Introduction
Methods
Objective of the EuroHYP-1 trial
Baseline characteristics | Intention-to-treat population | Per protocol population | ||
---|---|---|---|---|
Intervention group | Control group | Intervention group | Control group | |
Centre | ||||
- name of centre 1, N (%) | ||||
- name of centre 2, N (%) | ||||
- name of centre 3, N (%) | ||||
- etc | ||||
Intention to perform thrombolysis, N (%) | ||||
Surface cooling, N (%) | ||||
Males, N (%) | ||||
Stroke severity (NIHSS), mean (SD), N | ||||
Age ≤ 65 years, N (%) | ||||
Age, mean (SD), N | ||||
Visible ischaemic lesion on brain imaging, N (%) | ||||
Time since symptom onset, N ≤ 4 hours (%) |
Outcome | Proportion or mean value in control group | Standard deviation in the control group for continuous outcome | Minimal relevant intervention effect - absolute risk reduction relative to control group | Power |
---|---|---|---|---|
Score of NIHSS at 91 +/-14 days (sample size = 800) | 8 pointsa
| 5 pointsa
| 2 pointsa
| 1.00 |
Serious adverse events at 91 +/-14 days (sample size = 800) | 20% | NR | 10% | 0.98 |
Death or dependency, defined as modified Rankin score > 2 at 91 +/-14 days (sample size = 800) | 63% | NR | 7.25% | 0.55 |
Brain infarct size at 48 +/-24 hours (sample size = 800) | 10 mla
| 15 mla
| 2 mla
| 0.47 |
EQ-5D-5 L score at 91 +/-14 days (sample size = 800) | 0.50 points | 0.40 points | 0.05 points | 0.42 |
Death at 91 +/-14 days (sample size = 800) | 17% | NR | 3.84% | 0.33 |
The sample size
Adjusting variables
-
Intention to perform thrombolysis (yes compared to no).
-
Method of cooling (surface compared to endovascular).
-
Sex (male compared to female).
-
Stroke severity (National Institutes of Health Stroke Score (NIHSS)) 6–12 compared to 13 or higher).
-
Age (≤ 65 years compared to > 65 years).
-
Visibility of a relevant ischaemic lesion on the first brain imaging (yes compared to no).
-
Time since symptom onset (≤ 4 hours compared to 4–6 hours).
Flow of patients and baseline characteristics
Definition of the efficacy and safety outcomes
The primary outcome
The secondary outcomes originally selected
-
Death or dependency, defined as a score on the mRS > 2 at outcome assessment in the period day 91 ± 14 days after randomisation. Type: binary.
-
Death at outcome assessment in the period day 91 ± 14 days after randomisation. Type: binary.
-
Score on National Institute of Health Stroke Scale (NIHSS) at outcome assessment in the period day 91 ± 14 days after randomisation. Type: continuous.
-
EuroQoL quality-of-life (EQ-5D-5 L) score at outcome assessment in the period day 91 ± 14 days after randomisation. Type: continuous.
-
World Health Organization Disability Assessment Schedule II (WHODAS 2.0) score at outcome assessment in the period day 91 ± 14 days after randomisation. Type: continuous.
-
Brain infarct size at imaging assessment in the period 48 ± 24 hours after randomisation. Type: continuous.
Safety outcomes
-
Proportion of participants with at least one serious adverse event (SAE) until outcome assessment in the period day 91 ± 14 days after randomisation. Type: binary.
-
Number of SAEs per patient until outcome assessment in the period day 91 ± 14 days after randomisation. Type: rate.
Health economic outcome
-
Incremental cost utility (cost per quality-adjusted life years (QALY)) and incremental cost effectiveness (cost per death or disability averted) ratios. Type: continuous.
