6b.2 - Combination Therapy Trials

Combination therapy trials are an example where the appropriateness of a placebo control must be carefully considered.

Suppose that for a particular disease or condition, there exists a standard therapy that is accepted as the best available treatment (standard-of-care). The standard-of-care could be a drug, a medical device, a surgical procedure, diet, exercise, etc., or some combination of these various regimens.

In the MIRACLE trial, the standard-of-care for the eligible patients with heart failure during the course of the trial consisted of some combination of the following medications:

• Diuretic
• Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker
• Digitalis
• Beta-blocker

Suppose that the experimental therapy is of a different modality or different mechanism of action than the standard-of-care. If so, then it may be possible to use the experimental therapy in combination with the standard-of-care and we can consider designing a two-armed trial that compares:

standard-of-care + experimental therapy

versus

standard-of-care + placebo therapy

This situation is comparable to a superiority trial because the research objective is to demonstrate superiority of the combination therapy to the standard-of-care.

In the MIRACLE trial, for example, the comparison consisted of:

standard-of-care + pacemaker

versus

standard-of-care + inactive pacemaker

In other situations, a superiority trial is not feasible. If the experimental therapy is a similar modality as one of the components of standard-of-care, then it may not be appropriate to combine the experimental therapy with the standard-of-care.

There are two other possibilities to consider for designing the clinical trial, namely, an equivalence trial and a non-inferiority trial.