Background & Aims

The use of rescue medication (RM), commonly paracetamol, in placebo-controlled clinical trials involving pain intends to offer a potential source of pain relief for the participants receiving placebo, or in case the investigational product fails to deliver satisfactory efficacy. Almost all osteoarthritis (OA) trials permit the use of RM, with varying restrictions [1]. Studies have shown that OA trials are associated with high placebo responses (PR) [1–3], which are believed to have contributed to the long list of failed OA trials [4]. Adequate control of RM use often lacks, which in turn may impact the interpretation of OA trial results and contribute to explaining PR [5].
This analysis aims to provide information on the typical patterns of use, and whether common clinical and demographic characteristics are associated with the use of rescue medication in OA trials.

Methods

The data is based on a post-hoc analysis of three phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-arm trials (RCTs) (EudraCT: Study 1 (S1): 2019-004515-31, S2: 2020-000249-14, S3: 2021-003395-13) for femorotibial OA in adults using paracetamol as RM. The three RCTs involved a total sample size of 638 in a typical knee OA population in terms of radiographic severity and WOMAC A pain score at screening and baseline.
For this post-hoc analysis, we analyzed participants receiving placebo. Categorical data were summarized using percentages and continuous data using mean and standard deviation. Dichotomization of data based on the median were presented with boxplots and tested for differences of the means with two-sided t-tests. Multivariate relationships with use of RM among variables were analyzed using multiple regression. The dose of RM used was logarithmically transformed to achieve a normal distribution. A p-value of <0.05 was statistically significant.

Results

283 participants receiving placebo completed the three RCTs (S1-S3). Baseline demographics include overall mean (SD) age 61.1 (8.5) years, female sex 60.8%, BMI 30.7 (5.0) kg/m2, white race 92.6%, and WOMAC pain score 34.2 (8.5).
68.6% took at least one dose of RM during the study period. The average RM use for RM users was 2657 mg/week. The average RM use for the total population was 1876 mg/week.
Test differences in RM use by sex (male vs female), and groups based on BMI, age, and baseline WOMAC pain score for the three RCTs can be seen in Figure 1, and indicated that female sex and older age might use a higher average dose of RM.
The multiple regression analysis indicated that female sex and greater BMI seems to be associated with a higher RM use. The associations with other variables are not consistent.

Conclusions

The observed average RM use may be useful for the planning of clinical trials involving pain going forward, and to be taken into account in assessment of an investigational product’s efficacy. However, further studies are needed to provide a more nuanced understanding of RM use in OA RCTs. RM use might be important for participant retention rates, but it can influence the dynamics of especially long-term clinical studies. Therefore, we propose that it should be systematically reported sequentially along with other variables as the average use in mg per study week.

References

1. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008 Dec 1;67(12):1716–23.
2. Bannuru RR, McAlindon TE, Sullivan MC, Wong JB, Kent DM, Schmid CH. Effectiveness and Implications of Alternative Placebo Treatments. Ann Intern Med. 2015 Sep 1;163(5):365–72.
3. Karsdal MA, Michaelis M, Ladel C, Siebuhr AS, Bihlet AR, Andersen JR, et al. Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future. Osteoarthritis Cartilage. 2016 Dec;24(12):2013–21.
4. Huang Z, Chen J, Hu QS, Huang Q, Ma J, Pei FX, et al. Meta-analysis of pain and function placebo responses in pharmacological osteoarthritis trials. Arthritis Res Ther. 2019 Dec 15;21(1):173.
5. Zeidler H. Paracetamol and the Placebo Effect in Osteoarthritis Trials: A Missing Link? Pain Res Treat. 2011 Jun 6;2011:1–6.

Presenting Author

Jakob Mejdahl Bentin

Poster Authors

Jakob Bentin

MD

University of Aalborg

Lead Author

E-mail

Lars Arendt-Nielsen

PhD

Aalborg University

Lead Author

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Ida Sofie Adrian

NBCD A/S, Søborg, Denmark

Lead Author

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Pratiksha Poudel

MSc

NBCD A/S, Søborg, Denmark

Lead Author

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Jeppe Ragnar Andersen

MSc

NBCD A/S, Søborg, Denmark

Lead Author

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Alan Reynolds

BTech

AKL Therapeutics, Stevenage, United Kingdom

Lead Author

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Alessandra Pavesio

MSc

Doron Therapeutics, Durham, United States

Lead Author

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Helene Rovsing

MD

Sanos Clinic, Gandrup, Denmark

Lead Author

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Bernt Husøy

MD

Sanos Clinic, Herlev, Denmark

Lead Author

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Peter Alexandersen

MD

Sanoc Clinic, Vejle, Denmark

Lead Author

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Asger Reinstrup Bihlet

MSc

NBCD A/S, Søborg, Denmark

Lead Author

E-mail

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Rheumatology, Arthritis, and Other

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