Monotherapy trial design: conversion versus de novo

It is difficult to design valid and well-controlled monotherapy trials that satisfy regulatory requirements and, at the same time, demonstrate the usefulness of a new drug in clinical practice. The conversion design is a drug-substitution trial in which patients with uncontrolled seizures are assigned to add-on treatment with an investigational drug and, usually, an appropriate control, after which pre-existing treatment is gradually discontinued. In the most utilised design, patients are randomised to receive a high dose versus low dose of the new drug, while concomitant medication is gradually discontinued. Exit criteria are predetermined to prevent excessive deterioration of seizures, and treatment retention time is used as the primary outcome variable to measure the effectiveness of the allocated treatments: the goal is to demonstrate higher retention rates in the high-dosage group. Conversion studies may help to fill some gaps in knowledge regarding efficacy and tolerability as monotherapy before larger-scale de-novo studies are started. In the de-novo design, newly diagnosed patients are randomised to receive the investigational drug or an active control. In equivalence (or non-inferiority) trials, the active control is usually an established antiepileptic drug (AED) such as carbamazepine or valproate, and outcome parameters may include proportion of patients achieving a predefined (for example, 6-month) seizure remission or the proportion of patients remaining in the trial (retention rate, a combined measure of efficacy and tolerability). In regulatory trials designed to show a difference, newly diagnosed patients are randomised to a high versus a low dose of the investigational drug, and exit criteria are again predetermined for patients whose seizures are not adequately controlled. In this case, outcome parameters may include time to first seizure in addition to retention in the trial. Comparative monotherapy trials in newly diagnosed patients are relevant to approximately 50% of the patients who develop epilepsy and can be satisfactorily managed with a single drug. These trials allow direct head-to-head comparisons and avoid the confounding effects of baseline drugs and co-medication withdrawal present in conversion studies. Long-term follow-up of patients who are receiving a drug in monotherapy at adequate doses gives the most clinically relevant answers regarding the usefulness of a new drug. It is concluded that the de-novo design is the gold standard when studying AEDs as monotherapy, but the conversion-to-monotherapy design can be used before starting the de-novo program in order to obtain estimates of efficacy and tolerability of the AED as monotherapy in a population of difficult-to-treat patients. With both designs, the use of suboptimal comparators incorporated into some of the regulatory trials is a cause of ethical concern.