Hypothesis testing for two-stage designs with over or under enrollment

Simon’s two-stage designs are widely used in cancer phase II clinical trials for assessing the efficacy of a new treatment. However in practice, the actual sample size for the second stage is often different from the planned sample size, and the original inference procedure is no longer valid. Previous work on this problem has certain limitations in computation. In this paper, we attempt to maximize the unconditional power while controlling for the type I error for the modified second stage sample size. A normal approximation is used for computing the power, and the numerical results show that the approximation is accurate even under small sample sizes. The corresponding confidence intervals for the response rate are constructed by inverting the hypothesis test, and they have reasonable coverage while preserving the type I error

Bayesian design of superiority clinical trials for recurrent events data with applications to bleeding and transfusion events in myelodyplastic syndrome: Bayesian Design of Superiority Clinical Trials for Recurrent Events Data with Applications

In many biomedical studies, patients may experience the same type of recurrent event repeatedly over time, such as bleeding, multiple infections and disease. In this article, we propose a Bayesian design to a pivotal clinical trial in which lower risk myelodysplastic syndromes (MDS) patients are treated with MDS disease modifying therapies. One of the key study objectives is to demonstrate the investigational product (treatment) effect on reduction of platelet transfusion and bleeding events while receiving MDS therapies. In this context, we propose a new Bayesian approach for the design of superiority clinical trials using recurrent events frailty regression models. Historical recurrent events data from an already completed phase 2 trial are incorporated into the Bayesian design via the partial borrowing power prior of Ibrahim et al. (2012, Biometrics 68, 578–586). An efficient Gibbs sampling algorithm, a predictive data generation algorithm, and a simulation-based algorithm are developed for sampling from the fitting posterior distribution, generating the predictive recurrent events data, and computing various design quantities such as the type I error rate and power, respectively. An extensive simulation study is conducted to compare the proposed method to the existing frequentist methods and to investigate various operating characteristics of the proposed design

Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) Following Blinatumomab-Induced Remission in Pediatric Patients with Relapsed/Refractory (r/r) B-Precursor Acute Lymphoblastic Leukemia (ALL): Preliminary Results from a Phase I/II Stud

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Multivariate Recurrent Events in the Presence of Multivariate Informative Censoring with Applications to Bleeding and Transfusion Events in Myelodysplastic Syndrome

<div><p>We propose a general novel class of joint models to analyze recurrent events that has a wide variety of applications. The focus in this article is to model the bleeding and transfusion events in myelodysplastic syndrome (MDS) studies, where patients may die or withdraw from the study early due to adverse events or other reasons, such as consent withdrawal or required alternative therapy during the study. The proposed model accommodates multiple recurrent events and multivariate informative censoring through a shared random-effects model. The random-effects model captures both within-subject and within-event dependence simultaneously. We construct the likelihood function for the semiparametric joint model and develop an expectation–maximization (EM) algorithm for inference. The computational burden does not increase with the number of types of recurrent events. We utilize the MDS clinical trial data to illustrate our proposed methodology. We also conduct a number of simulations to examine the performance of the proposed model.</p> </div

Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx Results of Phase 1 and Phase 2 Studies

Targeting angiotensinogen (AGT) may provide a novel approach to more optimally inhibit the renin-angiotensin-aldosterone system pathway. Double-blind, placebo-controlled clinical trials were performed in subjects with hypertension as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with IONIS-AGT-LRx versus placebo up to 2&nbsp;months. IONIS-AGT-LRx was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function. IONIS-AGT-LRx significantly reduced AGT levels compared with placebo in all 3 studies. Although not powered for this endpoint, trends were noted in blood pressure reduction. In conclusion, IONIS-AGT-LRx significantly reduces AGT with a favorable safety, tolerability, and on-target profile. (A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx; NCT04083222; A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure; NCT03714776; Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ionis AGT-LRx in Healthy Volunteers; NCT03101878)

