple questions" and Days alive outside ICU
6. 180-day outcomes: Survival

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Christian Hingstrup Hassager

Public contact point

Organisation

Rigshospitalet

Contact name

Christian Hingstrup Hassager

Third parties 3

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications