The primary feasibility outcomes
Our primary feasibility outcomes are:
The lower limit of the confidence interval of the inclusion ratio (the proportion
of included participants randomised compared to all eligible patients). For example,
if the number of eligible patients who agree to participate is 44 out of 60, then
the proportion will be 73% with a 95% confidence interval (CI) between 60% and 84%.
The lower limit for this feasibility outcome is set at 60%; if the lower limit of
the confidence interval of the gathered data of the HUT-TBI Trial is higher, then
the trial is considered to be successful in terms of inclusion.
The lower limit of the confidence interval of the intervention success rate defined
as the proportion of participants allocated to the experimental intervention who received
at least 60% of the planned exercise sessions. For example, if the number of participants
receiving 60% of the exercise is 70% (21 out of 30) of the participants randomised
to the experimental intervention group, the lower limit of the confidence interval
will be 52%. Accordingly, if the lower limit of the confidence interval of the gathered
data of the HUT-TBI Trial is above 52%, the trial will be considered to be successful
in terms of exercise completeness.
Our safety outcomes are defined as either proportion of participants with serious adverse events (SAEs)
and reactions (SARs) or adverse events or adverse reactions not considered serious
(AEs or ARs) (
</a>). SAEs are defined as any undesirable event that result in death, is life-threatening,
requires prolongation of existing hospitalisation, results in persistent or significant
disability or incapacity, or requires intervention to prevent permanent impairment
or damage, whether considered related to the trial intervention or not. AEs are defined
as any undesirable event not considered serious occurring to a participant during
the trial. The proportion of participants with at least one SAE, SAR, AR, or AE during
the intervention period will be compared between the two intervention groups. The
proportion of serious adverse events will be assessed through inspection and through
statistical analysis (see below). </p>
Exploratory clinical outcomes
For the exploratory clinical outcomes, we have chosen three outcomes: The Coma Recovery
Scale - Revised (CRS-R), the Early Functional Ability scale (EFA), and the Functional
Independence Measure (FIM). The CRS-R reflects changes in consciousness and will be
analysed at the four-week time point (end of intervention period) comparing the two
intervention groups. The EFA evaluates early functional changes and the FIM evaluates
the ability to independently perform functions and activities of daily living. Both
will be evaluated at the three-month time point. Secondly, the data for all three
exploratory clinical outcomes will be presented as longitudinal data in a figure including
confidence intervals. At the one-year follow up, the same three outcome scales are
used and supplemented by the Glasgow Outcome Scale – Extended (GOSE), as it is used
routinely at the department for the one-year follow-up.
Exploratory physiological outcomes
For exploratory physiological outcomes we have measured the haemodynamic response
to a head-up tilt at baseline, after two weeks, and after four weeks in both groups.
From these data we will calculate the cerebral autoregulation index (Mxa) measured
by transcranial Doppler ultrasound of the middle cerebral artery at each time point.
In short, mean arterial blood pressure and mean middle cerebral artery flow velocity
are correlated using a Pearson correlation coefficient. Correlations are calculated
during 300 seconds in the supine position (rest) and 300 seconds during head up tilt
with 70 degrees head elevation. The Mxa will then principally be considered dichotomously
in order to reflect intact cerebral autoregulation of blood flow, with a correlation
equal to or below 0.3 or impaired if it is above 0.3 (
</a>). Data at four weeks will be compared between groups. Secondarily, we will analyse
the Mxa as a continuous variable and we will utilise other methods such as the Gosling
Pulsatile index, or the cerebrovascular resistance index.</p>
Concerning heart rate variability, we will measure heart rate for five consecutive
days from the time of randomisation. A steady period of five minutes before the first
head up tilt will be analysed for low frequency, high frequency, and the ratio between
low and high frequency both percentage and normalised units (frequency domain) (
</a>). For comparison between groups, a five minutes interval before the tilt test performed
at the 4<sup>th</sup> week (end of intervention) will be used. Further, a comparison of each head-up tilt
test (2 weeks and 4 weeks) will be analysed using the same domain parameters for between
group comparison as longitudinal analysis. Finally, the frequency domain indices will
be used in the attempt to establish a model for predicting the risk of experiencing
orthostatic hypotension or impaired cerebral autoregulation at each head-up tilt test.
Afterwards, 24-hour analysis of the heart rate variability will be made within the
time domain using the root mean square of successive RR intervals and the standard
deviations of NN intervals in normalised units (
</a>). First, we will analyse the differences between groups at the three-day time point.
Then the 24-hour analysis will be compared between groups as longitudinal data from
the first day of inclusion till day five. Finally, the time domain parameters at the
first day after randomisation will be used for a prediction model for clinical outcomes
at four-weeks (CRS-R) and at three months (EFA and FIM).</p>
Statistical analysis will be handled using STATA (StataCorp, College Station, Texas,
All baseline characteristics will be presented for each intervention group. Continuous
variables will be summarised using means and standard deviations or medians and interquartile
range depending on distribution of data. Discrete variables will be presented as frequencies,
proportions, and percentages.
Timing of outcome assessments can be found in the published protocol in figure 1 (
All our analyses will primarily be intention-to-treat, i.e. all randomised participants
will be included in the primary analyses. We will secondly perform per protocol analyses
including the participants allocated to the intervention who received at least 60%
of the planned exercise sessions.
If we do not reach the desired number of participants in the trial, we will consider
to analyse our data using Trial Sequential Analysis (
</a>, <a href="#_ENREF_18">
Analysis will start after the last three-month follow-up has been collected and after
submission of this statistical analysis plan (end of March 2019). The analysis of
the one-year follow-up data will start after data from the last patient has been collected
in late December 2019.
The first two primary feasibility outcomes will be derived from the trial with the
above-mentioned lower limits of the proportions, and these two outcomes will not undergo
statistical testing. For the intervention to be feasible, both feasibility outcomes
should be achieved.
All analysis described below using general linear regression, logistic regression,
or mixed-model linear regression will be adjusted for the protocol specified stratification
variable (high or low GCS).
We will use inspection of data to evaluate adverse events due to the low power. Secondly,
we will use logistic regression to compare the proportions of participants with one
or more SAEs, SARs, Ars, and AEs between the two groups (
</a>). Accordingly, we will use an alpha of 5%. Each patient with at least one SUSAR
during the intervention period will be analysed as exploratory feasibility outcome
also using logistic regression analysis. Where appropriate we will present data with
a 95% confidence interval.</p>
Exploratory clinical outcome
All exploratory clinical outcomes and physiological outcomes are on a continuous interval
The exploratory clinical outcomes will primarily be compared between groups at specified
time points. The CRS-R will be analysed at the four-week time point and EFA and FIM
will be analysed at the three-month time point using general linear regression analysis.
Secondarily, as a sensitivity analysis, longitudinal data will be analysed using mixed
model linear regression with each participates as a random effect and the clinical
outcome as the fixed effect for analysis of longitudinal data over multiple time points.
Each outcome, the outcomes minimal relevant difference, standard deviation and power
level can be found in Supplementary table 1. The one-year follow up data for CRS-R,
EFA, and FIM will be analysed in the same way only the three-month time-point will
be replaced with one-year. Furthermore, for the one-year analysis the Glasgow outcome
scale extended will be compared between groups using general linear regression and
adjusting for stratification specific variables.
In case the regression models described above (linear regression and mixed model)
cannot be fitted due to breach of their underlying assumptions (e.g. skewed distribution
of data/residuals), non-parametric methods (e.g. Van Elteren test) taking the stratified
randomisation into account will be employed. Analysis will in all cases be conducted
at the prespecified time points stipulated above. As described in our protocol, P-values of any size will not be interpreted as significant due to the low power of
Exploratory physiological outcomes
The exploratory physiological outcomes measuring cerebral autoregulation will be compared
at the 4-week time point (or end of intervention). To do this, we will use logistic
regression with the Mxa (binary) as the dependent and further adjusting for age and
sex. The Mxa will also be tested as a continuous variable (ranging from -1 to 1) using
general linear regression analysis and mixed-model linear regression with each participant
as a random effect for analysis of longitudinal data over multiple time points. The
same approach will be used for the Gosling Pulsatile index and the cerebrovascular
It is our intention to analyse and publish data on the heart rate variability frequency
domain and time domain indices. The statistical analysis plan for these outcomes will
be made public in a separate report.
