Tight controlled dose reduction of biologics in psoriasis patients with low disease activity: a randomized pragmatic non-inferiority trial

Selma Atalay, Juul M P A van den Reek, Lieke J van Vugt, Marisol E Otero, Peter C M van de Kerkhof, Alfons A den Broeder, Wietske Kievit, Elke M G J de Jong, Selma Atalay, Juul M P A van den Reek, Lieke J van Vugt, Marisol E Otero, Peter C M van de Kerkhof, Alfons A den Broeder, Wietske Kievit, Elke M G J de Jong

Abstract

Background: Psoriasis is an immune-mediated chronic inflammatory skin disorder for which several targeted biologic therapies became available in the last 10 years. Data from patients with rheumatoid arthritis revealed that dose tapering combined with tight control of disease activity is successful. For psoriasis patients the lowest effective dose of biologics needs to be determined. The objective was to assess whether dose tapering of biologics guided by Psoriasis Area and Severity Index (PASI) and Dermatology Quality of Life Index (DLQI) scores in psoriasis patients with controlled disease activity is non-inferior (NI) to usual care.

Methods/design: This is a multicenter, pragmatic, randomized, non-inferiority trial with cost- effectiveness analysis. One hundred and twenty patients with stable low disease activity (PASI ≤ 5 and DLQI ≤ 5) for at least 6 months with a stable use of adalimumab, etanercept or ustekinumab will be randomized 1:1 to the dose reduction group or usual care. In the dose reduction group, the treatment intervals will be prolonged stepwise, resulting in a 33% and 50% dose reduction, respectively. Disease activity is monitored every three months with PASI and DLQI. In case of flare the treatment is adjusted to the previous effective dose. The primary outcome (PASI) at 12 months will be analyzed with ANCOVA in which the baseline PASI will be included as covariate to gain efficiency. The secondary outcomes include number of and time to disease flares, health-related quality of life, serious adverse events, and costs.

Discussion: With this study we want to assess whether disease activity guided dose reduction of biologics can be achieved for psoriasis patients with low stable disease activity, without losing disease control. By using the lowest effective dose of biologics, we expect to minimize side effects and save costs.

Trial registration: This trial was registered at ClinicalTrials.gov ( NCT 02602925 ). Trial registration date October 9 2015.

Trial registration: ClinicalTrials.gov NCT02602925.

Keywords: Adalimumab; Biologics; Cost-effectiveness; Dose reduction; Etanercept; Non- inferiority; Psoriasis; Therapy; Ustekinumab.

Figures

Fig. 1
Fig. 1
Patients using adalimumab, etanercept or ustekinumab will be randomized to dose tapering or usual care. Control visits will be planned every 3 months for the assessments of PASI, DLQI, cost-effectiveness questionnaires, drug levels and anti-drug antibodies (at trough moment). Ustekinumab blood samples for immunologic analyses are taken at deviating time points (trough moments) due to the low frequency of injections. CEQ = Cost-effectiveness questionnaires (SF-36, iMTA Medical Consumption Questionnaire and productivity cost questionnaire), PASI = Psoriasis Area and Severity Index, DLQI = Dermatology Quality of Life

