Designing a response-over-continuous-intervention (ROCI) randomised trial: Implementation in the Phase 2C part...

Area of Science:

• Clinical trial design
• Pharmacometrics
• Infectious disease epidemiology

Background:

• Tuberculosis (TB) treatments are lengthy and complex, necessitating efficient trial designs.
• Standard non-inferiority trials are often used for evaluating shorter TB treatment regimens.
• The response-over-continuous-intervention (ROCI) design is a novel approach for optimizing continuous treatment variables like duration.

Purpose of the Study:

• To demonstrate the utility of simulation in designing ROCI trials for TB.
• To use the PARADIGM4TB Phase 2C trial as a case study for ROCI design simulation.
• To optimize novel TB treatment durations against a standard 6-month regimen.

Main Methods:

• Simulation modeling was employed to design a ROCI trial for TB treatment optimization.
• The PARADIGM4TB Phase 2C trial's duration-ranging component served as a case study.
• Fractional polynomial modeling (degree 1) was used to analyze the duration-response relationship.

Main Results:

• A ROCI design with 200 patients (5 novel regimen arms, 40 standard-of-care) provides adequate power to identify optimal TB treatment durations.
• Fractional polynomial modeling enhances power for selecting shorter durations compared to pairwise comparisons.
• A 5-duration ROCI design demonstrates superior operating characteristics over a 3-duration design when duration-response curves are not flat.

Conclusions:

• The ROCI trial design is a promising option for optimizing TB treatment regimens.
• Simulation studies are crucial for effectively designing ROCI trials and exploring key considerations.