Understanding onset and extent of response using different clinical endpoints in Atopic Dermatitis
Maria Luisa Sardu (1), Paul Matthias Diderichsen (1), Monica Simeoni (2), Núria Buil-Bruna (2)
(1) Certara USA, Inc., Princeton NJ, (2) Clinical pharmacology modelling and simulation, GSK UK
Objectives:
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous lesions and intense pruritus [1]. Numerous different scoring systems have been proposed for assessing the severity of atopic dermatitis [2]. They use various methods including grid patterns and objective disease features and extent, and some scales incorporate patient reported outcomes [3]. The inconsistencies in clinical trial endpoints make it difficult to directly compare results between therapies [4].
Understanding the onset and extent of response for different endpoints across different drug classes and how they correlate between them is crucial for designing clinical trials in AD, which includes optimising endpoint selection, sample size and timing of interim and primary analyses.
Methods:
Certara’s atopic dermatitis clinical trial outcome database was used in the analysis (supported by GSK) [5]. We have selected three of the most used endpoints to assess the effect of a treatment in clinical trials:
- EASI (Eczema Area and Severity Index) is a 0-to-72 scale which summarises the assessment of four disease characteristics of AD (erythema, infiltration/papulation, excoriations, and lichenification), and accounts for the body surface area affected in different body regions [6]. From raw EASI scores, PCFB-EASI (percentage change from baseline in EASI) and EASI-75 (proportion of patients achieving 75% reduction in the EASI score from baseline) are derived.
- IGA (Investigator’s Global Assessment Scale) is a five-point scale (from 0 to 4) that provides a global clinical assessment of AD severity [3]. Response is generally defined as achieving an IGA score of 0 or 1 (IGA01) or a reduction ≥2 points from baseline.
- Pruritus Numerical Rating Scale (NRS) is a tool for patients to report the daily intensity of their itch (on a scale from 0 to 10, with 0 indicating “no itch” and 10 being “worst itch imaginable”). It has been suggested that Pruritus NRS response can be defined as a reduction of ≥3-4 points [7].
The clinical outcomes database captured the published response data as aggregate responses within treatment arm, i.e. mean EASI score, fraction of patients with IGA01, and fraction of Pruritus NRS responders.
Analysis focused on placebo-controlled studies including moderate to severe adolescents and adult AD patients. Drug classes included in the analysis were: anti-IL-13, anti-il-31, anti-IL-4/13, anti-OX40 monoclonal antibodies and Janus kinase (JAK) inhibitors. All timepoints were included up to week 16. If primary timepoint was less than week 16, the last observation carried forward method was applied.
Endpoint variables were explored graphically based on placebo-corrected outcomes normalised to primary timepoint. Onset of response based on change from baseline (mean EASI only) and placebo relative to primary timepoint was analysed using nonlinear regression implemented in the generalised nonlinear least squares (gnls) routine in R (4.0.2). Both non-parametric and parametric (exponential) approaches were investigated.
Correlations between raw endpoints were explored using the lm function in R.
Results:
The total number of studies reporting IGA01, EASI-75, PCFB-EASI and pruritus responders were 19, 18, 19 and 15, respectively. Only one study included anti-OX40 and therefore this drug class was excluded from the analysis.
Parametric models based on class specific exponential onset could adequately describe the observed data for all endpoints. Plateau was reached earlier by JAK inhibitors compared to monoclonal antibodies across all endpoints. There were no major differences in the onset of response for the monoclonal antibodies between different mechanisms of action. PCFB-EASI was the endpoint that reached plateau earlier (week 8), followed by EASI-75 and pruritus responders. IGA01 showed the slowest onset of response, with an average of 73% of total week 16 response achieved around week 8.
Endpoints at primary timepoint appear to be very correlated (R2 > 0.71 and R2 adjusted >0.70). Strongest correlation (R2=0.90 and R2 adjusted=0.90) was found between IGA01 and EASI-75.
Conclusions:
We have assessed the differences in onset of response between the most frequently used endpoints in AD clinical trials. JAK inhibitors achieved plateau of response at around week 8, whereas monoclonal antibodies showed a 70-80% of the total week 16 response at week 8. These analyses can be instrumental to optimise the design of clinical trials in AD.
References:
[1] Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016; 387(10023):1109-1122.
[2] Clinical Review Report: Dupilumab (Dupixent): (Sanofi-Aventis Canada Inc.): Indication: Moderate-to-severe atopic dermatitis (AD) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Jul. Appendix 5, Validity of Outcomes Measures. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539234/
[3] Eichenfield, L. F., Tom, W. L., Chamlin, S. L., Feldman, S. R., Hanifin, J. M., Simpson, E. L., ... & Sidbury, R. (2014). Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. Journal of the American Academy of Dermatology, 70(2), 338-351
[4] Wei, E. X., Kirsner, R. S., & Eaglstein, W. H. (2016). End points in dermatologic clinical trials: a review for clinicians. Journal of the American Academy of Dermatology, 75(1), 203-209
[5] Certara. Atopic Dermatitis Clinical Outcomes Database version 20221215 In, https://codex.certara.com/codex/atopic-dermatitis/
[6] Schram, M. E., Spuls, P. I., Leeflang, M. M. G., Lindeboom, R., Bos, J. D., & Schmitt, J. E. A. S. I. (2012). EASI,(objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference. Allergy, 67(1), 99-106.
[7] Simpson EL, Beck LA, Gadkari A, Eckert L, Reaney M. Defining a responder on the Peak Pruritus Numerical Rating Scale (NRS) in patients with moderate-to-severe atopic dermatitis: detailed analysis from randomized trials of dupilumab [abstract]. JAAD. 2017;76(6 Suppl 1):AB93.