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

Patients will be recruited from the outpatient clinics of the Departments of Dermatology of the Academic Medical Center (AMC) Amsterdam, Erasmus University Medical Center (EMC) Rotterdam, and the Radboud University Medical Center (RUMC) Nijmegen. Moreover, other dermatologists will be contacted to recruit and refer eligible patients to the participating centers. Participants must meet the inclusion criteria and none of the exclusion criteria (Table 2) in order to participate. These criteria will be assessed at the screening visit. Potential participants who are deemed ineligible at screening will be allowed a second screening visit if the reason for ineligibility is a temporary status (e.g., latent tuberculosis).

All patients receive adalimumab 40 mg subcutaneously every other week starting 1 week after a loading dose of 80 mg and will be randomized 1:1 to receive either oral MTX 10 mg weekly (combination group) or no addition of MTX (monotherapy group). MTX therapy will be initiated 2 weeks prior to adalimumab therapy, and administration will be followed by folic acid 5 mg 24 hours after MTX intake (see Table 1).

In case of MTX toxicity (e.g., liver toxicity or leukopenia) or intolerability, dosing can be paused (for a maximum of 2 weeks up to four times during the entire study), or the dose can be adjusted to 7.5 mg. Moreover, patients are allowed to switch from oral to subcutaneous administration. In case of adalimumab toxicity or intolerability, dosing can be paused (for a maximum of 2 weeks up to four times during the entire study).

Throughout the study, no systemic anti-psoriatic drugs are allowed for treatment other than the study medication (Table 3). If medically necessary (i.e., to control intolerable psoriasis activity), rescue treatment with topical corticosteroids, vitamin D derivates (calcipotriol/betamethasone or calcitriol), or calcineurin inhibitors may be provided to study patients at the discretion of the investigator after baseline and through week 145 (end of study) (Table 4).

Consecutive patients will be prospectively enrolled and randomly assigned if eligible to either the intervention (adalimumab with MTX) or control (adalimumab monotherapy) group after obtaining informed consent. Each consecutive patient will be assigned a randomization number according to a computer-generated randomization list (ALEA) using random block sizes of 2, 4, 6, and 8 to ensure allocation concealment. Randomization is stratified for TNFα-blocker exposure status to achieve balance with regard to prior TNFα-blocker exposure in the study population.

This is an observer-blinded study. The observer (outcome assessor) will perform clinical outcome assessments of disease severity (Psoriasis Area and Severity Index (PASI) and investigator global assessment (IGA)) at each study visit. The clinician performs all other study procedures and is not blinded. Both clinician and participant know the treatment allocation; as such, no special measures are required to allow for breaking of treatment codes. However, treatment allocation will not be revealed to the recruiting physician until participants’ details and key stratification variables have been irrevocably entered onto the web-based randomization site.

The primary outcome is adalimumab drug survival (number of patients still on adalimumab treatment) at week 49.

Secondary outcomes are the following:

Patients will visit the outpatient clinic at screening, baseline, week 5, week 13, and every 12 weeks thereafter until study completion (weeks 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145) (Table 1). A variety of parameters will be collected during each visit to assess efficacy, including physician- (PASI/IGA (static; scale 0–4 [30])) and patient-reported (patient-reported global assessment (PGA static; scale 0–4)) outcomes. Quality of life assessment will be performed using Skindex and DLQI questionnaires. Safety will be assessed by evaluating the incidence of (serious) adverse events, obtaining a detailed medical history, thorough physical examination, vital signs, clinical laboratory testing, and urinalysis (including pregnancy tests for females of childbearing potential at screening). Concomitant medication and medical procedures will be collected from obtainment of informed consent up to end of study. Patients will receive a diary in which they will register the administration dates of adalimumab (and MTX in the combination group), any changes in their health status, and/or changes in concomitant medication used. The local investigator reviews the diary to determine drug adherence and the incidence and type of adverse events. An independent Data Safety Monitoring Board (DSMB) has been established to review efficacy and safety data periodically in an unblinded fashion.

