What is the recommended placebo used in a clinical trial?

Placebo Design in Clinical Trials

General Principles of Placebo Selection

The placebo used in a clinical trial should be matched as closely as possible to the active treatment in formulation, color, taste, and smell, while remaining pharmacologically inert, and should be administered in a blinded fashion to minimize expectancy bias. 1

Key Characteristics of Appropriate Placebos

Physical Matching Requirements

• Placebos must be described in detail with consideration given to matching the formulation, color, taste, and smell as closely as possible to that of the active treatment. 1

• The administration of both treatment and placebo should be given in a described blinded fashion to maintain study integrity. 1

• For feeding trials specifically, placebo diets should ideally represent the study population's "usual" diet and are often based on relevant national nutrition survey data or national apparent consumption data. 1

Pharmacological Considerations

• A placebo may be either a pharmacologically active or an inert substance, depending on the trial design and ethical considerations. 2

• When pharmacologically inert placebos are used, they should have no therapeutic effect on the condition being studied while maintaining physical similarity to the active treatment. 2

• For oral medications in routine clinical use, thiamine at low doses has been suggested as an acceptable oral placebo option. 2

Context-Specific Placebo Design

Dietary/Feeding Trials

• In feeding trials, placebo diets should be carefully designed to be "inert" while matched for all other dietary components not under investigation. 1

• For clinical populations, the "usual diet" placebo may differ substantially from the national average diet, and this should be factored into placebo diet design. 1

• Opaque containers and careful meal preparation can help safeguard blinding in feeding trials. 1

Pharmaceutical Trials

• The placebo formulation should match the active drug's delivery system, method of delivering dose, and extent of exposure. 1

• For trials involving subcutaneous injections (such as GLP-1 receptor agonists), matching placebos would need to replicate the injection experience. 1

Acupuncture and Procedural Trials

• Sham acupuncture has been used as placebo, though the location, depth, and manipulation of sham needles varies widely across trials. 1

• Some evidence suggests that sham acupuncture itself might have therapeutic effects, complicating interpretation of results. 1

Ethical and Methodological Considerations

When Placebo Use is Justified

• Placebo controls are ethically justifiable when supported by sound methodologic considerations and when their use does not expose research participants to excessive risk of harm. 3, 4

• Placebo use is appropriate when: (1) no proven effective treatment exists; (2) withholding treatment poses negligible risks; (3) compelling methodological reasons exist and withholding treatment does not pose serious harm; or (4) the research develops interventions for the study population and does not require participants to forgo otherwise available treatment. 4

Duration Considerations

• For conditions like irritable bowel syndrome, prolonged placebo treatment (beyond 4-12 weeks) may pose ethical problems and make it difficult to persuade patients to participate. 1

• The natural variation in symptom severity and expected high dropout rates complicate long-term placebo-controlled trials. 1

Blinding Success Evaluation

• Blinding success should be evaluated and reported using contingency tables or statistical methods such as Cohen's kappa, chi-square test, or validated blinding indices like James' BI or Bang's BI. 1

• Participants can be asked to guess their treatment assignment on a binary, 3-point, or 5-point scale to assess blinding effectiveness. 1

Common Pitfalls to Avoid

• Do not use potent drugs like glucocorticoids as placebos in mild disease or non-disease states, as this cannot be ethically justified. 2

• Avoid designs where placebo effects are confounded by spontaneous improvement due to regression toward the mean, particularly in conditions with fluctuating symptom severity. 1

• In trials with active comparators, ensure that the placebo (if used) does not introduce bias through differential side effect profiles that could unmask treatment allocation. 1

• For run-in periods using placebo, identification of non-adherers or placebo responders must occur before randomization to maintain statistical validity. 1