The primary study objective was to assess the overall preference of RA patients for continuous MTX treatment with either the medium-concentration formulation (MC) (2.0 ml of 10 mg/ml solution; need to apply needle) or the high-concentration formulation (HC) (0.4 ml of 50 mg/ml pre-filled syringe; pre-attached needle) by repeated SC injections.

Secondary objectives included satisfaction, usability and local tolerability assessed by patients, physicians and study nurses.

This open, comparative, within-patient controlled, multicentre study enrolled 132 patients at 16 centres in Germany between November 2007 and November 2008. Patient enrolment by centre ranged between 1 and 24 patients. Patients received 20 mg MTX administered SC via MC (2 ml of the 10 mg/ml solution) once weekly for 3 weeks followed by HC (0.4 ml of the 50 mg/ml solution) for another three weeks. The physicians or the study nurses performed the first injection of every type of syringe (1^st and 4^th injection within the study), the following two injections of every type of syringe were performed by the patients themselves (2^nd, 3^rd, 5^th and 6^th injection within the study). Questionnaires and visual analogue scales were used to document satisfaction, usability and local tolerability. Safety laboratory testing (haematology and biochemistry) were performed at baseline, after 3 weeks and at the end of the study.

The study included patients with a diagnosis of RA according to the ACR criteria [6]. Patients were 18 to 75 years old and had received oral MTX- which is among parenteral application also in accordance with national recommendations for treatment of RA [7] - for at least 6 weeks prior to study start and required an intensified therapy due to remaining RA activity (DAS28 > 2.6). After study termination every patient received appropriate RA treatment at the discretion of the investigator.

The main exclusion criteria were: prior treatment with parenteral MTX or biologicals; concomitant treatment with another DMARD or a biological; renal insufficiency (serum creatinine > 1.5 x ULN); liver function test abnormalities (AST or ALT > 2 x ULN, bilirubin > 5 mg/dl); impaired haematopoiesis (platelets < 100 x 10⁹/l, leukocytes < 3.5 x 10⁹/l), anaemia (haemoglobin < 10 g/dl); severe acute or chronic infections; malignant disease; alcohol or drug addiction; history of generalised allergic reactions or serious adverse reactions to the study medication or other components of the injection solution; women with child-bearing potential without reliable contraception; men who had a partner with child-bearing potential and did not use a condom or a cervical cap/diaphragm with spermicide during the study and for at least 6 months thereafter; pregnant or breast-feeding women; any other subcutaneously administered drugs (e.g. insulin, heparin); concurrent vaccination with live vaccines.

Previous therapy with other DMARDs and concomitant therapy with nonsteroidal antirheumatic drugs or corticosteroids were permitted during the study: combination therapy with one or more DMARDs or a biological immuno-modulator (e.g. TNF-α blockers); drugs causing folate deficiency (e.g. sulfonamides, trimethoprim-sulfamethoxazole); live-virus vaccinations. Patients were allowed to receive oral folic acid once a week, 24 hours after the MTX dose, with the dose to remain constant throughout the study.

Table 1 summarises questions and answers concerning patient-reported, physician-reported and study nurse/physician-reported outcomes.

All patients who received at least one dose of study medication were evaluated for the occurrence of adverse events, serious adverse events and clinical laboratory abnormalities. Severity of adverse events was assessed by the investigator as mild, moderate, severe and life-threatening whereas clinical laboratory values were judged with respect to clinical significance.

Study drug consisted of the commercially available MTX medium-concentration formulation (10 mg/ml solution; need to apply a needle; metex^®in Germany, metoject^® in other countries, manufacturer: medac Gesellschaft für klinische Spezialpräparate mbH, Hamburg, Germany) and a prefilled syringe MTX high-concentration formulation (50 mg/ml solution; pre-attached needle) (Fig. 1); both formulations were provided by medac GmbH, Germany.

Fig. (1). Comparison of the methotrexate prefilled syringe 10 mg/ml and 50 mg/ml true to scale. MTX=methotrexate.

