More complex research questions are being posed in early-phase oncology clinical trials, necessitating design strategies tailored to contemporary study objectives. This paper describes the proposed design of a Phase I trial concurrently evaluating the safety of a hematopoietic progenitor kinase-1 inhibitor (Agent A) as a single agent and in combination with an anti-PD-1 agent in patients with advanced malignancies. The study’s primary objective was to concurrently determine the maximum tolerated dose (MTD) of Agent A with and without anti-PD-1 therapy among seven possible study dose levels.

Our solution to this challenge was to apply a continual reassessment method shift model to meet the research objectives of the study.

The application of this method is described herein, and a simulation study of the design’s operating characteristics is conducted. This work was developed through collaboration and mentoring between the authors at the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual AACR/ASCO Methods in Clinical Cancer Research Workshop.

The aim of this manuscript is to highlight examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying modern design conditions. Although the design is presented using an investigation of Agent A with and without anti-PD-1 therapy as an illustrative example, the approach described is not specific to these agents and could be applied to other concurrent monotherapy and combination therapy studies with well-defined binary safety endpoints.

We describe how patient and public involvement (PPI) was integrated into the design of an intervention for a randomised controlled trial (RCT) based within primary care. The RCT, known as the PLEASANT trial, aimed to reduce unscheduled medical contacts in children with asthma associated with start of the new school year in September with a simple postal intervention, highlighting the importance of maintaining asthma medication for helping to prevent increased asthma exacerbations.

PPI is a key feature of UK health research policy, and is often a requirement of funding from the National Institute for Health Research. There are few detailed accounts of PPI in the design and conduct of clinical trials in the PPI literature for researchers to learn from.

We held PPI consultation events to determine whether the proposed intervention for the trial was acceptable to children with asthma and their parents, and to ascertain whether enhancements should be made. Two PPI consultation events were held with children with asthma and their parents, prior to the research commencing. Detailed field notes were taken by the research team at each consultation event.

At the first consultation event, parents and children endorsed the trial’s rationale, made suggestions to the wording of the trial intervention letter, and made recommendations about to whom the letter should be sent out. At the second consultation event, parents discussed the timing of the intervention, commented on the lay summary of the Research Ethics Application, and were invited to join the trial’s steering committee, while the children selected a logo for the study. PPI has resulted in enhancements to the PLEASANT study’s intervention. A further PPI consultation event is scheduled for the end of the trial, in order for children with asthma and their parents to contribute to the trial’s dissemination strategy.

Response to antidepressant medication is higher in comparator versus placebo-controlled randomized controlled trials (RCTs). Patient expectancy is an important influence on clinical outcome in the treatment of depression and may explain this finding. The results are reported from a pilot RCT studying expectancy and depression outcome in placebo-controlled versus comparator treatment conditions.

Out-patients aged 18–65 years with major depressive disorder (MDD) were enrolled in this 8-week RCT. Subjects were randomized to placebo-controlled (escitalopram or placebo) or comparator (escitalopram or citalopram) administration of antidepressant medication. Subjects reported their expected likelihood and magnitude of depression improvement before and after randomization using questions from the Credibility and Expectancy Scale (CES). A regressed change model of post-randomization expectancy of improvement was fit to the data to determine whether subjects in the comparator group reported greater expectancies of improvement than subjects in the placebo-controlled group.

Twenty subjects with mean age 56.5±11.7 years, a baseline Hamilton Depression Rating Scale (HAMD) score of 24.2±5.3, baseline Beck Depression Inventory (BDI) score of 24.9±6.4 and baseline Clinical Global Impressions (CGI) – Severity score of 4.0±0.3 were enrolled in the study. Adjusting for other factors, the effect of group assignment on expected magnitude of improvement was significant and large (effect size 1.5). No group differences in expected likelihood of improvement were found.

Randomization to comparator versus placebo-controlled administration of antidepressant medication produced greater expectancies of how much patients would improve during the trial. This expectancy difference may explain the higher response and remission rates that are observed in comparator versus placebo-controlled trials.