An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Richard B Warren, Ulrich Mrowietz, Ralph von Kiedrowski, Johannes Niesmann, Dagmar Wilsmann-Theis, Kamran Ghoreschi, Ina Zschocke, Thomas M Falk, Norbert Blödorn-Schlicht, Kristian Reich
2017 The Lancet  
A 52-week double-blind placebo-controlled study of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate-to-severe plaque-type psoriasis (METOP) Role of the funding source (see also below) The study was an investigator-initiated trial supported by a grant from Medac to K.R. Manuscript 2 Summary Background: We report the study of an intensified dosing schedule of subcutaneous methotrexate (MTX) in patients with moderate-to-severe psoriasis. Methods: In this
more » ... tive, double-blind, multicentre phase 3 study (METOP) eligible patients were 18 years or older with a diagnosis of chronic plaque psoriasis at least 6 months before baseline, had a psoriasis area and severity index (PASI) of 10 or more or 10% or greater body-surface area involvement or a dermatology life quality index (DLQI) of 10 or more and were naïve to treatment with MTX. Participants were randomly assigned 3:1 by computer-generated random sequence integrated in the electronic data capture system to receive either MTX at a starting dose of 17.5 mg/week or placebo for the first 16 weeks, followed by open-label MTX treatment of all patients up to 52 weeks (MTX/MTX and PLC/MTX groups, respectively). Dose escalation to 22.5 mg/week was allowed after 8 weeks of MTX therapy if patients failed to achieve an at least 50% improvement of their baseline PASI (PASI50); blinding was maintained by a corresponding volume increase of placebo injections. Treatment was combined with folic acid 5 mg/week. The primary efficacy endpoint was the proportion of patients achieving a PASI75 response at week 16 analysed by intention to treat with non-responder imputation. This study is registered with the European Medicines Agency, EudraCT number 2012-002716-10. Findings: Between February 2013 and May 2015 120 patients were randomly assigned to receive subcutaneous MTX (n=91) or placebo (n=29). The primary endpoint was met; the PASI75 response rate at week 16 was 41% (n=37) in the MTX group compared to 10% (n=3) in the placebo group [p=0.0026; effect size 30.3% (95% CI 15.3-45.3) MTX vs placebo]. Subcutaneous MTX was generally well tolerated; no cases of serious infections, malignancies, major adverse cardiovascular events or deaths were noted. Serious adverse events were observed in 3 patients started on MTX during the 52-week study period. Interpretation: The study documents a favourable 52-week benefit-risk profile of subcutaneous MTX in psoriasis. The route of administration and the intensified dosing schedule should be considered when using MTX in patients with psoriasis. Word count 347 4 Methods Study design and participants METOP was conducted as a double-blind, placebo-controlled randomised investigator-initiated trial. Eligible participants were aged 18 years or older, were naïve to MTX and had a diagnosis of plaquetype psoriasis for at least 6 months with currently moderate-to-severe disease based on the definition by Finlay. 12 Patients were required to have a normal chest x-ray within 6 months prior to study entry and were excluded if hepatic enzymes (ALT, AST, or GT) were elevated above 2x the upper limit of normal or total leukocyte counts were below 3.0 x 10 9 /L in screening laboratory tests. Previous treatment with biologics had to be discontinued at least 5 times their half-life, other systemic therapies and phototherapies used for the treatment of psoriasis at least 4 weeks and topical therapies at least 2 weeks before study entry. Bland emollients were allowed during the study. Patients with a previous diagnosis of psoriatic arthritis (PsA) could be enrolled; however, patients with currently active PsA as defined by 5 or more tender or swollen joints and peripheral Creactive protein levels above 2x the upper limit of normal were excluded. The complete list of inclusion and exclusion criteria is available in supplementary table S1. The study was conducted according to the protocol and in conformance with the ICH-guideline "Note for Good Clinical