Supplement. Supplementary Material
TABLE OF CONTENTS Supplement 1: Data Review Committee – Adjudication of Causality for Mortality Supplement 2: Proportional Hazards Modeling Supplement 3: List of Investigators
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SUPPLEMENT 1: DATA REVIEW COMMITTEE – ADJUDICATION OF CAUSALITY FOR MORTALITY 1. Assessment of attributable mortality in all patients was defined as follows: a. Patients with stable disease or progression of disease at time of death. b. Patients with a partial response to treatment who died as the result of an event involving any of the sites of the original Aspergillus infection. Patients who died as a result of the toxicity of antifungal treatment.
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SUPPLEMENT 2: PROPORTIONAL HAZARDS MODELING Post-hoc analyses were conducted to compare outcomes in subgroups of clinical interest. Time to all-cause week 6 mortality was analyzed using Cox-proportional hazards model (SAS, version 9.2, PROC PHREG [SAS Institute, Cary, NC]). Patients who were alive at week 6 or withdrew consent prior to week 6 were censored. In the mITT analysis data set, there were 277 patients with 65 deaths. We began to develop the model with a list of independent variables that included the treatment effect, 16 baseline covariates (5 continuous, 10 binary, and 1 with 3 categories), and 7 screened interactions terms of baseline covariates with treatment. Two final models were developed: one with only the independent baseline covariates (Main Effects Model) and another one that included independent baseline covariates along with screened interactions of the baseline covariates with treatment (Interaction Effects Model). The following steps were used to choose a final model: 1. All the covariates included in the final model were available through the CRFs or Data Review Committee adjudication forms. The following three variables were calculated using information from the CRFs: a. Prior antifungal use (Yes or No) was obtained from the concomitant medications CRF. This included use of any systemic antifungal that has activity against Aspergillus spp. (excluding topical drugs and antifungals lacking activity against molds). b. Elevated bilirubin was considered to be positive if the total bilirubin at baseline was >2 and negative, if total bilirubin ≤2. If total bilirubin was missing at baseline, then total bilirubin measured on study days 2 and 3 were used to assess elevated bilirubin.
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c. Baseline neutropenia was assessed using either absolute neutrophil count or % neutrophil count and white blood cell count. If absolute neutrophil count 0.4 between any two covariates). 4. None of the covariates, except ‘prior antifungal use’ covariate showed a departure from the assumption of proportional hazards. The assumption was tested using Kolmogorovtype supremum test (1) based on a sample of 1000 simulated residual patterns. The hypothesis of constant hazard ratio was rejected if the P-value was
TABLE OF CONTENTS Supplement 1: Data Review Committee – Adjudication of Causality for Mortality Supplement 2: Proportional Hazards Modeling Supplement 3: List of Investigators
Downloaded From: http://annals.org/ by a University of Pittsburgh User on 05/03/2015
SUPPLEMENT 1: DATA REVIEW COMMITTEE – ADJUDICATION OF CAUSALITY FOR MORTALITY 1. Assessment of attributable mortality in all patients was defined as follows: a. Patients with stable disease or progression of disease at time of death. b. Patients with a partial response to treatment who died as the result of an event involving any of the sites of the original Aspergillus infection. Patients who died as a result of the toxicity of antifungal treatment.
Downloaded From: http://annals.org/ by a University of Pittsburgh User on 05/03/2015
SUPPLEMENT 2: PROPORTIONAL HAZARDS MODELING Post-hoc analyses were conducted to compare outcomes in subgroups of clinical interest. Time to all-cause week 6 mortality was analyzed using Cox-proportional hazards model (SAS, version 9.2, PROC PHREG [SAS Institute, Cary, NC]). Patients who were alive at week 6 or withdrew consent prior to week 6 were censored. In the mITT analysis data set, there were 277 patients with 65 deaths. We began to develop the model with a list of independent variables that included the treatment effect, 16 baseline covariates (5 continuous, 10 binary, and 1 with 3 categories), and 7 screened interactions terms of baseline covariates with treatment. Two final models were developed: one with only the independent baseline covariates (Main Effects Model) and another one that included independent baseline covariates along with screened interactions of the baseline covariates with treatment (Interaction Effects Model). The following steps were used to choose a final model: 1. All the covariates included in the final model were available through the CRFs or Data Review Committee adjudication forms. The following three variables were calculated using information from the CRFs: a. Prior antifungal use (Yes or No) was obtained from the concomitant medications CRF. This included use of any systemic antifungal that has activity against Aspergillus spp. (excluding topical drugs and antifungals lacking activity against molds). b. Elevated bilirubin was considered to be positive if the total bilirubin at baseline was >2 and negative, if total bilirubin ≤2. If total bilirubin was missing at baseline, then total bilirubin measured on study days 2 and 3 were used to assess elevated bilirubin.
Downloaded From: http://annals.org/ by a University of Pittsburgh User on 05/03/2015
c. Baseline neutropenia was assessed using either absolute neutrophil count or % neutrophil count and white blood cell count. If absolute neutrophil count 0.4 between any two covariates). 4. None of the covariates, except ‘prior antifungal use’ covariate showed a departure from the assumption of proportional hazards. The assumption was tested using Kolmogorovtype supremum test (1) based on a sample of 1000 simulated residual patterns. The hypothesis of constant hazard ratio was rejected if the P-value was
