Optimal sample size division in two-stage seamless designs.

Inferentially seamless 2/3 designs are increasingly popular in clinical trials. It is important to understand their relative advantages compared with separate phase 2 and phase 3 trials, and to understand the consequences of design choices such as the proportion of patients included in the phase 2 portion of the design. Extending previous work in this area, we perform a simulation study across multiple numbers of arms and efficacy response curves.

REMAP Periop: a randomised, embedded, multifactorial adaptive platform trial protocol for perioperative medicine to determine the optimal enhanced recovery pathway components in complex abdominal surgery patients within a US healthcare system.

Introduction: Implementation of enhanced recovery pathways (ERPs) has resulted in improved patient-centred outcomes and decreased costs. However, there is a lack of high-level evidence for many ERP elements. We have designed a randomised, embedded, multifactorial, adaptive platform perioperative medicine (REMAP Periop) trial to evaluate the effectiveness of several perioperative therapies for patients undergoing complex abdominal surgery as part of an ERP.

Allocation in platform trials to maintain comparability across time and eligibility.

Platform trials, with arms entering and leaving the trial over time, are complex. In addition to trial changes over time, certain arms in a platform may come with patient restrictions. Both of these issues (time and eligibility) can create biases in comparing active arms to control.

Design and logistical considerations for the randomized adaptive non-inferiority storage-duration-ranging CHIlled Platelet Study.

Background: Platelet transfusion is a potentially life-saving therapy for actively bleeding patients, ranging from those undergoing planned surgical procedures to those suffering unexpected traumatic injuries. Platelets are currently stored at room temperature (20°C-24°C) with a maximum storage duration of 7 days after donation. The CHIlled Platelet Study trial will compare the efficacy and safety of standard room temperature-stored platelets with platelets that are cold-stored (1°C-6°C), that is, chilled, with a maximum of storage up to 21 days in adult and pediatric patients undergoing complex cardiac surgical procedures.

The Bayesian Time Machine: Accounting for temporal drift in multi-arm platform trials.

Background: Multi-arm platform trials investigate multiple agents simultaneously, typically with staggered entry and exit of experimental treatment arms versus a shared control arm. In such settings, there is considerable debate whether to limit analyses for a treatment arm to concurrent randomized control subjects or to allow comparisons to both concurrent and non-concurrent (pooled) control subjects. The potential bias from temporal drift over time is at the core of this debate.

National Institutes of Health Stroke Scale as an Outcome in Stroke Research: Value of ANCOVA Over Analyzing Change From Baseline.

National Institutes of Health Stroke Scale (NIHSS), measured a few hours to days after stroke onset, is an attractive outcome measure for stroke research. NIHSS at the time of presentation (baseline NIHSS) strongly predicts the follow-up NIHSS. Because of the need to account for the baseline NIHSS in the analysis of follow-up NIHSS as an outcome measure, a common and intuitive approach is to define study outcome as the change in NIHSS from baseline to follow-up (ΔNIHSS).

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial.

Background: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome.

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis.

Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis.

Strategies to Promote ResiliencY (SPRY): a randomised embedded multifactorial adaptative platform (REMAP) clinical trial protocol to study interventions to improve recovery after surgery in high-risk patients.

Introduction: As the population ages, there is interest in strategies to promote resiliency, especially for frail patients at risk of its complications. The physiological stress of surgery in high-risk individuals has been proposed both as an important cause of accelerated age-related decline in health and as a model testing the effectiveness of strategies to improve resiliency to age-related health decline. We describe a randomised, embedded, multifactorial, adaptative platform (REMAP) trial to investigate multiple perioperative interventions, the first of which is metformin and selected for its anti-inflammatory and anti-ageing properties beyond its traditional blood glucose control features.

Dabrafenib plus trametinib in patients with BRAF-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.

Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF-mutated cancers.

Reducing Patient Burden in Clinical Trials Through the Use of Historical Controls: Appropriate Selection of Historical Data to Minimize Risk of Bias.

Historical data have been used to augment or replace control arms in some rare disease and pediatric clinical trials. With greater availability of historical data and new methodology such as dynamic borrowing, the inclusion of historical data in clinical trials is an increasingly appealing approach for larger disease areas as well, as this can result in increased power and precision and can minimize the burden on patients in clinical trials. However, sponsors must assess whether the potential biases incurred with this approach outweigh the benefits and discuss this trade-off with the regulatory agencies.

In response: Letter on update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol.

ClinicalTrials.gov: NCT03509350. Registered on 26 April 2018.

Comparison of response adaptive randomization features in multiarm clinical trials with control.

We investigate multiple features of response adaptive randomization (RAR) in the context of a multiple arm randomized trial with control, where the primary goal is the identification of the best arm for use in a broader patient population. We maintain constant control allocation and vary the length of time until RAR is started, interim frequency, the underlying quantity used to calculate the randomization probabilities, and a threshold resulting in temporary arm dropping. We evaluate the designs on five metrics measuring benefit to the internal trial population, the future external population, and statistical estimation.

Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

Background: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock.

Methods And Design: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis.

Comparison of methods for control allocation in multiple arm studies using response adaptive randomization.

Background/aims: Response adaptive randomization has many polarizing properties in two-arm settings comparing control to a single treatment. The generalization of these features to the multiple arm setting has been less explored, and existing comparisons in the literature reach disparate conclusions. We investigate several generalizations of two-arm response adaptive randomization methods relating to control allocation in multiple arm trials, exploring how critiques of response adaptive randomization generalize to the multiple arm setting.

Using Bayesian adaptive designs to improve phase III trials: a respiratory care example.

Background: Bayesian adaptive designs can improve the efficiency of trials, and lead to trials that can produce high quality evidence more quickly, with fewer patients and lower costs than traditional methods. The aim of this work was to determine how Bayesian adaptive designs can be constructed for phase III clinical trials in critical care, and to assess the influence that Bayesian designs would have on trial efficiency and study results.

Methods: We re-designed the High Frequency OSCillation in Acute Respiratory distress syndrome (OSCAR) trial using Bayesian adaptive design methods, to allow for the possibility of early stopping for success or futility.

A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb-004) in metastatic soft-tissue sarcomas.

Background: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma.

Methods: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m gemcitabine on days 1 and 8 and 75 mg/m docetaxel on day 8).

The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

Background: Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study.

Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock: The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial.

Importance: Sepsis induces profound metabolic derangements, while exogenous levocarnitine mitigates metabolic dysfunction by enhancing glucose and lactate oxidation and increasing fatty acid shuttling. Previous trials in sepsis suggest beneficial effects of levocarnitine on patient-centered outcomes.

Objectives: To test the hypothesis that levocarnitine reduces cumulative organ failure in patients with septic shock at 48 hours and, if present, to estimate the probability that the most efficacious dose will decrease 28-day mortality in a pivotal phase 3 clinical trial.