Practice" (CPMP/ICH/135/95.Study documents were approved by a master ethical committee (University of Kiel, Germany) and investigational review boards at each site. All patients signed an informed consent before undergoing study-related procedures. In total 16 sites were selected in Germany (13 sites), France, Netherlands, and the UK (1 site each). Randomisation and masking The randomisation list was generated using the randomisation software randlist 1.2 and the randomisation number assigned at the baseline visit in an ascending order to subjects eligible for treatment after inclusion and exclusion criteria had been checked and the investigator had confirmed the randomisation of the patient. Eligible patients were randomised in a ratio of 3:1 to receive either MTX or placebo (PLC) injections for the first 16 weeks. Between week 16 and week 52 patients from both treatment groups were entitled to receive MTX injections, i.e. either continued on MTX (MTX/MTX group) or crossed-over from placebo (PLC/MTX group). The trial was performed in a double-blind manner from the time of randomisation until an interim database lock for the data up to and including week 16. All trial drugs were supplied in identical packages. The syringes for placebo and active drug were not distinguishable and fully coated to prevent identification of colour differences between MTX and placebo injections. From week 16 on, MTX injections were open-label. Procedures From week 0 to week 16 patients received once weekly s.c. injections of 17.5 mg MTX (metex®, metoject®; concentration 50 mg/ml) in a volume of 0.35 mL or 0.35 mL placebo injections. If PASI50 was not reached after 8 weeks, patients received injections with 22.5 mg MTX/week in a volume of 0.45 mL or 0.45 mL placebo injections. The first injection at day 0 and the injection at day 112 were given at the study sites; all other injections were self-administered by the patient. From week 16 to week 52 patients originally started on MTX remained on the same dose unless they were receiving 17.5 mg MTX/week and at week 24 had failed to reach PASI 75, in which case they could be dose-escalated to 22.5 mg MTX/week. If patients were already dosed with 22.5 mg 5 MTX/week at week 24 and PASI50 was not reached, patients were excluded from continuing with study treatment. Patients originally started on placebo and switched to MTX at week 16 received 17.5 mg of s.c. MTX weekly with possible dose-escalation to 22.5 mg MTX/week at week 24 if PASI50 was not achieved. According to protocol, patients originally treated with placebo and achieving a PASI75 response at week 16 received no further injections until the disease relapsed, when they were treated with 17.5 mg MTX/week as described above. Patients from all treatment groups received 5 mg of oral folic acid 24 hours after each injection. Outcomes The primary endpoint was the percentage of patients achieving an at least 75% improvement of the baseline PASI (PASI75) at week 16. Key secondary endpoints included the PASI75 response rate at week 52, and the following outcomes assessed at weeks 16 and 52: PASI50 and PASI90 response rates, a static physicians' global assessment (sPGA) measured on a 7-point scale ranging from 0=clear to 6=severe, the Nail Psoriasis Severity Index (NAPSI) of the finger nails, the dermatology life quality index (DLQI) and the EQ-5D with 5 levels ranging from level 1 (no problems) to level 5 (extreme problems) . Safety was assessed based on reported adverse events (AEs), laboratory values, vital signs, physical examinations, and assessments of local drug tolerability collected and observed at study visits during the 52-week study period. AEs were classified as drug-related if the relationship was classified as "related" or "possible" by the investigator. All AEs appeared during treatment and fulfilled the criterion of treatment-emergent AEs. Levels of the amino-terminal propeptide of type-III procollagen (PIIINP) were assessed at baseline, week 16, week 32, and week 52. Biopsy sub-study Two punch biopsies (3 mm in diameter) were obtained from 27 patients from the edge of a representative psoriatic plaque, each at baseline and from the same plaque at week 16. One biopsy taken at each time point was immediately transferred to 4% buffered formalin, the other was fixed in RNAlater solution (Qiagen, Hilden, Germany) for subsequent RNA extraction. All biopsies were handled and analysed by personnel blinded to treatment and time points. RNA was isolated by means of the RNeasy Fibrous Tissue Mini Kit (Qiagen). Briefly, cDNA was synthesized using the Applied Biosystems High Capacity cDNA Reverse Transcription Kit (Life Technologies, Grand Island, NY, USA). Quantitative real-time PCRs were carried out in duplicate using a Bio-Rad iQ5 Cycler (Bio-Rad Laboratories, Hercules, CA, USA) as described. 