A proposed approach for analyzing post-study therapy effect in survival analysis.

Clinical trials that explore long-term endpoints may confound the analysis when post-study therapy effects are considered. This article introduces a procedure to mediate the effects of confounding and allow inferences of first-line experimental treatments in the presence of post-study therapy. The procedure is evaluated by intensive simulation analyses and applied to an analysis of a clinical cancer trial.

Predicting analysis time in events-driven clinical trials using accumulating time-to-event surrogate information.

For clinical trials with time-to-event endpoints, predicting the accrual of the events of interest with precision is critical in determining the timing of interim and final analyses. For example, overall survival (OS) is often chosen as the primary efficacy endpoint in oncology studies, with planned interim and final analyses at a pre-specified number of deaths. Often, correlated surrogate information, such as time-to-progression (TTP) and progression-free survival, are also collected as secondary efficacy endpoints. It would be appealing to borrow strength from the surrogate information to improve the precision of the analysis time prediction. Currently available methods in the literature for predicting analysis timings do not consider utilizing the surrogate information. In this article, using OS and TTP as an example, a general parametric model for OS and TTP is proposed, with the assumption that disease progression could change the course of the overall survival. Progression-free survival, related both to OS and TTP, will be handled separately, as it can be derived from OS and TTP. The authors seek to develop a prediction procedure using a Bayesian method and provide detailed implementation strategies under certain assumptions. Simulations are performed to evaluate the performance of the proposed method. An application to a real study is also provided. Copyright © 2015 John Wiley & Sons, Ltd.

A proposed statistical framework for the management of subgroup analyses for large clinical trials.

Planned and unplanned subgroup analyses of large clinical trials are frequently performed and the results are sometimes difficult to interpret. The source of a nominal significant finding may come from a true signal, variation of the clinical trial outcome or the observed data structure. Quantitative assessment is critical to the interpretation of the totality of the clinical data. In this article we provide a general framework to manage subgroup analyses and to interpret the findings through a set of supplement analyses to planned main (primary and secondary) analyses, as an alternative to the commonly used multiple comparison framework. The proposed approach collectively and coherently utilizes several quantitative methods and enhances the credibility and interpretability of subgroup analyses. A case study is used to illustrate the application of the proposed method.

Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation.

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.

Dose conversion and titration with a novel, once-daily, OROS osmotic technology, extended-release hydromorphone formulation in the treatment of chronic malignant or nonmalignant pain.

The objective of this open-label, repeated-dose, single-treatment, multicenter study was to evaluate the outcomes associated with a standardized conversion from prior opioid therapy to a novel, once-daily, OROS osmotic technology, extended-release (ER) hydromorphone formulation in an outpatient population with chronic malignant or nonmalignant pain. The study period was divided into 3 phases: the prior opioid stabilization phase (> or =3 days), the conversion and titration phase (3-21 days), and the maintenance phase (14 days). Patients were evaluated at 5 visits during the study period. Analgesic efficacy was measured using the Brief Pain Inventory (BPI). At baseline, patients were required to have daily oral morphine equivalent requirements of > or =45 mg. Prior oral or transdermal opioid therapy was converted to single daily doses of ER hydromorphone (8, 16, 32, and 64 mg tablets) at a 5:1 (morphine equivalent to hydromorphone) ratio. Immediate-release (IR) hydromorphone was given as rescue medication for breakthrough pain. Among the 445 patients who enrolled, 404 received the study medication. Of these, 73 (18.1%) had chronic malignant pain and 331 (81.9%) had chronic nonmalignant pain. Dose stabilization (defined as a 3-day period during which the total daily dose of ER hydromorphone remained unchanged and < or =3 doses of IR hydromorphone per day were required) was attained by 73.8% of patients (298/404), of whom 70.1% (209/298) were stabilized with < or =2 titration steps. The mean +/- standard deviation (SD) time to dose stabilization was 12.1 +/- 5.7 days (range of 3 to 33 days). The mean +/- SD final daily dose of ER hydromorphone was 63.4 +/- 129.2 mg. The mean +/- SD final daily dose of IR hydromorphone was 11.5 +/- 36.4 mg, and the mean +/- SD final number of daily doses of IR hydromorphone was 1.7 +/- 1.3. Intent-to-treat and completer analysis demonstrated significant improvements in BPI ratings from prior opioid therapy to the end of ER hydromorphone therapy (P < 0.01 for all pairwise comparisons). Adverse events were consistent with those expected of an opioid agonist in such a patient group, affecting primarily the gastrointestinal and central nervous systems. This uncontrolled study delineates a regimen by which patients with chronic malignant or nonmalignant pain can be readily converted from prior opioid therapy and titrated to an appropriate maintenance dose of ER hydromorphone. Controlled longitudinal studies are required to further evaluate the use of ER hydromorphone in patients with discrete chronic malignant or nonmalignant pain conditions.

Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of moderate or severe acute low back pain.

BACKGROUND: Introduced in 1997, the combination of hydrocodone and ibuprofen is the only fixed-dose combination analgesic containing an opioid and ibuprofen that has been approved by the US Food and Drug Administration. OBJECTIVE: This study compared the efficacy and tolerability of combination hydrocodone 7.5 mg and ibuprofen 200 mg (HC/IB) with those of combination oxycodone 5 mg and acetaminophen 325 mg (OX/AC) in the treatment of moderate or severe acute low back pain. METHODS: This was a multicenter, randomized, double-blind, parallel-group, repeat-dose study lasting up to 8 days. The recommended dosing of the study medications was 1 tablet every 4 to 6 hours, not to exceed 5 tablets per day. If adequate pain relief was not obtained, patients were permitted to take up to 4 doses per day of supplemental analgesic medication-the nonopioid component of the assigned study medication (ibuprofen 200 mg or acetaminophen 325 mg). Measures of efficacy included mean daily pain relief scores (0 = no relief, 1 = slight relief, 2 = moderate relief, 3 = good relief, and 4 = complete relief), mean daily number of tablets and doses of study medication, mean daily number of tablets and doses of supplemental analgesic medication, global evaluation (poor, fair, good, very good, or excellent), and results on the modified 36-item Short-Form Health Survey (SF-36). All efficacy measures were analyzed on an intent-to-treat basis. Tolerability was evaluated based on adverse events reported spontaneously or elicited by the in vestigators using nonsuggestive questioning, as well as on the number of patients discontinuing treatment because of adverse events. RESULTS: The study enrolled 147 patients (75 HC/IB, 72 OX/AC). The most common cause of low back pain was muscular/ligamentous injury (97/147; 66.0%), followed by degenerative disk disease (27/147; 18.4%). At baseline, 80 patients (54.4%) reported experiencing moderate pain, and 67 patients (45.6%) reported experiencing severe pain. There were no significant differences between HC/IB and OX/AC with regard to mean ( +/- SD) daily pain relief scores (2.40 +/- 1.06 vs 2.50 +/- 1.01, respectively), mean daily number of tablets of study medication (1.80 +/- 1.70 vs 2.20 +/- 1.60), mean daily number of doses of study medication (1.80 +/- 1.65 vs 2.10 +/- 1.58), mean daily number of tablets of supplemental analgesic medication (0.60 +/- 1.13 vs 0.50 +/- 0.99), mean daily number of doses of supplemental analgesic medication (0.60 +/- 1.07 vs 0.50 +/- 0.90), global evaluations, or mean scores on the modified SF-36. In addition, there were no significant differences in the proportion of patients experiencing adverse events with HC/IB (47; 62.7%) and OX/AC (45; 62.5%). Adverse events were consistent with those generally associated with the component analgesics and predominantly involved the central nervous system and gastrointestinal system. CONCLUSIONS: The results of this study suggest that HC/IB and OX/AC are similarly effective and tolerable in relieving moderate or severe acute low back pain. Additional controlled longitudinal trials are necessary to evaluate the clinical utility of HC/IB in treating acute low back pain.