Clinical trial NCT03141099: Blood Pressure and OXygenation Targets After OHCA
Official title: Blood Pressure and Oxygenation Targets in Post-resuscitation Care, a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Out-of-Hospital Cardiac Arrest
Blood Pressure
Hemodynamic Instability
Keywords: OHCA
Hemodynamic
TTM
post-rescusitation care
Blood pressure targets
Oxygenation targets
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
First posted: 2017-05-04
Enrollment: 802
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Multicenter, randomized trial in 2\*2 factorial design allocating comatose OHCA patients to one of two target blood pressures (double blind) and restrictive vs. liberal oxygenation (open label) during ICU stay with blinded outcome evaluation.

Sample size: 800 patients. Patient will be allocated 1:1; for all interventions, no interaction with regards to outcome is expected.
Primary purpose: TREATMENT

Brief summary: This study compares two blood pressure targets and two oxygenation targets in the post-resuscitation care of comatose out-of-hospital cardiac arrets patients. Using a novel method the blood pressure-intervention is double-blinded. The oxygenation-intervention is open-label. As a subordinate study, the patients will be randomized 1:1 to active fever-control with an automated feedback temperature control-device for 36 or 72 hours following return of spontaneous circulation.

Detailed description: In comatose patients resuscitated from out of hospital cardiac arrest (OHCA), neurological injuries remain the leading cause of death. The in-hospital mortality is reported at 30-50%, and the total mortality, although improved substantially over the last decade, remain to be significant, in most countries at up to 90%. An adequate blood pressure must be maintained in the post-cardiac arrest patient i order to optimize neurological recovery and avoid further brain injury. Blood pressure targets in post-resuscitation guidelines are based on limited clinical evidence. Furthermore registry and clinical data suggest a u-shaped relationship of outcome with levels of oxygen supplementation. Blinded, randomized, clinical trials addressing specific blood pressure- or oxygenation-targets during the post-resuscitation care, have not been performed.

The current trial addresses strategies for neuroprotection using a 2-by-2 design of two different target blood pressure levels and two different oxygenation levels.

Intervention:

* 'Low-normal MAP' (appoximately 63 mmHg) vs. 'high-normal MAP' (approximately 77 mmHg) (double blind intervention) and
* Low-normal oxygenation (9-10 kPa) vs. high-normal oxygenation (13-14) kPa (open label).
* As a subordinate study, the patients will be randomized 1:1 to active fever-control with an automated feedback temperature control device for 72 hours or to 36 hours following return of spontaneous circulation.

Design: National collaborative, randomized clinical trial randomizing 800 comatose out-of-hospital cardiac arrest patients undergoing targeted temperature management (TTM) to the specified interventions.

The investigators have planned the following sub-studies:

Sub-study 1: Devopment and validation af a method for double blinded allocation to different blood pressure targets.

Hypothesis: It is possible to develop a method for double blinded allocation of patients to different blood pressure targets in clinical trials.

Sub-study 2: Assessment of different blood pressure targets and relation to renal function during TTM.

Hypothesis: Different blood presure goals will affect biomarkes of renal function after cardiac arrest.

Sub-study 3: To investigate the hemodynamic profil in relation to different blood pressure targets after cardiac arrest.

Hypothesis: Blood pressure and vassopressor-doses are related to hemodynamic parameters, such as systemic vaskular resistence index and cardiac index.

Sub-study 4: To investigate the hemodynamic profil in relation to different oxygenation targets after cardiac arrest.

Hypothesis: Lower oxygenation targets are related to higher pulmonary vascular resistance.

Sub-study 5: The prognostic value of automated videobased assessment of pupillary dilatation and reaction to light. Derivation and validation of relevant cut-off for introducing pupillomtry as part of the prognostication

INTERIM ANALYSIS There will be an independent DSMC arranging an independent statistician to conduct primarily a blinded interim analysis at time points of their choosing. The DSMC will be able to request unblinding of data coordinated by the data managing agency. An interim analysis is planned after inclusion of 200 and 400 patients.

For the BP intervention, a blinded interim analysis of vasorepressor need and recorded blood pressures is planned after 50 patients, to monitor blinding of treatment allocation and that a clinically relevant blood pressure separation between groups is achieved. Vasopressor needs in terms of vasopressor need in a variance component model is expected to differ. New sites will be monitored for these factors after inclusion of 50 patients.

