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'25 at 25': Optimising treatments using the ROCI design

21 Nov 2024

Over the 25-year history of the MRC Clinical Trials Unit at UCL, our methodology researchers have pioneered several innovative designs to make randomised clinical trials more efficient and robust. This piece in our ‘25 at 25’ series focuses on one such design, called Response Over Continuous Intervention (ROCI).

The ROCI design is used in late-phase trials when an aspect of the treatment is continuous, such as duration, dose or frequency. A continuous treatment implies that there are lots of possible values to test, and we need to select an option that is neither too much nor too little.

But most late-phase trials involve choosing two treatment options and then comparing the results between the two groups. These treatment options may be along the lines of ‘short duration vs. long duration’ or ‘no treatment vs. a specific treatment dose’.

This approach comes with some challenges. The dose, duration or frequency chosen for the trial may not be the optimal dose, duration or frequency. What if a medium duration is as good as a long duration? What if a lower dose works just as well as the dose used in the clinical trial?

Even if the current treatment ‘works’, there are problems associated with overtreatment. For example, overtreatment with antibiotics can encourage the development of antimicrobial resistance. Long tuberculosis (TB) drug regimens mean that patients often struggle with sticking to their treatment plans. Frequent dosing regimens in cancer treatment may increase drug side-effects and worsen patients’ quality of life.

The ROCI design aims to avoid choosing arbitrary treatment options and instead explore several options to identify which one is best. Researchers randomise participants to, for example, a specific treatment duration from a range of possible durations. They can then estimate how treatment outcomes depend on the duration.

The figure compares the design of two-arm trials vs ROCI trials. The left panel shows three different two-arm trials; one testing two possible doses, one testing two possible frequencies and one testing two possible durations. Green dots represent the options that resulted in better outcomes (minimum for dose, maximum for frequency and minimum for duration). The right panel shows three ROCI comparisons to identify the optimal dose, optimal frequency or optimal duration. Dose, frequency and duration are represented as a continuous sliding scale. Blue dots represent the options that resulted in better outcomes, each somewhere in the middle of the minimum and maximum dose, frequency and duration.

Initially named ‘DURATIONS’, the ROCI design was born from a need to design a clinical trial comparing different durations of antibiotic treatment for children with community-acquired pneumonia in Africa. Current World Health Organization treatment guidelines recommend at least five days of intravenous treatment in hospital, before they can switch to oral antibiotics. But this can be expensive for families and healthcare systems and increases the risk of hospital-acquired infections.

The trial, called PediCAP, opened in 2019 and presented its first results at the ESCMID Global conference in April this year. PediCAP showed that children recover just as well if they switch from injectable to oral antibiotics earlier, once a healthcare worker confirms that they are improving. Using the ROCI design, the trial found that just 4 days’ total treatment was as good as 8 days’ treatment. Adopting this strategy could shorten treatment duration for community-acquired pneumonia and allow children to leave hospital sooner.

Following on from PediCAP, researchers within and beyond the MRC CTU at UCL are now using the ROCI design in a variety of other healthcare settings. REFINE-Lung is run by Imperial College London in patients with non-small cell lung cancer. The trial aims to find out if it is possible to give immune checkpoint inhibitors (a type of immunotherapy) less frequently and still have the same effect on the cancer.

Meanwhile, the Unit’s PARADIGM4TB trial (part of the UNITE4TB programme) is testing multiple drug regimens and treatment durations for TB. The trial has two main stages. The first will assess the safety and effectiveness of each drug combination given for 16 weeks. Researchers will then choose the most promising drug combination to progress to the second stage, which aims to find the optimal length of treatment (between 8 and 16 weeks) to be used in separate, large-scale phase 3 trials. 

In an emergency care setting, researchers at the Intensive Care National Audit & Research Centre are carrying out the Threshold for Platelets (T4P) study. This trial uses the ROCI design to define the threshold platelet count below which critically ill patients should receive a platelet transfusion before an invasive procedure.

To encourage researchers to implement the ROCI design, MRC CTU methodologists have developed helpful guidance on how to design ROCI trials.

In the future, the team plans to continue extending the capabilities of the ROCI design, for example, developing more efficient ways to calculate sample size, or allowing for multiple trial stages and interim analyses.

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