The Power Derivative Principle, and Its Application to How and When to Perform a One-Shot Unblinded Reassessment Sample Size.

BACKGROUND: In adaptive two-group clinical trials, a current method is to perform a one-shot unblinded sample size reassessment. Whereas the interim unblinded look of the data is adjusted for inference by using the weighted Cui-Hung-Wang statistics, some questions remain: how and when to reassess the sample size? METHODS: We define the Power Derivative Principle as follows: a sample size is optimal when the derivative of the power with respect to the sample size has reached some implicit value. Applied to two-group clinical trials, this Power Derivative Principle determines a new one-shot unblinded sample size reassessment rule (including the determination of futility bounds). A full Power Derivative Strategy induces furthermore an optimal information fraction for the interim analysis. The Power Derivative Strategy is then compared to adaptive design methods proposed in the literature and to group sequential strategies. For this comparison, we used, on the one hand, the very common information fraction f = 0.5 and, on the other hand, the information fraction found as being optimal with the Power Derivative Principle. RESULTS: The optimal information fraction depends only on α-and ß-risks. For usual values of these risks, the optimal information fraction value is very close to 0.9. Moreover, with this unexpected optimal value, reassessment methods become roughly comparable (it is definitely not the case when f=0.5). CONCLUSIONS: Our results suggest that a sample size reassessment is more beneficial when considered close to the planned end of a trial, allowing a study with borderline interim results to be saved.

Enoxaparin in the treatment of deep vein thrombosis with or without pulmonary embolism: an individual patient data meta-analysis.

STUDY OBJECTIVES: Low-molecular-weight heparins have been compared with unfractionated heparin (UFH) for treatment of deep vein thrombosis (DVT). However, a comparison of their efficacy in the presence or absence of pulmonary embolism (PE) has not been studied. We estimated the efficacy and safety of enoxaparin vs UFH in patients with proximal DVT with/without symptomatic PE using a meta-analysis of individual data from randomized controlled trials. DESIGN AND SETTING: Randomized controlled trials were identified from MEDLINE, EMBASE, abstracts from international meetings on venous thromboembolism (VTE), previous meta-analyses, and trial data provided by the sponsor. PARTICIPANTS: For inclusion, randomized controlled trials had to be properly randomized; include patients with objectively diagnosed DVT; compare enoxaparin twice daily with UFH; use objective methods to assess recurrent symptomatic VTE, major bleeding, and death at 3 months; and include blind evaluation of clinical events. MEASUREMENTS: A meta-analysis was performed using the logarithm of the relative risk (RR) method. Enoxaparin in DVT treatment with/without symptomatic PE was considered noninferior to UFH for preventing VTE at 3 months if the upper limit of the 95% confidence interval (CI) of the RR (enoxaparin/UFH) was lower than a prespecified noninferiority margin (1.61). No increase in major bleeding or mortality should be observed. RESULTS: The meta-analysis included individual data from three randomized controlled trials (749 patients and 754 patients in the enoxaparin and UFH groups, respectively). The observed RR (enoxaparin/UFH) of VTE was 0.81 (95% CI, 0.52 to 1.26) for the intention-to-treat population (RR, 0.70; 95% CI, 0.43 to 1.13; for per-protocol analysis). Results did not differ for patients with clinical PE (235 patients; RR, 0.84) and without clinical PE (1,268 patients; RR, 0.71), with a nonsignificant heterogeneity test between groups (p = 0.76). A trend in favor of enoxaparin was observed for reduced mortality and major bleeding. CONCLUSIONS: The efficacy and safety of enoxaparin vs UFH for DVT treatment is not modified by the presence of symptomatic PE.

Prognostic factor analysis in patients with advanced prostate cancer treated by castration plus anandron or placebo: a final update.

PURPOSE: Different outcome results have been published in trials comparing maximal androgen blockade (MAB) with chemical or surgical castration alone. The conflicting results could be explained by the fact that patients were included with different prognostic factors. In this new analysis of the Anandron European Study, independent prognostic factors have been evaluated in order to identify those which could influence the study outcome and the impact of the treatment. MATERIAL AND METHODS: 399 out of 457 patients recruited in this study were divided in a good or poor prognostic group depending on the presence of two or more poor prognostic factors, these were pain requiring treatment, >5 bone metastases, hydronephrosis, and alkaline phosphatase >2 ULN. RESULTS: When expressed as a percentage, the improvement in time to progression, overall and cancer specific survival in the Anandron treated patients was identical in both groups. In absolute terms this improvement, however, was greater in the good prognostic group. CONCLUSION: In comparison with surgical castration MAB using Anandron, in patients with metastatic prostate cancer improves the time to objective progression, overall and cancer specific survival, irrespective of certain poor prognostic factors.