EARLY STOPPING CRITERIA After an interim analysis the DSMC may suggest to the steering committee that the trial should be stopped early. No specific criteria to guide the DSMB will be put forward.

ACCOUNTABILITY PROCEDURE FOR MISSING DATA/POPULATION FOR ANALYSIS Trial sites will be asked to complete all CRFs and other forms if missing data is found in the electronic database. Missing data will be reported in the publications. More than 5% missing data will result in multiple imputation with the creation of 5-10 imputed datasets to be analysed separately and the aggregated into one estimate of intervention effect on the primary and secondary outcomes. Analyses will be performed according to the modified intention to treat principle with patients lost to follow up included in the denominator.

SUBGROUP ANALYSIS AND DESIGN VARIABLES Subgroups will be analysed according to pre-defined design variables: over or under median age, shockable rhythm, gender, the presence of shock at admission, diagnosed AMI and time from arrest to ROSC. Difference in intervention effect estimates according to subgroup will be declared exclusively based on a statistically significant test of interaction.

DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION The principal investigator and the site investigators will permit monitoring, audits, review of ethical committees and regulatory authorities direct access to source data and documentation, blinded to treatment allocation.

DATA HANDLING AND RECORD KEEPING Individual patient data will be handled as ordinary chart records and will be kept according to the legislation (e.g. data protection agencies) of the countries of each health system. The study database will be stored for 15 years and anonymised if requested by the relevant authorities.

Danish legislation regarding the respect for patients physical and mental integrity and rights will be respected, Approval for storing data relevant to the trial, including potentially sensitive information has been approved by the relevant authorities.

QUALITY CONTROL AND QUALITY ASSURANCE A monitoring plan will be published before start of the trial. The monitoring will include: inclusion and absence of exclusion criteria, consent obtained in all patients.

All trial sites will be provided with sufficient information to participate in the trial. The site investigator will be responsible for that all relevant data is entered into the electronic CRFs. The CRFs will be constructed in order to assure data quality with predefined values and ranges on all data entries.

STATISTICAL METHODS The combined primary outcome will be reported as proportional hazard of experiencing one of two endpoints (death or poor neurological status at hospital discharge), differences tested with a log rank test. Other proportions are expected to be normally distributed; therefore a t-test is applied. Survival analyses are performed using proportional hazard models, survival is adjusted for site.

Furthermore pre-specified analysis of interaction for design variables: sex, age (median), time to ROSC (median), shockable rhythm, STEMI, pre-existing hypertension, pre-existing chronic obstructive pulmonary disease.

SIGNIFICANCE A two-sided significance level of 0.05 will be applied to all endpoints. No adjustment for the factorial design is made, as no interaction is expected.

SAMPLE SIZE ESTIMATION Sample size estimation is based on blinded BP target allocation and on the assumption that no interaction of the two interventions exist.

The combined primary outcome is time to death or hospital discharge in a state of CPC 3 or 4. The investigators are planning a study with 400 subjects in each group, an accrual interval of 48 months, and additional follow-up after the accrual interval of 3 months. Prior data indicate the 6 months mortality is 33% overall. Assuming a mortality of 28% in the superior group compared to 38% in the inferior groups the investigators will need to include 732 patients in total or 846 patients in total to achieve a power of 0.8 and 0.9 respectively. The Type I error probability associated with this test of the null hypothesis that the experimental and control survival curves are equal is 0.05.

Loss of final measurement is expected but from the experience from previous trial the number of missing follow-up assessments is small (\<5%) and will not result in an increase of the number of patients needed.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years
2. OHCA of presumed cardiac cause
3. Sustained ROSC
4. Unconsciousness (GCS \<8) (patients not able to obey verbal commands) after sustained ROSC

Exclusion Criteria:

1. Conscious patients (obeying verbal commands)
2. Females of childbearing potential (unless a negative HCG test can rule out pregnancy within the inclusion window)
3. In-hospital cardiac arrest (IHCA)
4. OHCA of presumed non-cardiac cause, e.g. after trauma or dissection/rupture of major artery OR Cardiac arrest caused by initial hypoxia (i.e. drowning, suffocation, hanging).
5. Known bleeding diathesis (medically induced coagulopathy (e.g. warfarin, NOAC, clopidogrel) does not exclude the patient).
6. Suspected or confirmed acute intracranial bleeding
7. Suspected or confirmed acute stroke
8. Unwitnessed asystole
9. Known limitations in therapy and Do Not Resuscitate-order
10. Known disease making 180 days survival unlikely
11. Known pre-arrest CPC 3 or 4
12. \>4 hours (240 minutes) from ROSC to screening
13. Systolic blood pressure \<80 mm Hg in spite of fluid loading/vasopressor and/or inotropic medication/intra-aortic balloon pump/axial flow device
14. Temperature on admission \<30°C.