Trials conducted in the ICU are at high risk of missing data alone on the account
of the patient´s condition (
</a>). If data are missing, we will consider using multiple imputation according to the
recommendations by Jakobsen and colleagues (<a href="#_ENREF_20">
</a>). For all continuous clinical outcomes, we will analyse survivors, and in a sensitivity
analysis impute the lowest possible value for participants who died or dropped out
as well as the best possible value. We will present the results of both analyses.</p>
Trial status and profile
The inclusion period ended in December 2018 with only 38 patients included during
a two-year period. End of the three-month follow-up period will be in March 2019 and
the one-year follow up will be in December 2019. Flow of patients will be presented
in a CONSORT diagram as reported in the protocol (
</a>). We will report the number of screened patients, the number of included patients,
and the main reason for exclusion of eligible patients. Furthermore, we will present
the number of patients who died within the four-week intervention period, within the
first three months from randomisation, and within the first year. </p>
We plan to publish the following papers:
The primary feasibility outcomes and the analyses of the exploratory clinical outcomes
will be published separately to establish feasibility of the intervention and the
sample size of a larger multicentre study (publication I).
Analysis of the exploratory outcomes with the focus of investigating a specific physiological
effect on cerebral autoregulation after a series of orthostatic exercises during head
up tilt (publication II).
Analysis of one-year follow-up data once all data are collected, which is expected
to be in December 2019 (publication III).
Presentation of results in tables and figures
Publication I: The CONSORT flow chart diagram will be presented as Figure 1. To assess
the balance of our randomisation, description of baseline characteristics will be
presented in a table (Table 1). Variables will be summarized as either frequencies
and percentages or as continues or ordinal variables as mean with standard deviations
(SD) or median and interquartile range (IQR) (see Appendix 1).
The primary feasibility outcome will be presented in Table 2 and Table 3. The first
table will consist of the proportion of patients included in the trial as well as
the number of patients who successfully received more than 60% of the intended interventions.
Table 3 will present and describe the adverse events seen during the intervention
period as well as the logistic regression analysis.
The exploratory clinical outcome will be presented as shown in Table 4, with the absolute
numbers of each outcome at each time point in a Supplementary table 2. Furthermore,
the longitudinal analysis will be presented in a figure showing each time point with
confidence intervals (not illustrated).
Publication II: The second publication will present Table 1 as a demographic table.
The results will be presented in a figure with included table (Figure 2). The figure
will consist of three graphs (A, B and C) with data summarized beneath, showing heart
rate (HR, mean arterial blood pressure (MAP), and middle cerebral artery blood flow
velocity (MCAVmean) Δ-values between supine position and during head up tilt at baseline,
after 2 weeks and after 4 weeks. As supplementary material we will present a spaghetti-plot
of each of the above variables in supine and in standing (Supplementary figure 1).
Table 5 shows the Mxa values in supine and in standing for both groups at the end
of the intervention period. Alongside this, a Figure 2 will illustrate the time line
for Mxa, with Mxa on the y-axis and time on the x-axis, showing a mean with confidence
intervals for each time point (baseline, 2 weeks, 4 weeks). Figure 2A will illustrate
Mxa in the supine and Figure 2B in standing. Lastly, a Table 6 will show the frequency
of intact cerebral autoregulation in the two groups with P-values indicating group differences.
Publication III: As in publication I this publication will analyse the outcomes after
one year. Similarly, the data will be presented as Table 1 and Table 4 with the added
1-year data on each outcome as well as Glasgow outcome scale extended at the 1-year