13 Results for IL17A, IFNG and TNFA were evaluated using the iQ5 Optical System Software, Version 2.0 (Bio-Rad Laboratories). Quantification was based on ΔΔCT calculations. Samples were normalized based on 2 reference genes, B2M and UBC. Psoriatic micro-anatomical features (epidermal thickness, parakeratosis, presence of epidermal microabscesses) and immunohistochemical markers (CD3-positive T cells, CD1a-and CD11c-positive dendritic cells, Ki-67-positive keratinocytes) were investigated and semi-quantitatively assessed on paraffin-embedded sections using the AxioVision SE64 Rel. 4.8 system (Zeiss, Oberkochen, Germany) on digitally scanned images as described. 13 Statistical analysis 6 The METOP study intended to show that an intensified s.c. MTX dosing scheme is superior to PLC in inducing a PASI75 response at week 16 based on two-sided Pearson's Chi-square test with an alpha level of 0.05 of the mITT population with non-responder imputation. The sample size estimation of n=120 treated patients was based on this statistical approach, an assumed PASI75 response rate among MTX-treated patients at week 16 of 35% and among patients receiving placebo of 10%, a power of 80%, and a 3:1 randomization of active drug vs. placebo. All outcomes were analysed based on the intention to treat population of all patients who had received at least one injection with study drug (modified ITT; mITT) with non-responder imputation (NRI), i.e. missing data were handled as indicating "no response". The mITT population included n=120 patients (n=91 patients started on MTX and n=29 patients started on PLC). All randomised patients received at least one injection of study drug. Post-hoc comparisons of secondary and non pre-specified endpoints at week 16 were also based on the mITT population with non-responder imputation and were performed using the two-sided Pearson's Chi-Square test with an alpha level of 0.05. These analyses were considered exploratory and no adjustment for multiple testing was made. Selected clinical outcomes at week 52 are also presented based on an as-observed analysis. Two-sided 95% confidence intervals for PASI response rates over time were calculated according to Clopper-Pearson. For the relative risk and the effect size to achieve a PASI75 response at week 16 in response to MTX therapy vs placebo a two-sided asymptotic 95% confidence interval was calculated. Safety analyses were based on the dataset of all patients who received at least one dose of study medication. Safety data are reported both prior to and after week 16. Data of the biopsy sub-study were analysed using descriptive statistics. Scores of cutaneous cells positive for CD3, CD11c, or Ki67 in biopsies from week 16 were compared with values from paired biopsies taken at baseline using the Stuart-Maxwell test. Ratios of post-vs. pre-treatment cutaneous mRNA levels of INFG, IL17A, and TNFA were analysed for a difference from a median of "1" using the Wilcoxon test. Statistical tests were two-sided and performed at an alpha level of 0.05. Role of the funding source METOP was an investigator-initiated trial supported by a grant from Medac Germany to KR. Medac also supplied study medication, but had no influence on study conduct or interpretation. The study was designed by consultant experts in psoriasis (RBW, UM and KR) and by employees of SCIderm GmbH, Germany, which served as the clinical research organisation (CRO) for study management, data collection and statistical analysis. Data analysis was done by RBW, UM and KR. Safety data were reviewed at regular intervals by an independent data monitoring committee. RBW and KR prepared the manuscript. All co-authors participated in the collection and final interpretation of the data, reviewed the final manuscript and made the decision to submit for publication. 