A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide

<p>Abstract</p> <p>Background</p> <p>Lenalidomide treatment in myelodysplastic syndrome (MDS) may lead to thrombocytopenia and dose reductions/delays. This study evaluated the safety and tolerability of the thrombopoietin mimetic romiplostim and its effects on the incidence of clinically significant thrombocytopenic events (CSTEs) in lower risk MDS patients receiving lenalidomide.</p> <p>Methods</p> <p>Patients were assigned to weekly placebo (n = 12) or romiplostim 500 μg (n = 14) or 750 μg (n = 13) for four 28-day lenalidomide cycles.</p> <p>Results</p> <p>The treatment groups were generally similar with respect to baseline disease characteristics. Del(5q) abnormalities were noted in 1 (8%) patient in the placebo group, 3 (21%) in the romiplostim 500 μg group, and two (15%) in the 750 μg group. CSTEs were noted in 8 (67%) patients in the placebo group, 4 (29%) in the romiplostim 500 μg group, and 8 (62%) in the romiplostim 750 μg group. Throughout the study, median platelet counts trended lower in placebo-treated than in romiplostim-treated patients. Thrombocytopenia-related adjustments in lenalidomide occurred in 6 (50%) patients in the placebo group, 5 (36%) in the romiplostim 500 μg group, and 2 (15%) in the 750 μg group. Although the percentages of patients who received platelet transfusions were similar across treatment groups, there was a trend toward lower numbers of transfusions in both romiplostim groups during each treatment cycle. There were two serious treatment-related adverse events during the treatment period (cerebrovascular accident, placebo; worsening thrombocytopenia, romiplostim 500 μg). Two patients (romiplostim 500 and 750 μg, respectively) had an increase in bone marrow blasts to >20% during treatment, but had no post-treatment biopsy to confirm or exclude the diagnosis of progression to AML.</p> <p>Conclusions</p> <p>These data suggest that romiplostim administered to MDS patients during lenalidomide treatment may decrease the frequency of dose reductions/delays due to thrombocytopenia. Additional study is needed to confirm the results of this preliminary trial.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00418665</p

Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data

<p><strong>Article full text</strong></p> <p><br> The full text of this article can be found <a href="https://link.springer.com/article/10.1007/s12325-016-0447-x"><b>here</b>.</a><br> <br> <strong>Provide enhanced digital features for this article</strong><br> If you are an author of this publication and would like to provide additional enhanced digital features for your article then please contact <u>[email protected]</u>.<br> <br> The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.<br> <br> Other enhanced features include, but are not limited to:<br> • Slide decks<br> • Videos and animations<br> • Audio abstracts<br> • Audio slides<u></u></p

Subcutaneous or Intravenous Administration of Romiplostim in Thrombocytopenic Patients With Lower Risk Myelodysplastic Syndromes

BACKGROUND: Romiplostim is a peptibody protein that augments thrombopoiesis by activating the thrombopoietin receptor. METHODS: In this phase 2, multicenter, open-label study, 28 thrombocytopenic patients with lower risk myelodysplastic syndromes (MDS) were assigned to receive romiplostim 750 mu g administered subcutaneously either weekly or biweekly or administered as biweekly intravenous injections for 8 weeks. Patients also could enter a 1-year study extension phase. RESULTS: At least 1 adverse event was observed in 93% of patients. The most common adverse events were fatigue and headache (18% for both, and 5 events were grade 3 or 4. There was 1 serious treatment-related adverse event in the biweekly intravenous cohort (hypersensitivity). This hypersensitivity resolved without discontinuation of study treatment. No patients developed neutralizing antibodies or bone marrow fibrosis. Of the patients who completed 8 weeks of treatment, 57% had a complete platelet response, an additional 8% had a major platelet response, and 61% did not require a platelet transfusion during this period. Weekly subcutaneous injections achieved the highest mean trough concentrations. CONCLUSIONS: The safety and efficacy profiles of romiplostim in this study suggested that weekly subcutaneous administration of 750 jig romiplostim is an appropriate starting dose for future clinical studies in patients with MDS and thrombocytopenia. Cancer 2011;117:992-1000. (C) 2010 American Cancer Society