Clinical trial NCT03114033: Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest
Official title: TAME Cardiac Arrest Trial: Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest: A Phase III Multi-Centre Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Out-Of-Hospital Cardiac Arrest
Keywords: Cardiac Arrest
Intensive Care Unit
Therapeutic Mild Hypercapnia
Normocapnia
Mortality
Neurological function
Lead sponsor: Australian and New Zealand Intensive Care Research Centre
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
name: Health Research Board, Ireland
First posted: 2017-04-14
Enrollment: 1700
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel assignment
Primary purpose: TREATMENT

Brief summary: The TAME Cardiac Arrest trial will study the ability of higher arterial carbon dioxide (PaCO2) levels to reduce brain damage, comparing giving patients 'normal' to 'slightly higher than normal' blood PaCO2 levels and assessing their ability to return to normal life-tasks. It will be the largest trial ever conducted in heart attack patients in the intensive care unit. This therapy is cost free and, if shown to be effective, will improve thousands of lives, transform clinical practice, and yield major savings.

Detailed description: Cardiac arrest is a common and catastrophic event with substantial human and financial costs. It is well understood that cardiac arrest leads to brain injury. However, what is not widely appreciated is that, after circulation has been restored, cerebral hypoperfusion continues. Ongoing cerebral vasoconstriction and cerebral hypoxia has been demonstrated using technologies that include positron emission tomography, ultrasound, jugular bulb oxygen saturation and cerebral oximetry.

A likely mechanism responsible for sustained early cerebral hypoperfusion relates to impaired cerebrovascular auto-regulation. Such impaired cerebral auto-regulation may make even a normal arterial carbon dioxide tension (PaCO2) (the major physiological regulator of cerebral blood flow) insufficient to achieve and maintain adequate cerebral perfusion and, consequently, cerebral oxygenation. However, PaCO2 is the major determinant of cerebral blood flow and an increased PaCO2 (hypercapnia) markedly increases cerebral blood flow. Moreover, arterial carbon dioxide is modifiable and, as such, is a potential therapeutic target.

The TAME Cardiac Arrest Trial is a definitive phase III multi-centre randomised controlled trial in resuscitated cardiac arrest patients. This trial will determine whether targeted therapeutic mild hypercapnia (TTMH) applied during the first 24 hours of mechanical ventilation in the intensive care unit (ICU) improves neurological outcome at 6 months compared to standard care (targeted normocapnia (TN).

Supported by compelling preliminary data, significant improvements in patient outcomes are achievable with this proposed simple and cost free therapy. Recruiting 1,700 patients, for multiple sites in many countries, this will be the largest trial ever conducted involving resuscitated cardiac arrest patients admitted to the ICU. If the TAME Cardiac Arrest Trial confirms that TTMH is effective, its findings will improve the lives of many, transform clinical practice and yield major economic gains worldwide.

Eligibility criteria: Inclusion Criteria:

* Adult (age ≥18 years or older)
* Out-of-hospital cardiac arrest of a presumed cardiac or unknown cause
* Sustained ROSC - defined as 20 minutes with signs of circulation without the need for chest compressions
* Unconscious (FOUR-score motor response of \<4, not able to obey verbal commands after sustained ROSC) (Appendix D)
* Eligible for intensive care without restrictions or limitations
* Within \<180 minutes of ROSC

Exclusion Criteria:

* Unwitnessed cardiac arrest with an initial rhythm of asystole
* Temperature on admission \<30oC
* On ECMO prior to ROSC
* Obvious or suspected pregnancy
* Intracranial bleeding
* Severe chronic obstructive pulmonary disorder (COPD) with long-term home oxygen therapy

