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Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

ABSTRACT: The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases.This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past.OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy.NTR4499 . Registered on 7 April 2014.

SUBMITTER: Busard CI

PROVIDER: S-EPMC5288945 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

Busard C I CI Menting S P SP van Bezooijen J S JS van den Reek J M JM Hutten B A BA Prens E P EP de Jong E M EM van Doorn M B MB Spuls P I PI

Trials 20170202 1

<h4>Background</h4>The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficia ...[more]

PMID: 28148280

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Project description:Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure.ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e.g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment.The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative "umbrella" protocol design. The "umbrella" is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status.Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment - as defined by decrease in tumor cell proliferation - strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment.ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN:NCT01815242.

Project description:ImportanceMethotrexate is a first-line systemic agent for treating of psoriasis, although its onset of effects is slower and overall it is less effective than tumor necrosis factor blockers.ObjectiveTo differentiate the response of psoriatic disease to adalimumab and methotrexate sodium.Design, setting, and participantsSingle-center, randomized, assessor-blind, 2-arm clinical trial of 30 patients from the outpatient dermatology center of Tufts Medical Center, enrolled from August 18, 2009, to October 11, 2011. Patients aged 18 to 85 years with chronic plaque-type psoriasis, a minimum Physician Global Assessment score of 3 (higher scores indicate more severe disease), and a psoriatic plaque of at least 2 cm were randomized in a 1:1 fashion to receive subcutaneous adalimumab or oral methotrexate. Skin biopsy specimens obtained at baseline and weeks 1, 2, 4, and 16 were given a histologic grade by blinded assessors to evaluate treatment response. Analyses were conducted from April 16, 2013, to January 5, 2015.InterventionsA 16-week course of subcutaneous adalimumab (40 mg every 2 weeks after a loading dose) or low-dosage oral methotrexate sodium (7.5-25 mg/wk).Main outcomes and measuresChanges in genomic, immunohistochemical, and messenger RNA (mRNA) profiles.ResultsMethotrexate responders experienced significant downregulation of helper T-cell-related (T(H)1, T(H)17, and T(H)22) mRNA expression compared with methotrexate nonresponders. Comparisons among adalimumab-treated patients were limited by the number of nonresponders (n = 1). Between adalimumab and methotrexate responders, we found no significant differences in gene expression at any study point or in the expression of T-cell-related mRNA at week 16. Adalimumab responders demonstrated early downregulation of chemokine (C-C motif) ligand 20 (CCL20) mRNA (mean [SE] at week 2, -1.83 [0.52], P < .001; week 16, -3.55 [0.54], P < .001) compared with late downregulation for methotrexate responders (week 2, 0.02 [0.51], P = .96; week 16, -2.96 [0.51], P < .001). Similar differences were observed with interleukin 22 (IL22) mRNA showing early downregulation for adalimumab responders (week 2, -3.17 [1.00], P < .001; week 16, -3.58 [1.00], P < .001) compared with late downregulation for methotrexate responders (week 2, -0.44 [0.68], P = .64; week 16, -5.14 [0.68], P < .001). Analysis of variance findings for key mRNA and immunohistochemical marker expression over the study course were significant only for CCL20 (P = .03) and IL22 (P = .006) mRNA comparing adalimumab and methotrexate responders.Conclusions and relevanceMethotrexate is an immunomodulator with effects on helper T-cell signaling in psoriasis. Similar genomic and immunohistochemical response signatures and levels of mRNA downregulation at study completion among adalimumab and methotrexate responders suggest a disease-driven instead of therapeutic-driven pathway regulation. Adalimumab and methotrexate responses are differentiated by patterns of normalization of CCL20 and IL22 mRNA expression and may explain the varied onset and degree of clinical responses by each treatment.Trial registrationclinicaltrials.gov Identifier: NCT00932113.

Project description:Objective: To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis.Design: Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study.Setting: Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018.Participants: Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein.Interventions: Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab.Main outcome measures: The primary outcome was adjusted clinical disease activity index remission (CDAI?2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms.Results: 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms.Conclusions: All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.Trial registration: EudraCT2011-004720-35, NCT01491815.

Dataset Information

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

Publications

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

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