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CAPITAL DOREMI 2: Inotrope Versus Placebo Therapy for Cardiogenic Shock (DOREMI-2)

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ClinicalTrials.gov Identifier: NCT05267886
Recruitment Status : Recruiting
First Posted : March 4, 2022
Last Update Posted : January 10, 2023
Sponsor:
Information provided by (Responsible Party):
Ottawa Heart Institute Research Corporation

Brief Summary:
The investigators are interested in determining if there is a meaningful benefit from the use of medications purported to increase the pumping function of the heart (i.e. inotropes) among critically ill patients admitted to the Cardiac Intensive Care Unit (CICU). To do this, the investigators will conduct a multi-centre, double blind, randomized control trial with patients who are deemed to require these medications by their treating physician to one of the two most commonly used agents in Canada (Milrinone or Dobutamine) or placebo. Each patient will be closely monitored by their healthcare team. The dose of medication will be adjusted according to each patients' clinical status. After 12 hours, the participants will move to open label treatment and any continued use of inotropes will be at the discretion of their treating physician.

Condition or disease Intervention/treatment Phase
Shock, Cardiogenic Drug: Dobutamine Drug: Milrinone Drug: Normal Saline Phase 4

Detailed Description:

Cardiogenic shock (CS) is a state of inadequate end-organ perfusion due to cardiac dysfunction. Acute myocardial infarction (AMI) remains the most prevalent cause of CS, with mortality reaching upwards of 40% despite advances in emergent revascularization and accelerating use of mechanical circulatory support devices. International guidelines support the use of vasopressors and inotropes as a mainstay of medical therapy among this cohort of critically ill patients. Recently, the first head-to-head prospective randomized trial (CAPITAL DOREMI) comparing milrinone and dobutamine in a cohort of CS participants was performed and found no difference between agents.

There is a signal of harm associated with the use of inotropes in both acute, decompensated heart failure and in the longitudinal management of chronic heart failure. Inotrope use has also been associated with longer ICU and in-hospital length of stay, as well as higher in-hospital mortality. A recent network meta-analysis on treatment strategies in CS and found that while milrinone and dobutamine may reduce the risk of mortality compared to placebo, the evidence is of low certainty and the wide confidence intervals do not rule out the possibility of harm.

Despite their frequent use in the management of patients with CS, it remains unknown if inotropes are needed to augment successful initial resuscitation, reduce morbidity and mortality, or if they cause potential harm in this already critically ill patient population.

This study is a multi-centre, double blind, randomized controlled trial designed to examine the efficacy and safety of inotrope therapy against placebo in the initial resuscitation of SCAI class C to D cardiogenic shock. Consecutive patients admitted to an intensive care unit will be identified by the treating medical team as requiring new initiation of inotrope therapy for CS. All decisions to initiate inotrope therapy will be made by the primary care team with no involvement from the research team. The study hypothesis is that inotrope therapy will lead to an overall improvement in the primary outcome as compared to placebo.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 346 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel randomized control trial
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: CAPITAL DOREMI 2: Inotrope Versus Placebo Therapy for Cardiogenic Shock
Actual Study Start Date : March 5, 2022
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : December 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shock

Arm Intervention/treatment
Active Comparator: Inotrope
Participants randomized to receive the inotrope will be initiated on inotrope therapy at starting doses and titrated according to standard clinical care. During reassessment, the treating physicians will make a decision about adjustment of the inotrope dose (increase, maintain or decrease) based on hemodynamics, end-organ perfusion, vasopressor support and clinical exam. Dobutamine doses will be 2.5, 5.0, 7.5, 10 and >10 ug/kg/min and milrinone doses will be 0.125, 0.250, 0.375, 0.5 and >0.5 ug/kg/min. These dose stages are identical to those used in Capital Do-Re-Mi and reflect current standard of care.
Drug: Dobutamine
Dobutamine administered according to its clinical dose stage for cardiogenic shock
Other Name: Dobutrex, Inotrex

Drug: Milrinone
Milrinone administered according to its clinical dose stage for cardiogenic shock

Placebo Comparator: Placebo
Participants in the placebo arm will have an intravenous solution of 0.9% NaCl running at a standardized rate, comparable to the infusion rate of the inotrope arm.
Drug: Normal Saline
Normal saline running at a standardized rate




Primary Outcome Measures :
  1. Primary composite outcome [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]

    The primary outcome will be a composite of:

    1. All-cause mortality during the hospitalization
    2. Measured within the first 12 hours of starting the study intervention, any of:

      1. Sustained hypotension (mean arterial pressure ≤55mmHg) or sustained requirement of high dose vasopressors (norepinephrine >0.2 mcg/kg/min or norepinephrine 0.2 mcg/kg/min plus any additional agent) with any escalation in dose from time of randomization, for >/= 60 minutes
      2. Lactate greater than 3.5 mmol/L at 6 hours or thereafter
      3. Need for mechanical circulatory support device
      4. Atrial or ventricular arrhythmia leading to emergent electrical cardioversion
      5. Resuscitated cardiac arrest


Secondary Outcome Measures :
  1. All-cause in-hospital mortality [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Death resulting from any cause during hospitalization

  2. Renal failure requiring new initiation of renal replacement therapy [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Requiring new initiation of renal replacement therapy

  3. Need for cardiac transplant or mechanical circulatory support [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Identification of needing a cardiac transplant or mechanical circulatory support

  4. Atrial or ventricular arrhythmia leading to emergent electrical cardioversion [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Requiring emergent electrical cardioversion for atrial or ventricular arrhythmia

  5. Resuscitated cardiac arrest [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Cardiopulmonary arrest requiring chest compressions and/or defibrillation with successful return of spontaneous circulation (ROSC)

  6. Non-fatal myocardial infarction [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Non-fatal myocardial infarction

  7. Stroke or transient ischemic attack [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Defined as an episode of focal or global neurological deficit as diagnosed by a neurologist


Other Outcome Measures:
  1. Need for non-invasive or invasive mechanical ventilation [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Need for non-invasive or invasive mechanical ventilation after randomization

  2. Arrhythmia requiring pharmacologic intervention [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Atrial or ventricular arrhythmias requiring initiation of pharmacologic intervention (intravenous or oral anti-arrhythmic therapy)

  3. Acute kidney injury [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Acute kidney injury



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients ≥ 18 years of age admitted to an intensive care unit
  • SCAI class C or D cardiogenic shock

Exclusion Criteria:

  • Unwilling or unable to obtain informed consent by the participant or substitute decision maker
  • Patients who are currently pregnant or breast-feeding
  • Patients presenting with an out-of-hospital cardiac arrest (OHCA)
  • Administration of milrinone or dobutamine in the 24 hours preceding anticipated randomization
  • Severe obstructive valvular lesions, including aortic stenosis and/or mitral stenosis
  • Dynamic left ventricular outflow tract obstruction

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05267886


Contacts
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Contact: Rebecca Mathew, MD 613-696-7406 rmathew@ottawaheart.ca
Contact: Benjamin Hibbert, MD PhD 613-696-7115 bhibbert@ottawaheart.ca

Locations
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Canada, Ontario
University of Ottawa Heart Institute Recruiting
Ottawa, Ontario, Canada, K1Y4W7
Contact: Rebecca Mathew, MD    613-696-7406    rmathew@ottawaheart.ca   
Sponsors and Collaborators
Ottawa Heart Institute Research Corporation
Investigators
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Principal Investigator: Rebecca Mathew, MD Ottawa Heart Institute Research Corporation
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Responsible Party: Ottawa Heart Institute Research Corporation
ClinicalTrials.gov Identifier: NCT05267886    
Other Study ID Numbers: 20210386
First Posted: March 4, 2022    Key Record Dates
Last Update Posted: January 10, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The study data, protocol, SAP, ICF, and CSR will be made available at study completion/publication.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Study completion
Access Criteria: The above will be made publicly available

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ottawa Heart Institute Research Corporation:
cardiogenic
shock
inotrope
Additional relevant MeSH terms:
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Shock, Cardiogenic
Shock
Pathologic Processes
Myocardial Infarction
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Infarction
Ischemia
Necrosis
Dobutamine
Milrinone
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents
Platelet Aggregation Inhibitors
Vasodilator Agents
Phosphodiesterase 3 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors