Unblinding to treatment allocation in randomised placebo-controlled trials: A new process and analysis of patient perspectives from a trial of low-dose amitriptyline for irritable bowel syndrome (IBS) in primary care

Problem

Double-blinded trials typically maintain blinding of patient participants until trial completion. The associated delays can be challenging for ongoing clinical management and patients wanting to make sense of their lived experience. We addressed this issue within the ATLANTIS double-blind randomised placebo-controlled superiority trial of low dose amitriptyline for adults with IBS in primary care. We worked with patient partners and used qualitative methods to explore participants’ perspectives on unblinding at the point at which they personally finished the trial and to develop patient-facing information to support the unblinding process.

Approach

Patient participants (adults with ongoing troublesome IBS symptoms) were recruited first to the ATLANTIS trial and then to the qualitative study via GP surgeries in Wessex, West of England, West Yorkshire. 140 patients were invited to take part in a semi-structured audio-recorded telephone interview; all 42 who consented and were available were interviewed approximately 6 months post-randomisation, 19 were interviewed again approximately 12 months post-randomisation. Interviews broadly explored patients’ experiences; this paper focuses on patients’ perspectives on treatment allocation and unblinding, analysed inductively using thematic analysis. Interviews in the pilot phase (April - June 2020; n=16) informed the need for and development of the patient-facing leaflet. Interviews in the later phase (July 2020 – March 22; n=26) further explored participants’ experiences of treatment allocation, blinding and unblinding.

Findings

Patient partners and trial participants wanted and expected to be told about their treatment allocation in a timely manner. Trial participants constructed common-sense narratives about their treatment arm allocation based on perceived symptom improvement and side effects. Those who believed they were receiving amitriptyline based that on experiencing fewer/less severe IBS symptoms and/or experiencing side-effects commonly associated with amitriptyline e.g., drowsiness, dry mouth. Those who believed they were receiving placebo based that on experiencing no noticeable change in their IBS (‘no worse, no better’) and no side-effects. Patients expressed concerns about what would happen if their beliefs about their treatment turned out to be incorrect. Patients worried about feeling disappointed if they were actually on amitriptyline having thought it was placebo (putting them “back to square one” in their search for effective IBS treatment). Patients worried about feeling foolish if they were actually on placebo having thought they were on amitriptyline (because they did not understand how a placebo could change their symptoms).

Consequences

Because patients’ narratives were firmly embedded in the context of this particular trial, we worked with patient partners to develop trial-specific evidence-based resources to support patient unblinding at the end of their personal involvement in the trial. Written leaflets for patients and research staff clearly communicated the implications of the treatment allocation for future IBS management and for making sense of experiences in the trial.