7 Results Clinical findings Recruitment took place between February 2013 and May 2015 at 13 sites; 11 in Germany, 1 site each in Netherlands, France and United Kingdom. In total 120 patients in METOP were randomly assigned to receive weekly s.c. injections of either placebo (n=29) or MTX (n=91). The majority of patients were middle-aged white males with long-standing psoriasis and a mean weight above 90 kg and a mean BMI around 30 (table 1) . Main baseline disease activity characteristics were balanced between the groups with a mean PASI around 15 and a mean DLQI around 12 indicating moderateto-severe disease with a major impact on health-related quality of life according to severity definitions used in clinical trials and guidelines. 14 Disease duration tended to be longer in patients started on MTX and a previous diagnosis of PsA was documented more frequently in this treatment arm. 77 (85%) of patients in the MTX group and 22 (76%) in the placebo group completed the study through to 16 weeks (figure 1). Of those, 73% (n=56) continuing on MTX and 68% switching from placebo (n=22) completed the study through to 52 weeks. Significantly more patients in the MTX group (37/91; 40.7%) than in the placebo group (3/29; 10.3%) met the criterion for the primary end point of an at least 75% improvement in the baseline PASI at week 16 (p=0.0026; relative risk 3.93 [95% CI 1.31-11.81]; figure 2 and table 2). Dose escalation to 22.5 mg/week at week 8 was documented in 30.8% of patients (28/91) in the MTX group. A sPGA of clear or almost clear (sPGA 0/1) was observed in 27.5% at week 16 (25/91) and a PASI90 response in approximately 1/6 patients (16/91; 17.6%) treated with MTX compared to 6.9% (2/29) and 0%, respectively, in the placebo group ( figure 2 and table 2 ). Based on a non-responder imputation (NRI) analysis of the mITT population PASI75 response rates at week 52 were 45.1% in the MTX/MTX group (41/91) and 34.5% in the patients crossed over from placebo (19/29; figure 2 and table 2). Among patients crossed over from placebo dose escalation to 22.5 mg/week was documented in 22.7% (5/22) at week 24, i.e. 8 weeks after the initiation of active treatment. Five patients in the MTX/MTX group dose-escalated to 22.5 mg/week at week 24 (no PASI75 response). Response levels increased with continuous MTX therapy; PASI90 responses were seen in almost 28% and sPGA 0/1 responses in almost 40% of patients in both the MTX/MTX (25/91 and 36/91, respectively) and PLC/MTX (8/29 and 11/29, respectively) groups at week 52 (figure 2 and table 2). 78.4% (29/37) of patients achieving a PASI75 response at week 16 with MTX therapy still had this response at week 52. Among patients receiving MTX over the full 52-week treatment period PAS75/90/100 responses were seen in 73.2% (41/56)/44.6% (25/56)/17.9% (10/56) of patients and 64.3% (36/56) achieved a sPGA 0/1 response (as observed analyses; table 2). MTX reduced the activity of nail psoriasis within 16 weeks as measured by the NAPSI of the worst fingernail as a target nail while placebo had no effect (table 2) . After 52 weeks of MTX treatment 13.6% of all patients with an active target nail at baseline showed complete clearance of that nail. Improvements in the signs of psoriasis were paralleled by improvements in the health-related quality of life as assessed by the DLQI. An absolute DLQI ≤5 (mild effect of psoriasis on DLQI domains) and a DLQI of 0 or 1 (no effect of psoriasis on DLQI domains) at week 16 was found in 59.3% (54/91) and 42.9% (39/91) of patients treated with MTX, respectively, compared to 34.5% (10/29) and 10.3% (3/29) of patients receiving placebo (table 2). 71.4% (40/56) of patients 14. Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res 2011; 303: 1-10. A 52-week double-blind placebo-controlled study of an intensified dosing schedule of subcutaneous 1 methotrexate in patients with moderate-to-severe plaque-type psoriasis (METOP) 2 3 Richard B.
doi:10.1016/s0140-6736(16)32127-4 pmid:28012564 fatcat:27lyo3bnkzeghd2d4futsnx7bu