Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03141099 |
Other study ID # |
H-16033436 |
Secondary ID |
|
Status |
Completed |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
March 10, 2017 |
Est. completion date |
March 15, 2022 |
Study information
Verified date |
June 2022 |
Source |
Rigshospitalet, Denmark |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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.
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.