Blinding

Item 20b: If blinded, how blinding was achieved and description of the similarity of interventions

Examples

“Jamieson Laboratories Inc. provided 500-mg immediate release niacin in a white, oblong, bisect caplet. We independently confirmed caplet content using high performance liquid chromatography . . . The placebo was matched to the study drug for taste, color, and size, and contained microcrystalline cellulose, silicon dioxide, dicalcium phosphate, magnesium stearate, and stearic acid [353]."

“Placebo tablets were identical to NAC [N‐acetylcysteine] tablets in color, shape, size, and odor. They were all kept in identical containers and were administered by an investigational drug pharmacist [261]."

“The study treatment and placebo tablets and bottles were identical in physical appearance . . . The IWRS [interactive web response system] housed treatment codes and bottle numbers for study treatment. In case of an emergency, the investigator had the sole responsibility for determining if unmasking of a participant’s treatment assignment was warranted to provide appropriate medical care. Participant safety was always the first consideration in making such a determination. The IWRS was programmed with blind-breaking instructions to guide the investigator on how to obtain treatment assignment in the event of an emergency unmasking. The investigator was requested to contact the medical monitor promptly in case of any treatment unmasking. If a participant’s treatment assignment was unmasked, the sponsor was to be notified within 24 h after unmasking. The date and reason for the unmasking were recorded in the source documentation and electronic case report form, as applicable. Investigators broke the masking for four participants: one in ELEVATE UC 12 (on etrasimod) and three in ELEVATE UC 52 (on etrasimod) [297]."

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Explanation

Blinding of participants, healthcare providers, data collectors, and outcome assessors in a trial requires adequate procedures to both achieve and maintain blinding [346, 347]. Just as we seek evidence of adequate allocation concealment to assure us that assignment was truly random, we seek evidence on the method of blinding.

If researchers contend that the trial investigators, participants, and assessors were blinded, then they should provide information about the mechanism used to establish blinding (eg, placebo identical to the experimental intervention, sham intervention, sham surgery) [346, 347]. They should describe the similarity of treatment characteristics (eg, route of administration, appearance, smell, taste) and where relevant methods used to mask some characteristics of the treatments (eg, use of special flavours to mask a distinctive taste, opaque coverage to conceal intravenous treatments with different appearances, double-dummy procedures) [346, 347].

Blinding can be difficult to maintain over time because of dosage adaptation over time or the occurrence of specific side effects. Specific procedures to maintain blinding can be implemented (eg, centralised assessment of side effects, centralised adapted dosage, or provision of sham results of complementary investigations).

Even if blinding of participants and healthcare providers is not possible, blinding data collectors and outcome assessors could still be implemented to limit ascertainment bias. This could be achieved, for example, through centralised assessment of complementary investigation (eg, anonymised radiography), physician mediated data (eg, video, photography, audiotape), and clinical events (eg, adjudication of clinical events from extract of the case report form).

Details of how blinding was achieved are important because slight, but discernible, differences between interventions can lead to large problems in bias. Notably, inadequate matching related to discernible differences in colour and taste seem particularly problematic [354]. It is important that authors report any known compromises in blinding. For example, authors should report if it was necessary to unblind any participants at any point during the conduct of the trial. Moreover, authors should report the risk of unblinding but, unfortunately, such reporting is rare. In a random sample of 300 publications describing blinded randomised clinical trials indexed in PubMed, only 8% reported on risk of unblinding [355]. It is also important to report any procedures, pretrial or concurrent, that are intended to reduce or evaluate risk of compromised blinding [354-356]. Indeed, some pretrial assessments of unblinding may be helpful in reducing the risk of unblinding in the eventual randomised trial. Thus, authors of randomised trial articles should report procedures to avoid, document, and address cases of overt unblinding [354, 355].

Where appropriate, authors should also describe any procedures used for emergency unblinding (ie, disclosing the assigned intervention of a trial participant for specific reasons such as harms). They should indicate whether they used fixed code to indicate group assignment (eg, A=group 1; B=group 2) or a unique code for each participant. Use of a fixed code will increase the risk of unblinding because unblinding a participant could result in unblinding several or all trial participants [6, 286, 357].

Some people have advocated testing for blinding by asking participants or healthcare providers at the end of a trial whether they think the participant received the experimental or control intervention [358]. Because participants and healthcare providers will frequently know whether the participant has experienced the primary outcome, this makes it difficult to determine whether their responses reflect failure of blinding or accurate assumptions about the efficacy of the intervention [359]. Thus, given the uncertainty this type of information provides, the usefulness of tests of blinding has been questioned [354, 355, 360]. Testing for blinding was not an included item in CONSORT 2010, and still is not in CONSORT 2025. Nevertheless, if investigators decide to conduct tests of blinding, we encourage them to completely report their findings with appropriate limitations [356].