Clinical trial NCT06650501: Dabigatran for the Adjunctive Treatment of Staphylococcus Aureus Bacteremia
Official title: Dabigatran for the Adjunctive Treatment of Staphylococcus Aureus Bacteremia: the DABI-SNAP Nested Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Staphylococcus Aureus Endocarditis
Staphylococcus Aureus Septicemia
Staphylococcus Aureus Bacteremia
Staphylococcus Aureus Bloodstream Infection
S. Aureus Bacteremia
S. Aureus Bloodstream Infection
Keywords: S. aureus bacteremia
S. aureus bloodstream infection
S. aureus endocarditis
Dabigatran
Edoxaban
Rivaroxaban
Apixaban
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
Collaborators: name: University of Melbourne
First posted: 2024-10-21
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an open-label randomized controlled trial which will enroll patients with S. aureus bacteremia who are already taking oral anticoagulant medications (apixaban, edoxaban, or rivaroxaban) for an approved indication (stroke prevention in atrial fibrillation, prevention or treatment of venous thromboembolism). We will randomize patients to continue their existing medication or change to another medication (dabigatran) which is approved for the original indication.

Dabigatran is approved in many countries for the treatment or prevention of venous thromboembolism or preventing stroke in atrial fibrillation. Unlike the other medications listed above, dabigatran seems to have activity against S. aureus in the test tube, in animal models, and in a smaller randomized controlled trial. We wish to determine if changing to dabigratran will improve outcomes in S. aureus bacteremia in people who otherwise would have a reason to be taking it.

This study is an approved sub-study of The Staphylococcus aureus Network Adaptive Platform (SNAP) trial (NCT05137119).

If positive, this study will support a second RCT in people who do not currently have an indication for anticoagulation.


Eligibility criteria: The participant must meet all inclusion and exclusion criteria for the SNAP Platform (NCT05137119) and also the following inclusion and exclusion criteria:

Inclusion Criteria:

* Patient is taking an oral Xa inhibitor for: stroke prevention in atrial fibrillation, treatment or secondary prevention of deep venous thrombosis or pulmonary embolism, prevention of VTE in patients who have undergone elective total hip or total knee replacement surgery provided there are 30 or more days of planned treatment remaining at the time of enrolment.

Exclusion Criteria:

* Active bleeding (allowing up to 5 days from the index blood culture to randomize in the event anti-thrombotic therapy is resumed)
* Anticipated major cardiac surgery, neurosurgery, or spine surgery within the next 3 days
* Pregnancy
* Known use of dabigatran within last month
* Allergy to dabigatran
* Concomitant use of amiodarone, ketoconazole, rifampin, verapamil, clopidogrel, prasugrel, or ticagrelor
* eGFR \< 30mL/minute calculated by Cockcroft-Gault equation using adjusted weight \[if acute kidney injury can allow for up to 5 days from index blood culture to allow for recovery\]
* Off label use (e.g., metallic mechanical heart valve, left ventricular thrombus, antiphospholipid antibody syndrome)

Primary outcomes:
measure: Desirability of Outcome Ranking (DOOR)
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
Secondary outcomes:
measure: Clinical failure
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
measure: Serious Adverse Event or Adverse Event Leading to Discontinuation
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
measure: All cause mortality
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
measure: Infectious Complications
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
measure: Clinically relevant major bleeding
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
measure: Clinically relevant venous thromboembolic events
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
measure: Clinically relevant stroke
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
measure: Clinically relevant acute myocardial infarction
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
measure: Clinically relevant arterial thromboembolic event
timeFrame: Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119)
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital)
state: Quebec
Study officials:
affiliation: Research Institute of the McGill University Health Centre
name: Emily G McDonald, MD MSC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lerche CJ, Christophersen LJ, Goetze JP, Nielsen PR, Thomsen K, Enevold C, Hoiby N, Jensen PO, Bundgaard H, Moser C. Adjunctive dabigatran therapy improves outcome of experimental left-sided Staphylococcus aureus endocarditis. PLoS One. 2019 Apr 19;14(4):e0215333. doi: 10.1371/journal.pone.0215333. eCollection 2019.
citation: Butt JH, Fosbol EL, Verhamme P, Gerds TA, Iversen K, Bundgaard H, Bruun NE, Larsen AR, Petersen A, Andersen PS, Skov RL, Gislason GH, Torp-Pedersen C, Kober L, Olesen JB. Dabigatran and the Risk of Staphylococcus aureus Bacteremia: A Nationwide Cohort Study. Clin Infect Dis. 2021 Aug 2;73(3):480-486. doi: 10.1093/cid/ciaa661.
citation: Vanassche T, Verhaegen J, Peetermans WE, VAN Ryn J, Cheng A, Schneewind O, Hoylaerts MF, Verhamme P. Inhibition of staphylothrombin by dabigatran reduces Staphylococcus aureus virulence. J Thromb Haemost. 2011 Dec;9(12):2436-46. doi: 10.1111/j.1538-7836.2011.04529.x.
citation: Vanassche T, Verhaegen J, Peetermans WE, Hoylaerts MF, Verhamme P. Dabigatran inhibits Staphylococcus aureus coagulase activity. J Clin Microbiol. 2010 Nov;48(11):4248-50. doi: 10.1128/JCM.00896-10. Epub 2010 Sep 1.
citation: Peetermans M, Liesenborghs L, Peerlinck K, Wijngaerden EV, Gheysens O, Goffin KE, Hoylaerts MF, Jacquemin M, Verhaegen J, Peetermans WE, Verhamme P, Vanassche T; Staphylothrombin Investigators. Targeting Coagulase Activity in Staphylococcus aureus Bacteraemia: A Randomized Controlled Single-Centre Trial of Staphylothrombin Inhibition. Thromb Haemost. 2018 May;118(5):818-829. doi: 10.1055/s-0038-1639586. Epub 2018 Apr 3.
citation: Tong SYC, Mora J, Bowen AC, Cheng MP, Daneman N, Goodman AL, Heriot GS, Lee TC, Lewis RJ, Lye DC, Mahar RK, Marsh J, McGlothlin A, McQuilten Z, Morpeth SC, Paterson DL, Price DJ, Roberts JA, Robinson JO, van Hal SJ, Walls G, Webb SA, Whiteway L, Yahav D, Davis JS; Staphylococcus aureus Network Adaptive Platform (SNAP) Study Group. The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe. Clin Infect Dis. 2022 Nov 30;75(11):2027-2034. doi: 10.1093/cid/ciac476.