Statistical analysis plan for the EuroHYP-1 trial: European multicentre, randomised, phase III clinical trial of the therapeutic hypothermia plus best ... View Full Text


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Article Info

DATE

2017-11-29

AUTHORS

Per Winkel, Philip M. Bath, Christian Gluud, Jane Lindschou, H. Bart van der Worp, Malcolm R. Macleod, Istvan Szabo, Isabelle Durand-Zaleski, Stefan Schwab, for the EuroHYP-1 trial investigators

ABSTRACT

BackgroundCooling may reduce infarct size and improve neurological outcomes in patients with ischaemic stroke. In phase II trials, cooling awake patients with ischaemic stroke has been shown to be feasible and safe, but the effects in functional outcomes has not yet been investigated in an adequately sized randomised clinical trial.Methods/designThe EuroHYP-1 trial is a multinational, randomised, superiority phase III clinical trial with masked outcome assessment testing the benefits and harms of therapeutic cooling in awake adult patients with acute ischaemic stroke. The outcomes dealt with here include the primary outcome the Rankin score (mRS) at day 91 +/-14 days after randomisation. The secondary and exploratory outcomes at day 91 +/-14 days unless otherwise stated encompassing: (1) death or dependency, defined as mRS score > 2; (2) death; (3) National Institutes of Health Stroke Score; (4) brain infarct size at 48 +/-24 hours; (5) EQ-5D-5 L score, and (6) WHODAS 2.0 score. Other outcomes are: the primary safety outcome serious adverse events; and the incremental cost-effectiveness, and cost utility ratios. The analysis sets include (1) the intention-to-treat population, and (2) the per protocol population. The sample size is estimated to 800 patients (5% type 1 and 20% type 2 errors). All analyses are adjusted for the protocol-specified stratification variables (nationality of centre), and the minimisation variables. In the analysis, we use ordinal regression (the primary outcome), logistic regression (binary outcomes), general linear model (continuous outcomes), and the Poisson or negative binomial model (rate outcomes).DiscussionMajor adjustments compared with the original statistical analysis plan encompass: (1) adjustment of analyses by nationality; (2) power calculations for the secondary outcomes; (3) to address the multiplicity problem using of a fixed-sequence testing procedure starting with the primary outcome followed by the secondary outcomes ordered according to falling power; (4) assignment of worst possible score to patients who are not alive at the planned date of measurement of the continuous scores; (5) improved imputations; (6) outline of a supplementary exploratory analysis of the temperature measurements and time to death; and (7) substantial reduction of sample size.Trial registrationClinicaltrials.gov, identifier: NCT01833312. 4 April 2013. More... »

PAGES

573

Journal

TITLE

Trials

ISSUE

1

VOLUME

18

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13063-017-2302-z

DOI

http://dx.doi.org/10.1186/s13063-017-2302-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1093055910

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29187242


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31 schema:description BackgroundCooling may reduce infarct size and improve neurological outcomes in patients with ischaemic stroke. In phase II trials, cooling awake patients with ischaemic stroke has been shown to be feasible and safe, but the effects in functional outcomes has not yet been investigated in an adequately sized randomised clinical trial.Methods/designThe EuroHYP-1 trial is a multinational, randomised, superiority phase III clinical trial with masked outcome assessment testing the benefits and harms of therapeutic cooling in awake adult patients with acute ischaemic stroke. The outcomes dealt with here include the primary outcome the Rankin score (mRS) at day 91 +/-14 days after randomisation. The secondary and exploratory outcomes at day 91 +/-14 days unless otherwise stated encompassing: (1) death or dependency, defined as mRS score > 2; (2) death; (3) National Institutes of Health Stroke Score; (4) brain infarct size at 48 +/-24 hours; (5) EQ-5D-5 L score, and (6) WHODAS 2.0 score. Other outcomes are: the primary safety outcome serious adverse events; and the incremental cost-effectiveness, and cost utility ratios. The analysis sets include (1) the intention-to-treat population, and (2) the per protocol population. The sample size is estimated to 800 patients (5% type 1 and 20% type 2 errors). All analyses are adjusted for the protocol-specified stratification variables (nationality of centre), and the minimisation variables. In the analysis, we use ordinal regression (the primary outcome), logistic regression (binary outcomes), general linear model (continuous outcomes), and the Poisson or negative binomial model (rate outcomes).DiscussionMajor adjustments compared with the original statistical analysis plan encompass: (1) adjustment of analyses by nationality; (2) power calculations for the secondary outcomes; (3) to address the multiplicity problem using of a fixed-sequence testing procedure starting with the primary outcome followed by the secondary outcomes ordered according to falling power; (4) assignment of worst possible score to patients who are not alive at the planned date of measurement of the continuous scores; (5) improved imputations; (6) outline of a supplementary exploratory analysis of the temperature measurements and time to death; and (7) substantial reduction of sample size.Trial registrationClinicaltrials.gov, identifier: NCT01833312. 4 April 2013.
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37 schema:keywords EQ-5D-5
38 European multicentre
39 Health Stroke Score
40 II trial
41 Institute
42 L score
43 National Institute
44 Poisson
45 Rankin score
46 Secondary outcomes
47 Stroke Score
48 WHODAS 2.0 score
49 acute ischemic stroke
50 adjustment
51 adjustment of analysis
52 adult patients
53 adverse events
54 analysis
55 analysis plan
56 analysis set
57 assessment
58 assignment
59 awake adult patients
60 awake patients
61 benefits
62 best medical treatment
63 binomial model
64 brain infarct size
65 calculations
66 clinical trials
67 continuous scores
68 cooling
69 cost-utility ratio
70 date
71 date of measurement
72 day 91
73 days
74 death
75 dependency
76 effect
77 encompasses
78 events
79 exploratory analysis
80 exploratory outcomes
81 functional outcome
82 general linear model
83 harm
84 hours
85 hypothermia
86 identifiers
87 imputation
88 infarct size
89 intention
90 ischemic stroke
91 linear model
92 logistic regression
93 mRS score
94 masked outcome assessment
95 measurements
96 medical treatment
97 minimisation variables
98 model
99 multicentre
100 multiplicity problem
101 nationality
102 negative binomial model
103 neurological outcome
104 ordinal regression
105 outcome assessment
106 outcomes
107 outline
108 patients
109 phase II trial
110 phase III clinical trials
111 plan
112 population
113 possible score
114 power
115 power calculation
116 primary outcome
117 primary safety
118 problem
119 procedure
120 protocol population
121 randomisation
122 ratio
123 reduction
124 regression
125 safety
126 sample size
127 scores
128 serious adverse events
129 set
130 size
131 statistical analysis plan
132 stratification variables
133 stroke
134 substantial reduction
135 temperature measurements
136 testing procedures
137 therapeutic cooling
138 therapeutic hypothermia
139 time
140 treat population
141 treatment
142 trials
143 utility ratio
144 variables
145 worst possible score
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