Blood samples will be collected at each visit (serum samples are collected just before administration of adalimumab (3-day window) to ensure accurate determination of serum through levels) to monitor drug safety, to determine immunogenicity against adalimumab, and to measure adalimumab serum through levels. Samples for serum preparation are kept at room temperature for 1–2 hours for coagulation, followed by centrifugation at 3000 RPM for 15 minutes at room temperature. Supernatant is collected, aliquoted, and stored at −20 °C until further use. Adalimumab serum through levels will be determined using a non-commercial enzyme-linked immunosorbent assay (ELISA, Sanquin, Amsterdam, The Netherlands). Detection of anti-adalimumab antibodies will be performed through a radioimmunoassay (Sanquin). The antibody test will be considered positive when the antibody concentration exceeds 12 AU/mL. Concentrations between 12 and 100 AU/mL will be considered low antibody titers; those above 100 AU/mL will be considered high antibody titers [3].

Additionally, a single blood sample will be collected at screening from which DNA will be collected and stored at −80 °C. As scientific interest in this field is currently increasing, DNA analysis will be performed based upon accumulating data acquired from (ongoing) pharmacogenetic studies.

A total of 84 patients (randomized 1:1 to concomitant MTX or no MTX) will give the study at least 80% power at a 0.05 two-sided significance level using a two-sample chi-squared test to detect a difference of 28% in drug survival at week 49. We aim to enroll 93 patients to allow for an approximate 10% loss to follow-up. These calculations were performed using Nquery 6.0.2. Due to the lack of data in a psoriasis population, the expected clinically relevant difference in drug survival between both treatment groups was hypothesized based on studies performed in patients with RA. The prevalence of (clinically relevant) anti-drug antibody formation is estimated to be 45% in patients on adalimumab monotherapy (a similar percentage is found in patients with psoriasis [31] and around 17% in patients on adalimumab with low-dose (5–10 mg) MTX after 49 weeks [32]. A clear correlation between antibody formation and treatment failure (with subsequent treatment discontinuation) in patients on adalimumab has been demonstrated [31]. Based on these data, drug survival is estimated to be 83% (100 minus 17) for the experimental group and 55% (100 minus 45) for the control group after 49 weeks of follow-up.

The primary analysis will be conducted on the intention-to-treat population, including all randomized participants in the groups to which they were randomized. A per-protocol population (excluding major protocol violations) will be used to check the robustness of the primary analyses. The safety population will consist of all patients receiving at least one dose of the study drug.

Adverse events will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) adverse event classification. The overall incidence of (serious) adverse events and number and proportion of patients reporting such events will be summarized by treatment group.

Differences in dichotomous outcomes among the two study groups will be analyzed using the chi-squared test or Fisher’s exact test when the expected cell frequencies fall below 5. We will express differences in drug survival as absolute differences and relative risks, with associated 95% confidence intervals, with the group on adalimumab monotherapy as the reference. In case patients are lost to follow-up during the study period, we will analyze these data by means of survival analysis. We will construct cumulative survival curves (Kaplan-Meier method) for the treatment groups, and these curves will be compared using the log-rank test. One-way analysis-of-variance statistics will be calculated to compare continuous outcome measures between groups.

There are no formal planned interim analyses, but progress reports on all data issues are presented to the DSMB.

Patient recruitment started in March 2014 and is currently ongoing. Based on our experience so far, recruitment is limited by two main factors: prior use of adalimumab and intolerability or toxicity for MTX in the past.

Moreover, disease activity in patients who are transitioned from another biologic is often suppressed (<PASI 8). To enlarge the geographical area in which patients can participate in the study and to enhance patient recruitment, three additional hospitals have been activated for patient recruitment: Amphia Hospital (Breda) and Bravis Hospital (Bergen op Zoom) in The Netherlands and Ghent University Hospital in Belgium.