Primary outcomes:
measure: All-cause mortality or severe anoxic brain injury
timeFrame: 3 months after OHCA.
Secondary outcomes:
measure: Renal replacement therapy
timeFrame: 3 months
measure: Time to death
timeFrame: 180 days
measure: Neuron-Specific Enolase
timeFrame: 48 hours
measure: MOCA-score
timeFrame: 3 months
measure: Modified Ranking Scale
timeFrame: 3 months
measure: NT-pro-BNP
timeFrame: 3 months
measure: eGFR
timeFrame: 3 months
measure: LVEF
timeFrame: 3 months
measure: Vasopressor use
timeFrame: First week after cardiac arrest
measure: Renal function
timeFrame: 96 hours
Other outcomes:
measure: Vital status at 180 days post cardiac arrest
timeFrame: 180 days post cardiac arrest
measure: CPC category at 180 days post cardiac arrest
timeFrame: 180 days post cardiac arrest
Locations:
city: Copenhagen
country: Denmark
facility: Department of Cardiology, Copenhagen University Hospital, Rigshospitalet
state: København Ø
city: Odense
country: Denmark
facility: Depart med Cardiothoracic Intensive Care, Odense University Hospital
Study officials:
affiliation: Rigshospitalet, Denmark
name: Jesper Kjaergaard, Md, DMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hassager C, Schmidt H, Moller JE, Grand J, Molstrom S, Beske RP, Boesgaard S, Borregaard B, Bekker-Jensen D, Dahl JS, Frydland MS, Hofsten DE, Isse YA, Josiassen J, Lind Jorgensen VR, Kondziella D, Lindholm MG, Moser E, Nyholm BC, Obling LER, Sarkisian L, Sondergaard FT, Thomsen JH, Thune JJ, Veno S, Wiberg SC, Winther-Jensen M, Meyer MAS, Kjaergaard J. Duration of Device-Based Fever Prevention after Cardiac Arrest. N Engl J Med. 2023 Mar 9;388(10):888-897. doi: 10.1056/NEJMoa2212528. Epub 2022 Nov 6.
citation: Schmidt H, Kjaergaard J, Hassager C, Molstrom S, Grand J, Borregaard B, Roelsgaard Obling LE, Veno S, Sarkisian L, Mamaev D, Jensen LO, Nyholm B, Hofsten DE, Josiassen J, Thomsen JH, Thune JJ, Lindholm MG, Stengaard Meyer MA, Winther-Jensen M, Sorensen M, Frydland M, Beske RP, Frikke-Schmidt R, Wiberg S, Boesgaard S, Lind Jorgensen V, Moller JE. Oxygen Targets in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Oct 20;387(16):1467-1476. doi: 10.1056/NEJMoa2208686. Epub 2022 Aug 27.
citation: Kjaergaard J, Moller JE, Schmidt H, Grand J, Molstrom S, Borregaard B, Veno S, Sarkisian L, Mamaev D, Jensen LO, Nyholm B, Hofsten DE, Josiassen J, Thomsen JH, Thune JJ, Obling LER, Lindholm MG, Frydland M, Meyer MAS, Winther-Jensen M, Beske RP, Frikke-Schmidt R, Wiberg S, Boesgaard S, Madsen SA, Jorgensen VL, Hassager C. Blood-Pressure Targets in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Oct 20;387(16):1456-1466. doi: 10.1056/NEJMoa2208687. Epub 2022 Aug 27.
citation: Kjaergaard J, Schmidt H, Moller JE, Hassager C. The "Blood pressure and oxygenation targets in post resuscitation care, a randomized clinical trial": design and statistical analysis plan. Trials. 2022 Feb 24;23(1):177. doi: 10.1186/s13063-022-06101-6.
citation: Grand J, Hassager C, Schmidt H, Moller JE, Molstrom S, Nyholm B, Kjaergaard J. Hemodynamic evaluation by serial right heart catheterizations after cardiac arrest; protocol of a sub-study from the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Resusc Plus. 2021 Dec 10;8:100188. doi: 10.1016/j.resplu.2021.100188. eCollection 2021 Dec.