| Figure 1. Methodological quality summary: review authors' judgements about each methodological quality item for each included trial. |
| Figure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included trials. |
| Figure 3. Trial sequential analysis (TSA): peginterferon alpha-2a versus peginterferon alpha-2b on the outcome serious adverse events.The diversity-adjusted required information size of n = 4799 patients was calculated based upon a proportion of 13.0% of patients with serious adverse events in the peginterferon alpha-2b group, a relative risk reduction of 20% in peginterferon alpha-2a group, an alpha (type I error) of 5%, a beta (type II error) of 20%, and a diversity (D) of 0%. The solid blue curve presents the cumulative meta-analysis Z-score and the inward sloping red curves present the two-sided Lan-DeMets trial sequential monitoring boundaries. The cumulative Z-score reaches the area of futility delineated by the two trial sequential monitoring boundaries. |
| Figure 4. Funnel plot of comparison: 1 Peginterferon alpha-2a versus peginterferon alpha-2b, outcome: 1.4. Adverse events leading to treatment discontinuation. |
| Figure 5. Trial sequential analysis (TSA): peginterferon alpha-2a versus peginterferon alpha-2b on the outcome adverse events leading to treatment discontinuation.The diversity-adjusted required information size of n = 12,832 patients was calculated based upon a proportion of 9.0% of patients with treatment discontinuation in the peginterferon alpha-2b group, a relative risk reduction of 20% in peginterferon alpha-2a group, an alpha (type I error) of 5%, a beta (type II error) of 20%, and a diversity (D) of 81%. The solid blue curve presents the cumulative meta-analysis Z-score and the inward sloping red curves present the adjusted threshold for statistical significance according to the two-sided Lan-DeMets trial sequential monitoring boundaries. The cumulative Z-score does not cross any of the monitoring boundaries and does not reach the area of futility delineated by the two trial sequential monitoring boundaries which are not even drawn by the program due to the fact that the distance between the acquired and the required information size is too large. |
| Figure 6. Funnel plot of comparison: Peginterferon alpha-2a versus peginterferon alpha-2b, outcome: 1.8 Sustained virological response. |
| Figure 7. Trial sequential analysis (TSA): peginterferon alpha-2a versus peginterferon alpha-2b on the outcome sustained virological response. The diversity-adjusted required information size of n = 4257 patients was calculated based upon a proportion of 49.6 % of patients with sustained virological response in the peginterferon alpha-2b group, a relative risk reduction of a 10% in peginterferon alpha-2a group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity (D) of 51%. The solid blue curve presents the cumulative meta-analysis Z-score and the inward sloping red curves present the adjusted threshold for statistical significance according to the two-sided Lan-DeMets trial sequential monitoring boundaries. The cumulative Z-score reaches the area of futility (delineated by the two trial sequential monitoring boundaries), but then it crosses both the conventional significance boundary (two tailed P = 0.05) and the trial sequential monitoring boundary. |
| Figure 8. Trial sequential analysis (TSA): peginterferon alpha-2a versus peginterferon alpha-2b on the two subgroup analysis sustained virological response in participants infected with hepatitis C genotype 1 and 4. The diversity-adjusted required information size of n = 6375 patients was calculated based upon a proportion of 44.9% of patients with sustained virological response in the peginterferon alpha-2b group, a relative risk reduction of a 10% in peginterferon alpha-2a group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity (D) of 45%. The solid blue curve presents the cumulative meta-analysis test Z-score and the inward sloping red curves present the two-sided Lan-DeMets trial sequential monitoring boundaries. The cumulative Z-score almost reaches the area of futility (delineated by the two trial sequential monitoring boundaries), but then it crosses both the conventional significance boundary (two tailed P = 0.05 ) and the trial sequential monitoring boundary. |
| Figure 9. Trial sequential analysis (TSA): peginterferon alpha-2a versus peginterferon alpha-2b on the two subgroup analysis sustained virological response in patients infected with hepatitis C genotype 2 and 3.The diversity-adjusted required information size of n = 1113 patients was calculated based upon a proportion of 81.4% of patients with sustained virological response in the peginterferon alpha-2b group, a relative risk reduction of a 10% in peginterferon alpha-2a group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity (D) of 0%. The solid blue curve presents the cumulative meta-analysis Z-score and the inward sloping red curves present the two-sided Lan-DeMets trial sequential monitoring boundaries. The cumulative Z-score does not reach the area of futility (delineated by the two trial sequential monitoring boundaries), but it crosses the conventional significance boundary (two tailed P = 0.05). However, the cumulative Z-score does not cross the trial sequential monitoring boundary. |
| Figure 10. Trial sequential analysis (TSA): peginterferon alpha-2a versus peginterferon alpha-2b on the subgroup analysis on the outcome sustained virological response in trials with low risk of randomisation bias.The diversity-adjusted required information size of n = 5,624 patients was calculated based upon a proportion of 42.4 % of patients with sustained virological response in the peginterferon alpha-2b group, a relative risk reduction of a 10% in peginterferon alpha-2a group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity (D) of 71%. The solid blue curve presents the cumulative meta-analysis Z-score which reaches the area of futility (delineated by the two trial sequential monitoring boundaries), but then crosses both the conventional significance boundary (two tailed P = 0.05 not shown on the figure) and the trial sequential monitoring boundary. |
| Figure 11. Trial sequential analysis (TSA): peginterferon alpha-2a versus peginterferon alpha-2b on the subgroup analysis on the outcome sustained virological response in trials with low risk of blinding bias.The diversity-adjusted required information size of n = 2079 patients was calculated based upon a proportion of 68% of patients with sustained virological response in the peginterferon alpha-2b group, a relative risk reduction of a 10% in peginterferon alpha-2a group, an alpha (type I error) of 5%, a beta (type II error) of 10%, and a diversity (D) of 0%. The solid blue curve presents the cumulative meta-analysis Z-score and the inward sloping red curves present the two-sided Lan-DeMets trial sequential monitoring boundaries. The trial sequential monitoring boundaries were not broken by the cumulative Z-curve. |
| Analysis 1.1. Comparison 1 Peginterferon alpha-2a versus peginterferon alpha-2b, Outcome 1 All-cause mortality. |
| Analysis 1.2. Comparison 1 Peginterferon alpha-2a versus peginterferon alpha-2b, Outcome 2 Liver-related morbidity. |
| Analysis 1.3. Comparison 1 Peginterferon alpha-2a versus peginterferon alpha-2b, Outcome 3 Serious adverse events. |
| Analysis 1.4. Comparison 1 Peginterferon alpha-2a versus peginterferon alpha-2b, Outcome 4 Adverse events leading to treatment discontinuation. |
| Analysis 1.5. Comparison 1 Peginterferon alpha-2a versus peginterferon alpha-2b, Outcome 5 All other (non serious) adverse events. |
| Analysis 1.6. Comparison 1 Peginterferon alpha-2a versus peginterferon alpha-2b, Outcome 6 Sustained virological response. |
| Analysis 2.1. Comparison 2 Subgroup analysis, Outcome 1 Sustained virological response according to genotype. |
| Analysis 2.2. Comparison 2 Subgroup analysis, Outcome 2 Sustanied virological response according to treatment history. |
| Analysis 2.3. Comparison 2 Subgroup analysis, Outcome 3 Sustained virological response according to risk of bias from randomisation. |
| Analysis 2.4. Comparison 2 Subgroup analysis, Outcome 4 Sustained virological response according to risk of bias from blinding. |
| Analysis 2.5. Comparison 2 Subgroup analysis, Outcome 5 Sustained virological response in patients without HIV co-infection. |