The analysis sets
The intention-to-treat population of patients
The per protocol set of patients
The ‘learning curve’ population
Statistical analyses
Analytical principles
Missing values of the primary outcome
Power of the original secondary outcomes
Presentation of results in tables
Population studied | Intervention group | mRS = 0 | mRS = 1 | mRS = 2 | mRS = 3 | mRS = 4 | mRS = 5 | mRS = 6 | Common OR | P of difference |
---|---|---|---|---|---|---|---|---|---|---|
N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | (95% CI) | (reference = group 0) | ||
Intention-to-treat (ITT) | Group 0 | |||||||||
Group 1 | ||||||||||
Per protocol (PP) | Group 0 | |||||||||
Group 1 |
Population | Intervention group | Outcomes | |||||
---|---|---|---|---|---|---|---|
Death | mRS > 2 | ||||||
N (%) | Relative risk (RR) (95% CI) | P | N (%) | RR (95% CI) | P | ||
Intention-to-treat (ITT) | Group 0 | ||||||
Group 1 | |||||||
Per protocol (PP) | Group 0 | ||||||
Group 1 |
Outcome | Population | Intervention group | Percentiles | N | Mean (SD) | (Minimum, maximum) |
P of difference | ||
---|---|---|---|---|---|---|---|---|---|
25% | 50% | 75% | |||||||
NIHSS score Range of possible scores at 91+/-14 days (RS): 0 to 42 Worst = 42 | Intention-to-treat (ITT) | Group 0 | |||||||
Group 1 | |||||||||
Per protocol (PP) | Group 0 | ||||||||
Group 1 | |||||||||
EQ-5D-5 L score at 91+/-14 days RS: 0 to 100 Worst = 0 | ITT | Group 0 | |||||||
Group 1 | |||||||||
PP | Group 0 | ||||||||
Group 1 | |||||||||
Brain infarct size at 48 +/-24 hours Worst = 1 | ITT | Group 0 | |||||||
Group 1 | |||||||||
PP | Group 0 | ||||||||
Group 1 | |||||||||
WHODAS 2.0 score at 91+/-14 days | ITT | Group 0 | |||||||
Group 1 | |||||||||
PP | Group 0 | ||||||||
Group 1 |
Topic described in original statistical analysis plan | Handling of topic in the present amended statistical analysis plan | Reason for action |
---|---|---|
No adjustment for nationality. | Adjustment for nationality | To improve the power by preventing upward bias of the standard error of the outcome. |
Power calculation of secondary outcomes is missing | Calculation of power conditional on sample size | To be used when defining the test ordering of the secondary outcomes |
Difficulties involved in interpreting an effect on a secondary outcome that can only be measured in surviving patients was not addressed | The worst possible score is assigned to the dead patients | A surplus of patients in one group relative to the other group may die before the outcome is measured. In the other group the corresponding surviving patients may (or may not) have very poor outcomes |
No multiplicity adjustment | The fixed-sequence testing procedure will be applied with the primary outcome to be tested first and followed by the secondary outcomes ordered according to falling power | To keep the family-wise error rate ≤ 0.05 |
A search for auxiliary variables and if found followed by imputation of the primary outcome was not considered | Missing value handling procedure revised accordingly | To improve the efficiency of a multiple imputation of missing values of the primary outcome |
The analytic potential of the exploratory temperature data was not expanded on | An outline of an exploratory mixed model analyses of the temperature data and Cox analyses of time to death with censoring at end of treatment and at 91 days +/- 14 days is now included | To assess if the temperature has an impact on short-term and long-term mortality and supplement the result of the analysis of the second secondary outcome |
Sample size of 1500 participants | Sample size reduced to 800 participants | Due to exceptionally slow enrolment, we realised that this target was no longer realistic |
Multiplicity
Subgroup analysis
Sensitivity analyses
Analysis of the primary and the secondary outcome
The primary outcome
The secondary and the exploratory outcomes
Outline of exploratory analysis of the temperature variables and time to death
Health economic evaluation
Overview of changes to the original statistical analysis plan for the primary and the secondary outcomes
Types of events | Group 0 | Group 1 | ||||
---|---|---|---|---|---|---|
Events, N | Patients with at least one event, N | Patients assessed, N | Events, N | Patients with at least one event, N | Patients assessed, N | |
Any event | ||||||
Event type 1 | ||||||
Event type 2 | ||||||
Event type 3 | ||||||
Etc |