References

    1. Rapp SR, Feldman SR, Exum ML, Fleischer AB, Jr, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41(3 Pt 1):401–407. doi: 10.1016/S0190-9622(99)70112-X.
    1. Driessen RJ, Berends MA, Boezeman JB, van de Kerkhof PC, de Jong EM. Psoriasis treatment with etanercept and efalizumab: clinical strategies influencing treatment outcome. Br J Dermatol. 2008;158(5):1098–1106. doi: 10.1111/j.1365-2133.2008.08514.x.
    1. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1) Lancet. 2008;371(9625):1665–1674. doi: 10.1016/S0140-6736(08)60725-4.
    1. Gordon KB, Gottlieb AB, Langely RG, van de Kerkhof P, Belasco KT, Sundaram M, Okun M, Serra L. Adalimumab retreatment successfully restores clinical response and health-related quality of life in patients with moderate to severe psoriasis who undergo therapy interruption. J Eur Acad Dermatol Venereol. 2015;29(4):767–776. doi: 10.1111/jdv.12677.
    1. Welsing PM, Bijl M, van Bodegraven AA, Lems WF, Prens E, Bijlsma JW. Cost effectiveness of biologicals: high costs are the other face of success. Ned Tijdschr Geneeskd. 2011;155(29):A3026.
    1. Mrowietz U, de Jong EM, Kragballe K, Langley R, Nast A, Puig L, Reich K, Schmitt J, Warren RB. A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2014;28(4):438–453. doi: 10.1111/jdv.12118.
    1. Menter A, Tyring SK, Gordon K, Kimball AB, Leonardi CL, Langley RG, Strober BE, Kaul M, Gu Y, Okun M, et al. Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106–115. doi: 10.1016/j.jaad.2007.09.010.
    1. Papp K, Crowley J, Ortonne JP, Leu J, Okun M, Gupta SR, Gu Y, Langley RG. Adalimumab for moderate to severe chronic plaque psoriasis: efficacy and safety of retreatment and disease recurrence following withdrawal from therapy. Br J Dermatol. 2011;164(2):434–441. doi: 10.1111/j.1365-2133.2010.10139.x.
    1. Gordon KB, Gottlieb AB, Leonardi CL, Elewski BE, Wang A, Jahreis A, Zitnik R. Clinical response in psoriasis patients discontinued from and then reinitiated on etanercept therapy. J Dermatolog Treat. 2006;17(1):9–17. doi: 10.1080/09546630500472838.
    1. Moore A, Gordon KB, Kang S, Gottlieb A, Freundlich B, Xia HA, Stevens SR. A randomized, open-label trial of continuous versus interrupted etanercept therapy in the treatment of psoriasis. J Am Acad Dermatol. 2007;56(4):598–603. doi: 10.1016/j.jaad.2006.09.002.
    1. Blum R, Lebwohl M. Durability of treatment response in patients with moderate to severe psoriasis following withdrawal from or a dose reduction in adalimumab therapy. J Am Acad Dermatol. 2005;52:180. doi: 10.1016/j.jaad.2004.05.047.
    1. Papp K, Menter A, Poulin Y, Gu Y, Sasso EH. Long-term outcomes of interruption and retreatment vs. continuous therapy with adalimumab for psoriasis: subanalysis of REVEAL and the open-label extension study. J Eur Acad Dermatol Venereol. 2013;27(5):634–642. doi: 10.1111/j.1468-3083.2012.04515.x.
    1. Na JI, Kim JH, Park KC, Youn SW. Low-dose etanercept therapy in moderate to severe psoriasis in Korean. J Dermatol. 2008;35(8):484–490. doi: 10.1111/j.1346-8138.2008.00508.x.
    1. Rodrigo- Nicolas B G-CE. Adalimumab dose reduction in psoriasis: Results in a series of 12 patients. J Am Acad Dermatol. 2014:7775
    1. van Herwaarden N, van der Maas A, Minten MJ, van den Hoogen FH, Kievit W, van Vollenhoven RF, Bijlsma JW, van den Bemt BJ, den Broeder AA. Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ. 2015;350:h1389. doi: 10.1136/bmj.h1389.
    1. Finlay AY, Khan GK. Dermatology life quality index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210–216. doi: 10.1111/j.1365-2230.1994.tb01167.x.
    1. Zweegers J, Groenewoud JM, van den Reek JM, Otero ME, van de Kerkhof PC, Driessen RJ, van Lumig PP, Njoo MD, Ossenkoppele PM, Mommers JM et al. Comparison of the one and 5-years effectiveness of adalimumab, etanercept and ustekinumab in psoriasis patients in daily clinical practice: Results from the prospective BioCAPTURE registry. Br J Dermatol. 2016;176(4):1001–1009.
    1. Talamonti M, Botti E, Galluzzo M, Teoli M, Spallone G, Bavetta M, Chimenti S, Costanzo A. Pharmacogenetics of psoriasis: HLA-Cw6 but not LCE3B/3C deletion nor TNFAIP3 polymorphism predisposes to clinical response to interleukin 12/23 blocker ustekinumab. Br J Dermatol. 2013;169(2):458–463. doi: 10.1111/bjd.12331.
    1. Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. Translating the science of quality of life into practice: what do dermatology life quality index scores mean? J Investig Dermatol. 2005;125(4):659–664. doi: 10.1111/j.0022-202X.2005.23621.x.
    1. Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE, Nast A, Franke J, Antoniou C, Arenberger P, Balieva F, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res. 2011;303(1):1–10. doi: 10.1007/s00403-010-1080-1.
    1. Zweegers J, Roosenboom B, van de Kerkhof PC, van den Reek JM, Otero ME, Atalay S, Kuijpers AL, Koetsier MI, Arnold WP, Berends MA et al.: Frequency and predictors of a high clinical response in patients with psoriasis on biological therapy in daily practice: results from the prospective, multicenter BioCAPTURE cohort. Br J Dermatol. 2016
    1. Reich K, Nestle FO, Papp K, Ortonne JP, Wu Y, Bala M, Evans R, Guzzo C, Li S, Dooley LT, et al. Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial. Br J Dermatol. 2006;154(6):1161–1168. doi: 10.1111/j.1365-2133.2006.07237.x.
    1. Borm GF, Fransen J, Lemmens WA. A simple sample size formula for analysis of covariance in randomized clinical trials. J Clin Epidemiol. 2007;60(12):1234–1238. doi: 10.1016/j.jclinepi.2007.02.006.
    1. . Accessed 15 Nov 2016.
    1. GCP good clinical practice hin, coc. Accessed 15 Nov 2016.
    1. WBP, wet bescherming persoonsgegevens. .
    1. Soonawala D, Dekkers OM. ‘Non-inferiority’ trials. Tips for the critical reader. Research methodology 3. Ned Tijdschr Geneeskd. 2012;156(19):A4665.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe