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Original article

Vol. 149 No. 2930 (2019)

Estimation of treatment allocation in a randomised, double-blinded, placebo-controlled trial

  • Milica Popovic
  • Nicole Cesana-Nigro
  • Bettina Winzeler
  • Robert Thomann
  • Philipp Schütz
  • Beat Müller
  • Mirjam Christ-Crain
  • Claudine A. Blum
DOI
https://doi.org/10.4414/smw.2019.20114
Cite this as:
Swiss Med Wkly. 2019;149:w20114
Published
24.07.2019

Summary

AIM OF THE STUDY

The internal validity of double blinding in randomised placebo-controlled trials (RCTs) has become a target of criticism. The goal of this study was to investigate (a) how accurately the patients and their treating physicians were able to guess their assigned treatment, and (b) predictors for an accurate guess.

METHODS

Data on treatment estimation from patients (n = 382) and their physicians (n = 358 guesses) in an RCT investigating the role of adjunct prednisone for community-acquired pneumonia in a tertiary care setting were analysed. At discharge, patients and their physicians had to guess whether they had been assigned to the prednisone or to the placebo group. The alternative possibility was “uncertain”. Percentages and confidence intervals (CIs) were calculated for the proportion of patients guessing correctly. Chance finding was defined as having 50% or less correct guesses. To test for predictors for prednisone treatment guess, a mixed effects logistic regression model was performed.

RESULTS

In the prednisone group, 28.9% (55/190; 95% CI 22.6–36.0%) of the patients made a correct guess and the majority (61.6%, 117/190) was uncertain. In the placebo group, 13.0% (25/192; 95% CI 8.8–18.8%) guessed correctly, with the majority being uncertain (69.8%, 134/192). Physicians guessed correctly in 48.3% (87/180, 95% CI 40.8–55.9%) of cases in the prednisone group and in 66.3% (118/178, 95% CI 58.8–73.2%) of cases in the placebo group, which was above chance for the placebo group. The physicians were uncertain in 21.7% (39/180) of cases in the prednisone group, and in 15.2% (27/178) of cases in the placebo group. Significant predictors for guessing prednisone were the occurrence of hyperglycaemia (odds ratio [OR] 3.77, 95% CI 2.39–5.95; p<0.001) and a shorter time to clinical stability (OR 0.95, 95% CI 0.91–0.99; p = 0.02).

CONCLUSIONS

We confirmed that patient blinding was achieved in this study. Physicians made correct guesses more often than patients. Treatment estimation by both patients and physicians was led not only by the expectations of treatment effects of the study drug but also by known side effects of prednisone.

Trial registration no.:

NCT00973154

References

  1. White K, Kando J, Park T, Waternaux C, Brown WA. Side effects and the “blindability” of clinical drug trials. Am J Psychiatry. 1992;149(12):1730–1. doi:.https://doi.org/10.1176/ajp.149.12.1730
  2. Margraf J, Ehlers A, Roth WT, Clark DB, Sheikh J, Agras WS, et al. How “blind” are double-blind studies? J Consult Clin Psychol. 1991;59(1):184–7. doi:.https://doi.org/10.1037/0022-006X.59.1.184
  3. Rabkin JG, Markowitz JS, Stewart J, McGrath P, Harrison W, Quitkin FM, et al. How blind is blind? Assessment of patient and doctor medication guesses in a placebo-controlled trial of imipramine and phenelzine. Psychiatry Res. 1986;19(1):75–86. doi:.https://doi.org/10.1016/0165-1781(86)90094-6
  4. Moscucci M, Byrne L, Weintraub M, Cox C. Blinding, unblinding, and the placebo effect: an analysis of patients’ guesses of treatment assignment in a double-blind clinical trial. Clin Pharmacol Ther. 1987;41(3):259–65. doi:.https://doi.org/10.1038/clpt.1987.26
  5. Schnoll RA, Epstein L, Audrain J, Niaura R, Hawk L, Shields PG, et al. Can the blind see? Participant guess about treatment arm assignment may influence outcome in a clinical trial of bupropion for smoking cessation. J Subst Abuse Treat. 2008;34(2):234–41. doi:.https://doi.org/10.1016/j.jsat.2007.04.004
  6. Turner JA, Jensen MP, Warms CA, Cardenas DD. Blinding effectiveness and association of pretreatment expectations with pain improvement in a double-blind randomized controlled trial. Pain. 2002;99(1-2):91–9. doi:.https://doi.org/10.1016/S0304-3959(02)00060-X
  7. Carroll KM, Rounsaville BJ, Nich C. Blind man’s bluff: effectiveness and significance of psychotherapy and pharmacotherapy blinding procedures in a clinical trial. J Consult Clin Psychol. 1994;62(2):276–80. doi:.https://doi.org/10.1037/0022-006X.62.2.276
  8. Blum CA, Nigro N, Winzeler B, Suter-Widmer I, Schuetz P, Briel M, et al. Corticosteroid treatment for community-acquired pneumonia--the STEP trial: study protocol for a randomized controlled trial. Trials. 2014;15(1):257. doi:.https://doi.org/10.1186/1745-6215-15-257
  9. Blum CA, Nigro N, Briel M, Schuetz P, Ullmer E, Suter-Widmer I, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015;385(9977):1511–8. doi:.https://doi.org/10.1016/S0140-6736(14)62447-8
  10. Desbiens NA. In randomized controlled trials, should subjects in both placebo and drug groups be expected to guess that they are taking drug 50% of the time? Med Hypotheses. 2002;59(3):227–32. doi:.https://doi.org/10.1016/S0306-9877(02)00205-0
  11. Benedetti F, Carlino E, Piedimonte A. Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol. 2016;15(7):736–47. doi:.https://doi.org/10.1016/S1474-4422(16)00066-1
  12. Jakovljevic M. The placebo-nocebo response: controversies and challenges from clinical and research perspective. Eur Neuropsychopharmacol. 2014;24(3):333–41. doi:.https://doi.org/10.1016/j.euroneuro.2013.11.014
  13. Pagano G, Cavallo-Perin P, Cassader M, Bruno A, Ozzello A, Masciola P, et al. An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. J Clin Invest. 1983;72(5):1814–20. doi:.https://doi.org/10.1172/JCI111141
  14. Busillo JM, Cidlowski JA. The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore. Trends Endocrinol Metab. 2013;24(3):109–19. doi:.https://doi.org/10.1016/j.tem.2012.11.005
  15. Popovic M, Blum CA, Nigro N, Mueller B, Schuetz P, Christ-Crain M. Benefit of adjunct corticosteroids for community-acquired pneumonia in diabetic patients. Diabetologia. 2016;59(12):2552–60. doi:.https://doi.org/10.1007/s00125-016-4091-4

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