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The lessebo effect in randomized controlled trials of rituximab in patients with rheumatoid arthritis: a meta-analysis

Der Lesseboeffekt in randomisierten kontrollierten Studien mit Rituximab bei Patienten mit rheumatoider Arthritis: eine Metaanalyse

Abstract

Objective

The goal of this study was to assess the impact of negative expectations associated with receiving a placebo (the lessebo effect) on efficacy outcomes in randomized clinical trials (RCTs) of rituximab in patients with rheumatoid arthritis (RA).

Methods

We performed a meta-analysis on the American College of Rheumatology 20%, 50%, and 70% (ACR20, 50, 70) response rates in the placebo and active (biosimilar)-controlled groups (reference-pbo and reference-bs) of rituximab showing an insufficient response to methotrexate or tumor necrosis factor. We evaluated the difference in ACR20, 50, 70 response rates between the two groups (reference-bs vs. reference-pbo).

Results

Nine RCTs included a total of 2734 patients with RA. The pooled incidence of ACR20 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 53.1% (95% confidence interval [CI] 49.9–56.3%) and 75.0% (95% CI 71.2–78.4%), respectively. The difference in the ACR20 response rate between the placebo- and active-controlled groups was −20.9% (95% CI −26.9 to 61.9%, p < 0.001). The pooled incidence of ACR50 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 29.0% (95% CI 26.2–32.0%) and 47.4% (95% CI 43.2–51.6%), respectively. The ACR50 response rates were significantly higher in the active-controlled groups than in the placebo-controlled groups (−18.4%; 95% CI −18.4 to −13.4%, p < 0.001). The difference in the ACR70 response rate between the placebo- and active-controlled groups was −14.9% (95% CI −22.2 to −7.6%, p < 0.001). The ACR20, 50, 70 response rates were significantly higher in the active-controlled groups than in the placebo-controlled group.

Conclusion

This study shows that the use of a placebo can be associated with a clinically significant reduction in the magnitude of change of the ACR20, 50, 70 response rates in rituximab RCTs for RA. The lessebo effect has potential implications for the development of new treatments and appraisal of current treatment options for RA.

Zusammenfassung

Zielsetzung

Ziel dieser Studie war es, den Einfluss negativer Erwartungen, die mit dem Erhalt eines Placebos verbunden sind (Lessebo-Effekt), auf die Ergebnisse von randomisierten klinischen Studien (RCTs) zur Wirksamkeit von Rituximab bei Patienten mit rheumatoider Arthritis (RA) zu untersuchen.

Methoden

Wir führten eine Metaanalyse der 20-, 50- und 70-prozentigen ACR(American College of Rheumatology)-Ansprechraten (ACR20, 50, 70) in den Placebo- und den aktiven (Biosimilar-)kontrollierten Gruppen (Referenz-pbo und Referenz-bs) von Rituximab durch, die nicht ausreichend auf Methotrexat oder Tumornekrosefaktor ansprachen. Wir bewerteten den Unterschied in den ACR20-, -50- und -70-Ansprechraten zwischen den beiden Gruppen (Referenz-bs vs. Referenz-pbo).

Ergebnisse

Neun RCTs umfassten insgesamt 2734 RA-Patienten. Die gepoolte Inzidenz der ACR20-Ansprechrate in den placebo- und aktiv kontrollierten Gruppen der Rituximab-RCTs bei RA betrug 53,1% (95 %-Konfidenzintervall [95 %-KI] 49,9-56,3 %%) bzw. 75,0% (95 %-KI 71,2-78,4 %). Der Unterschied in der ACR20-Ansprechrate zwischen der placebo- und der aktiv kontrollierten Gruppe betrug -20,9 % (95 %-KI -26,9 bis 61,9 %, p < 0,001). Die gepoolte Inzidenz der ACR50-Ansprechrate in der Placebo- und der aktiv kontrollierten Gruppe der Rituximab-RCTs zur RA betrug 29,0 % (95 %-KI 26,2-32,0%) bzw. 47,4 % (95 %-KI 43,2–51,6 %). Die ACR50-Ansprechraten waren in den aktiv kontrollierten Gruppen signifikant höher als in den placebokontrollierten Gruppen (‑18,4 %; 95 %-KI -18,4 bis -13,4 %, p < 0,001). Der Unterschied bei der ACR70-Ansprechrate zwischen der Placebo- und der aktiv kontrollierten Gruppe betrug -14,9 % (95 %-KI -22,2 bis -7,6 %, p < 0,001). Die ACR20-, -50- und -70-Ansprechraten waren in den aktiv kontrollierten Gruppen signifikant höher als in der placebokontrollierten Gruppe.

Schlussfolgerung

Diese Studie zeigt, dass die Verwendung eines Placebos mit einer klinisch signifikanten Verringerung des Ausmaßes der Veränderung der ACR20-, 50- und 70-Ansprechraten in Rituximab-RCTs bei RA verbunden sein kann. Der Lessebo-Effekt hat potenzielle Implikationen für die Entwicklung neuer Therapien und für die Bewertung aktueller Behandlungsoptionen für RA.

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Acknowledgements

This research was supported by a grant of Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C0481, HC19C0052).

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Correspondence to Young Ho Lee MD PhD.

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Y.-K. Sung and Y.H. Lee declare that they have no competing interests.

For this article no studies with human participants or animals were performed by any of the authors. All studies performed were in accordance with the ethical standards indicated in each case.

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Ulf Müller-Ladner, Bad Nauheim

Uwe Lange, Bad Nauheim

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Sung, YK., Lee, Y.H. The lessebo effect in randomized controlled trials of rituximab in patients with rheumatoid arthritis: a meta-analysis. Z Rheumatol (2021). https://doi.org/10.1007/s00393-021-01126-9

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Keywords

  • Lessebo effect
  • Rituximab
  • Efficacy
  • Rheumatoid arthritis
  • Response rate

Schlüsselwörter

  • Lesseboeffekt
  • Rituximab
  • Wirksamkeit
  • Rheumatoide Arthritis
  • Ansprechrate