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Table 1 Summary of parameters to be determined, and methods and considerations for the choices made for Molnupiravir

From: Practical recommendations for implementing a Bayesian adaptive phase I design during a pandemic

Parameters

Motivation and method for choosing

Considerations

Chosen Value

Target (additional) toxicity rate, γ

Motivated by safety considerations. Clinical decision

The DLT definition should be consciously and extensively specified, with acceptable toxicity determined by the clinical context (e.g., availability of other treatments, severity of disease)

20%

Tolerance around target (additional) toxicity rate, δ

Motivated by safety considerations. Clinical decision

Any given set of doses is unlikely to contain a dose with DLT rate exactly equal to the target, so flexibility around the target should be considered. As above, this should consider the clinical context

5%

Upper (additional) toxicity bound, γtoxic

Motivated by safety considerations. Clinical decision

Level of unacceptable toxicity (here, toxicity above the control)

30%

Number of Doses, m

Motivated by knowledge of treatment. Clinical decision

Number of doses should ensure that the dose-toxicity curve is adequately explored

4 (300 mg bd, 400 mg bd, 600 mg bd, 800 mg bd)

Cohort size

Safety and practical considerations. Options can be evaluated using simulations based on discussion with clinicians

The number of participants the clinicians are comfortable dosing between decisions on dose escalation; how often the model will be updated. Results for various cohort sizes can be shown to clinicians

6 (4 on treatment, 2 control)

Sample Size, N

Practical considerations. Options can be evaluated using simulations based on discussion with clinicians

Sample size should ensure an accurate selection of target doses with high probability

30

Threshold controlling overdosing,  coverdose

Simulations; reference in the literature

The value from the literature for the 2-parameter logistic dose-toxicity model was chosen (to speed up simulations)

25%

Hyperparameter μ1 – the mean of the prior distribution for θ1

Historical information

Modelled as random variable to account for the uncertainty early in the pandemic

μ1 = logit(0.1) (fixed by 10% DLT rate on control)

Hyperparameters μ2, σ1, σ2 – mean of prior for θ2 and standard deviations of priors for θ1 and θ2

Simulations

Calibrated over a set of feasible dose-toxicity scenarios

μ2 =  − 0.05, σ1 = 1.10, σ2 = 0.30

Prior estimates of DLT risk on each dose (also known as the dose-toxicity skeleton), \({p}_j^{(0)}\)

May solely reflect existing knowledge of treatment doses, or may be evaluated via simulations

If determined by simulation, the DLT risks on each dose should still align with existing knowledge

17.5, 25, 32.5, 40%