Blood Pressure and OXygenation Targets After OHCA (BOX)
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|ClinicalTrials.gov Identifier: NCT03141099|
Recruitment Status : Completed
First Posted : May 4, 2017
Last Update Posted : June 30, 2022
|First Submitted Date ICMJE||April 30, 2017|
|First Posted Date ICMJE||May 4, 2017|
|Last Update Posted Date||June 30, 2022|
|Actual Study Start Date ICMJE||March 10, 2017|
|Actual Primary Completion Date||December 15, 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||All-cause mortality or severe anoxic brain injury [ Time Frame: 3 months after OHCA. ]
Death from any cause or discharge from hospital in Cerebral Performance Category 3 or 4
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures
|Original Other Pre-specified Outcome Measures||Same as current|
|Brief Title ICMJE||Blood Pressure and OXygenation Targets After OHCA|
|Official Title ICMJE||Blood Pressure and Oxygenation Targets in Post-resuscitation Care, a Randomized Clinical Trial|
|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.|
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.
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.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
Target blood pressure will be blinded by offsetting the blood pressure measurering module.
The oxygenation- and fever control interventions will be open label. Further life-sustaining treatment will be delivered according to standard procedures and withdrawal of active intensive care will be at the discretion of the treating physicians, but must be delayed for at least 108 hours post ROSC. The steering group and the management group will be blinded to the type of intervention during the entire trial period, when handling the trial database.
Follow-up at 30 days (phone call) and 90 days (meeting) will be performed by personnel unaware of the allocation group, treatment complications at the ICU, if they occurred or specialized neurological rehabilitation.
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||March 15, 2022|
|Actual Primary Completion Date||December 15, 2021 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Denmark|
|Removed Location Countries|
|NCT Number ICMJE||NCT03141099|
|Other Study ID Numbers ICMJE||H-16033436|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Current Responsible Party||Jesper Kjaergaard, Rigshospitalet, Denmark|
|Original Responsible Party||Same as current|
|Current Study Sponsor ICMJE||Jesper Kjaergaard|
|Original Study Sponsor ICMJE||Same as current|
|Collaborators ICMJE||Odense University Hospital|
|PRS Account||Rigshospitalet, Denmark|
|Verification Date||June 2022|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP