A multi-laboratory preclinical trial to assess treatment candidates for acute ischemic stroke

All data needed for the graphs published in Science Translational Medicine are provided.

Description of the data and file structure

Tables contain the results of the corner test, the MR imaging organized by subject ID. Treatment group data is available in the feasibility file. These are contained in the following files:

dt_feasibility_stm_paper_2023-08-21.xls
dt_outcome_corner_stm_paper_2023-08-21.xls
dt_outcome_mri_stm_paper 2023-08-21.xls
report_stm_paper_2023-07-29.html

The first 3 files are Excel files that contain data listings in tab 1 and data definition dictionay in tab 2. The treatment group variables can be found in the first file and applied to the remaining files by matching on the animal identity variable 'enro_animal_id'. The variable 'txas_tx_group' contains a code that gives the treatment group to which the subject was assigned. The variable 'txas_tx_group_actual' gives a code for the treatment group actually recieved. The corresponding drug treatment names can be found in tab 2 and in the main paper itself.

The final html file is a report used to define the various study populations, including the enrolled (pop_enro), the inelegible to be randomized, the intention to treat (pop_itt), the excluded animals, the procedural dropouts, the modified intention to treat (pop_mitt), the partial treatments, the per protocol treated animals, and the loss to followup (died) animals.

Sharing/Access information

Links to other publicly accessible locations of the data:

www.spannetwork.org is a repository of all SPAN SOPs

Code/Software

(Citations and figures can be found in the SPAN publication)
SPAN selected a recently developed MAMS design as it is more efficient than multiple individual trials. Validated, user-friendly MAMS R-code has been published (56) based on a generalized Dunnett’s procedure (33). SPAN implemented the MAMS design with four stages using predefined futility and efficacy boundaries( 33). Stages 1 – 3 ended with planned interim analyses performed after 25, 50 and 75% recruitment and one final analysis of the entire dataset after Stage 4. The Statistical Analysis Plans (see Supplemental Material) provide a detailed description of the planned analysis for each endpoint (30).
The primary outcome used in the MAMS was the 30-day corner test. To estimate needed sample size, simulations were performed using the MAMS R-package (92). From prior reports of the corner test in aged mice, we estimated mean of 0.55 and standard deviation (SD) of 0.262 turning index (left turns/total turns) for the control arm(47). We inflated the estimated standard deviation to 1.048 as a conservative assumption to account for probable variability among SPAN research laboratories. The power of 90% was calculated under the least favorable configuration, which was defined as the probability of rejecting only one null hypothesis in any stage(93). Total sample size was then adjusted assuming 10% animal death over 30 days.

At the end of each stage, an interim analysis of the primary outcome was performed that included all subjects up to that analysis. Each treatment was compared to the appropriate control group (pooled IV/IP or RIC sham), adjusting for laboratory, sex, baseline corner test index, animal model (stages 2-4) and whether the subjects remained under anesthesia during MCA occlusion (Stage 1 only). Stopping rules included an estimated treatment effect size ((intervention – control)/sd) greater than an upper limit of 50% (change of 0.5 x 0.55 = 0.275) and less than a lower limit of 6% (change 0.06 x 0.55 = 0.033) treatment effect size.” The projected boundaries at each interim analysis comprise a ‘triangle’ of upper and lower criteria for the five drug treatments compared against a pooled IV and IP control group (Fig. 3C). The RIC intervention was compared against the RIC sham group (Fig. 3D). The Steering Committee reviewed each interim analysis to decide which models to use and which interventions to continue in the next stage. At the end of Stage 3, the SC decided to study the one remaining intervention in young rats since all prior testing had been done in mice, other than SHRs. The Steering Committee making these decisions remained blinded to the treatment arm identity throughout all four stages.