6.5 Prior and Concurrent Medications Prior and concomitant medications will be coded using World Health Organization (WHO) drug dictionary version March 2013 (or higher), and will be summarised by preferred term and/or ATC class. Medications administered prior to the expected first dose of study will be considered prior medications. Concomitant therapies will be those that are taken on or after Study Day 1 through 30 days after the last dose of study drug. Medications started prior to Study Day 1 and continued into the treatment period will be included in the summary of concomitant therapies. Incidence of prior medication and concomitant therapies will be summarized by preferred term. 7 Efficacy Analyses Heat Biologics, Inc. Protocol HS410-101 HS410-101 SAP version 1.0 Page 19 of 25 All efficacy analyses for recurrence or progression will use standard TNM disease staging, specifically with the following T stage hierarchy: Ta<TIS<T1<T2<T3<T4, and Low Grade<High Grade. 7.1 Primary Efficacy Analysis The primary efficacy parameter is 1 year DFS and will be conducted on the ITT population. It will be calculated as the proportion of patients in the experimental groups and the control who remain disease free at 1 year. Hypothesis testing on the primary endpoint will be done one-sided at a level of significance of α = 0.10 using Fisher's exact test. The absolute difference in proportions, as well as the odds ratio, with the associated 95% confidence intervals will also be presented. The following rules will be used to determine whether a patient is disease free at 1 year or not  If a patient has a recurrence before day 394 (ie day 366+28 days) or has dropped out of the study before day 394, then the patient is considered to be not disease free at 1 year.  If a patient is shown to be free from disease on day 366 +/- 28 days, then the patient is considered to be disease free at 1 year.  If a patient has no recurrence before day 338 (ie day 366-28 days) and after day 394 (day 366+28 days), then the patient is considered to be disease free at 1 year. If the analysis of the primary endpoint does not suggest any dose response effect between the two vaccine arms, an exploratory analysis will be conducted where the two vaccine arms will be pooled and compared to the control arm for the primary endpoint (proportion of patients alive and disease-free at one year). The outcome will be presented as OR with 95% CI relative to the control group. In an additional exploratory analysis, the proportion of patients whose disease has recurred to a lower stage than at screening and the proportion of patients whose disease has recurred to the same extent (or greater) as at screening will be compared between the experimental and control groups and presented as an OR with 95% CI. 7.2 Secondary Efficacy Analyses For time-to-event endpoints (e.g. DFS, OS), Kaplan-Meier / product limit method will be used to estimate the survival distributions over time, and to estimate median time to event. Where appropriate, inference for time-to-event endpoints will be assessed using the Log-rank test statistic, and the treatment effect will be estimated using Cox proportional hazards model. The assumption of proportional hazards will be assessed graphically. The following will be analysed using Kaplan-Meier time-to-event methodology:  Time To Recurrence, defined as the time from randomization to recurrence. o Recurrence is defined as disease that has recurred to the same extent of disease (ie same stage / severity) or to a lower stage/severity of disease compared to screening. o If recurrence has not occurred in a patient, the date of last disease assessment will be used as the timepoint for censoring. o The analysis will be repeated in an exploratory manner where recurrence is defined as only those recurrences to the same extent of disease (or greater) as screening. Heat Biologics, Inc. Protocol HS410-101 HS410-101 SAP version 1.0 Page 20 of 25  Time To Progression, defined as the time from randomization to progression. o Progression is defined as an increase in T stage from CIS or Ta (at screening) to T1 (lamina propria invasion), development of T2 or greater or lymph node (N+) disease or distant metastasis (M1), or an increase in grade from low to high per the IBCG recommendations.. o If progression has not occurred in a patient, the date of last disease assessment will be used as the timepoint for censoring.  Disease-Free Survival, defined as the time from randomization to recurrence or progression. o If a patient has recurred or progressed, then the first date the recurrence or progression has occurred will be used as the timepoint for the event. o If a patient has neither recurred nor progressed, then the date of last disease assessment will be used as the timepoint for censoring.  Overall Survival, defined as the the time from randomization to death. o If a patient is still alive, then the patient will be censored on the date of most recent date known alive. o If a patient is lost to follow up, then the patient will be censored on the date last known alive.  Time to cystectomy, defined as the time from randomization to cystectomy. o If a patient has not undergone cystectomy, the patient will be censored on the date of last disease assessment.  Burden of repeat TURBT, defined as the proportion of patients with no repeat TURBT vs 1 TURBT vs 2 TURBT vs 3 TURBT etc within 12 months since randomization (ie day 366 or earlier), within 18 months since randomization (ie day 548 or earlier) and within 24 months since randomization (ie day 731 or earlier). For time to recurrence, time to progression, disease-free survival and overall survival, the Kaplan-Meier estimates on the proportion of patients free from the event of interest at 3, 6, 9, 12, 18 and 24 months from randomization will be presented. For time to cystectomy, the Kaplan-Meier estimates on the proportion of patients with cystectomy at 12, 18 and 24 months from randomization will be presented. In addition, the time to cystectomy from original TURBT will be analysed in a similar way, and the data will be presented as sensitivity analysis. For intensity of repeat TURBT, the same analysis will be repeated using the 12, 18 and 24 months since original TURBT, as sensitivity analysis. 7.3 Exploratory Analyses Heat Biologics, Inc. Protocol HS410-101 HS410-101 SAP version 1.0 Page 21 of 25 All primary and secondary efficacy endpoints will be reanalysed in the Per-protocol population. If available in a suitable timeframe before reporting, immunologic response data will be listed in the CSR. If applicable, summaries and exploratory analyses will be specified in a separate analysis plan and presented in a separate report. The following endpoints will be analysed:  immunologic response of PBMCs,  total PBMC counts by flow cytometry,  evaluation of tumour tissue obtained from pre-treatment resection for antigen expression by immunohistochemical analysis,  evaluation of tumour tissue obtained from repeat biopsy, if clinically indicated, for presence of infiltrating T-lymphocytes,  T cell receptor sequencing of peripheral blood T cells before and during the course of treatment  Tissue immune cell infiltration, and inflammatory cytokine levels in urine 8 Safety Analyses Safety comparisons will be performed on all patients who received at least one dose of experimental treatment in both phases of the study. The safety variables to be analyzed include vital sign measurements, AEs, ECGs, routine hematology, coagulation factors, serum chemistry, urinalysis , and deaths.