<p>Interim efficacy analysis plan BASICS trial</p><p>Summary of the BASICS trial Objective: Evaluate the efficacy and safety of additional IA therapy in addition to best medical management in patients with basilar artery occlusion. Study design: Randomised, multi-centre, open label, controlled phase III, treatment trial Study population: Patients, aged 18 or older, treated with IVT and with CTA, MRA or conventional angiography confirmed basilar occlusion. Intervention: Patients will be randomised between additional IA therapy followed by maximum supportive care versus maximum supportive care alone. IA therapy has to be initiated within 6 hours from estimated time of BAO. If treated with IVT as part of best medical management, IVT should be started within 4.5 hours of estimated time of BAO. Main study parameters/endpoints: Favourable outcome at day 90 defined as a modified Rankin Score (mRS – functional scale) of 0-3. Safety outcomes: Symptomatic intracranial haemorrhage at 24 hours CT imaging,  6 hours and mortality at 90 days. Sample size calculation: Assuming an odds ratio of 2.0 for favourable outcome at 90 days by additional IA therapy by comparison with maximum supportive care alone, we calculated that 282 patients would be needed. This calculation was based on a type 1 error of 5%, a type 2 error of 20%, and a presumed incidence of the primary outcome event of 30% in the maximum supportive care group. This latter incidence was based on data of the BASICS registry study.1 (nQuery Advisor, version 7) To account for potential dropout a target of 300 patients is set.</p><p>Interim analysis plan The BASICS trial will be analysed using a group sequential triangular design and the primary endpoint is favourable outcome (i.e. modified Rankin Score between 0 and 3) at 90 days. The study is designed to have 80% power to detect an odds ratio for pe vs. p0 of 2.0 (p0 = 30%) in favourable outcome between the additional IA therapy arm compared to the maximum supportive care alone arm with a two sided significance level of 5%. Using PEST 3.0 software, the boundaries of the triangular test were calculated (Figure 1). </p><p>The equations of the upper and lower boundaries are Z = 6.150 + 0.2436*V and -6.150 + 0.7308*V, respectively and the apex is located at V = 25.25 and Z = 12.30. These two lines delineate the continuation region (situated in between the lines) from the regions of non- rejection and of rejection of the null hypothesis. At each analysis, Z and V are computed from all the data collected since the beginning of the study and the Z is plotted against V, thus defining a point on the sequential plan. The consecutive points define a sample path. The trial is continued and new patients are included as long as the sample path remains in the continuation region. A conclusion is reached as soon as the sample path crosses one of the boundaries of the test. If the sample path crosses the upper boundary, the experimental treatment is demonstrated to be significantly superior to the control. If the sample path crosses the lower boundary before or after V = 3.202, the experimental treatment is significantly inferior to or non-significantly different from the control treatment, respectively.. Under the null hypothesis, an average of 159 patients in total (90th percentile = 250) would be needed and under the alternative hypothesis an average of 187 patients (90th percentile = 288) would be needed. For comparison, the total fixed sample size would be 277.</p><p>Interim analyses will be carried out after each additional 25 patients or after six months, whichever comes first. Figure 1: Adapted triangular test for the BASICS trial. (Upper boundary = 6.150 + 0.2436*V; Lower boundary = -6.150+0.7308*V)</p><p>Regarding safety the following stop criterion will be used. The BASICS registry observed that the risk of symptomatic intracranial haemorrhage in patients treated with IA therapy was 14% (95% CI 10-18%) and 7% (95%CI 3-11%) in those treated with IVT only.1 If during the monitoring of the BASICS trial the lower limit of the 95% confidence interval of the symptomatic intracranial haemorrhage rate in the group treated additional IA therapy is higher than 14% the DMC may advice to stop the trial.</p><p>The BASICS Trial Office will put an active follow-up system into effect, such that for each patient 90-day follow-up data and those on the occurrence of symptomatic intracranial haemorrhage are obtained without delay. After the collection of the follow-up data on twenty- five patients or after 6 months since the previous interim analysis – whichever comes first - and after each safety outcome these data will be sent to a statistician who is an intermediate between the Steering Committee and the DMC. This statistician (Dr. M.W.T. Tanck at Academic Medical Center Amsterdam) will perform an interim analysis with the PEST program and forward the results to the DMC. Every six months the DMC will advise the steering committee about the continuation of the trial. The recommendation on the continuation will be based on 1) stopping rules as described above and 2) the most recent information from medical literature or congresses in the field of cerebrovascular disease.</p><p>Reference </p><p>(1) Schonewille WJ, Wijman CAC, Michel P, Rueckert CM, Weimar C, Mattle HP, Engelter ST, Tanne D, Muir KW, Molina CA, Thijs V, Audebert H, Pfefferkorn T, Szabo K, Lindsberg PJ, de Freitas G, Kappelle LJ, Algra A, on behalf of the BASICS Study Group. Treatment and outcomes of patients with acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS); a prospective analysis of registry data. Lancet Neurol 2009;8:724-30.</p>