Primary outcomes:
measure: Neurological outcome
timeFrame: 6 months following enrolment
Secondary outcomes:
measure: Mortality at intensive care unit discharge
timeFrame: 6 months after randomisation
measure: Mortality at hospital discharge
timeFrame: 6 months after randomisation
measure: Health-related Quality of Life (EQ-5D-5L)
timeFrame: 6 months after randomisation
measure: modified Rankin scale (mRS)
timeFrame: 6 months after randomisation
measure: Montreal Cognitive Assessment (MoCA-blind)
timeFrame: 6 months after randomisation
measure: Mortality at 6 months
timeFrame: 6 months after randomisation
measure: Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE)
timeFrame: 6 months after randomisation
measure: Symbol Digit Modality Test
timeFrame: 6 months after randomisation
Other outcomes:
measure: Quality Adjust Life Years (QALYs)
timeFrame: 6 months after randomisation
measure: Health economic evaluation
timeFrame: 6 months after randomisation
measure: Pneumonia
timeFrame: Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
measure: Sepsis and septic shock
timeFrame: Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
measure: Bradycardia
timeFrame: Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
measure: Moderate or severe bleeding
timeFrame: Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
measure: Cooling device-related skin complications
timeFrame: Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
measure: Arrhythmia
timeFrame: Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Locations:
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Penrith
country: Australia
facility: Nepean Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Tiwi
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Chermside
country: Australia
facility: Prince Charles Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Sunshine Coast
country: Australia
facility: Nambour Hospital
state: Queensland
city: Sunshine Coast
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Ballarat
country: Australia
facility: Ballarat Base Hospital
state: Victoria
city: Epping
country: Australia
facility: The Northern Hospital
state: Victoria
city: Geelong
country: Australia
facility: University Hospital Geelong
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Health
state: Victoria
city: Melbourne
country: Australia
facility: Footscray Hospital-Western Health
state: Victoria
city: Melbourne
country: Australia
facility: Sunshine Hospital-Western Health
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Austin Health
state: Victoria
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires de Bruxelles Hospital Erasme
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg AV
city: Gent
country: Belgium
facility: University Hospital Ghent
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Besancon
country: France
facility: CHRU Jean Minjoz Besancon
state: Franche Comte
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centre
city: Grafton
country: New Zealand
facility: Auckland City Hospital CVICU
state: Auckland
city: Grafton
country: New Zealand
facility: Auckland City Hospital DCCM
state: Auckland
city: Otahuhu
country: New Zealand
facility: Middlemore Hospital
state: Auckland
city: Riccarton
country: New Zealand
facility: Christchurch Hospital
state: Christchurch
city: Newtown
country: New Zealand
facility: Wellington Regional Hospital
state: Wellington
city: Auckland
country: New Zealand
facility: North Shore Hospital
city: Rotorua
country: New Zealand
facility: Rotorua Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital - Ullevål
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Maribor
country: Slovenia
facility: University Medical Centre Maribor
city: Helsingborg
country: Sweden
facility: Skane Region-Helsingborg
city: Malmö
country: Sweden
facility: Skane Region Malmö
city: Cosham
country: United Kingdom
facility: Queen Alexandra Hospital Portsmouth
state: Portsmouth
city: Belfast
country: United Kingdom
facility: Royal Victoria Hospital Belfast
city: Birmingham
country: United Kingdom
facility: Birmingham University Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Cardiff
country: United Kingdom
facility: University Hospital Wales
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
Study officials:
affiliation: Monash University
name: Glenn M Eastwood, RN, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eastwood GM, Schneider AG, Suzuki S, Peck L, Young H, Tanaka A, Martensson J, Warrillow S, McGuinness S, Parke R, Gilder E, Mccarthy L, Galt P, Taori G, Eliott S, Lamac T, Bailey M, Harley N, Barge D, Hodgson CL, Morganti-Kossmann MC, Pebay A, Conquest A, Archer JS, Bernard S, Stub D, Hart GK, Bellomo R. Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial). Resuscitation. 2016 Jul;104:83-90. doi: 10.1016/j.resuscitation.2016.03.023. Epub 2016 Apr 7.