Fig. (2). Patients’ overall assessment of methotrexate prefilled syringe 10 mg/ml and 50 mg/ml.

Fig. (3). Study nurses’ and physicians’ overall assessment of methotrexate prefilled syringe 10 mg/ml and 50 mg/ml.

The primary objective, i.e. the proportion of patients deciding in favour of the HC syringe, was subjected to statistical testing by applying a two-sided one-group chi-square test on a significance level of 5%. For sample size estimation, sufficient power for the statistical test was required to detect an increase of the rate of patients deciding to use the HC syringe for future MTX treatment to at least 70%. A one-group chi-square test with a 5% two-sided significance level would have 90% power to detect the difference between the null hypothesis rate of 55% and the alternative rate of 70% with a sample size of 110 patients.

To assess the local tolerability at the site of injection, frequency distributions of mild, moderate and severe signs and symptoms of swelling, itching, erythema, haematoma and pain were presented. Treatment-specific differences between ordinal data were evaluated using Wilcoxon signed-rank tests on an explorative perspective. All other parameters were analysed descriptively using robust measures of location and dispersion such as medians and 1^st (Q1) and 3^rd quartiles (Q3).

The study was performed in accordance with the Good Clinical Practice guidelines recommended by the International Conference on Harmonization (ICH) of Technical Requirements. Ethics committees relevant to the respective study sites approved the study protocol. Written informed consent was obtained from all patients.

The study was supported by medac Gesellschaft für klinische Spezialpräparate mbH, Hamburg, Germany.

Of the 132 patients enrolled, one was excluded from the safety-analysis set (due to missing study visits (1^st, 2^nd and 4^th injection) and lack of any source data) and additional 3 were excluded from the full-analysis set (due to injection of merely one type of syringe). Of the 128 patients included in the full-analysis set, 34 were men and 94 women. Median age was 56 years (range: 18 to 75 years), median weight 78 kg (range: 49 to 116 kg) and median body height 165 cm (range: 150 to 188 cm). Median baseline Disease Activity Score of 28 joints (DAS28) was 4.3 (range 2 to 8) and median duration of RA in the patients was 3 years (range: 1 to 39 years). Sixty-three (49.2%) patients had previously received MTX treatment at dosages ranging between 7.5 to 25 mg/week and differed from those dosages given at study start. 85.1% of the patients received MTX dosages of 15 or 20 mg/week (6 patients received more than 20mg oral MTX, 1 patient received 25 mg, the other ones 22.5 mg).

Adverse events were coded according to the Medical Dictionary for Regulatory Affairs (MedDRA). Adverse events were reported in 25 (19.1%) of the 131 patients valid for safety analysis. The number of patients experiencing adverse events was 14 (10.7%) and 15 (11.5%) with MC and HC formulation, respectively (Table 2).

All adverse events expect the one documented within the system organ class “Injury, poising and procedural complications” were judged to be at least possibly drug-related. The most frequent adverse events and drug-related adverse events were gastrointestinal disorders (6.1%), investigations (3.8%) and general disorders and administration site conditions irritations (3.1%). Most adverse events were of mild and moderate intensity. No relevant differences were observed between the two MTX formulations with the exception of five cases of mild and moderate increases in liver enzymes documented within the system organ class investigations occurring during HC treatment compared to no cases during MC treatment.

Three serious adverse events were reported: One occurred during HC-treatment phase two days after the 5^th injection (cheek bone fracture) and two others (back pain and left ear mastoiditis) within 28 days after the final examination. All events were considered unrelated to study medication by the investigator.

Three subjects discontinued study participation due to adverse events. These included coughing, dizziness and nausea/sicca symptoms/pain. All events were non-serious and considered as possibly related to study medication.

With regard to overall local tolerability including erythema, swelling, itching, pain and haematoma at the injection site, HC treatment was slightly better tolerated than MC treatment. Physicians’ assessment of the injection site showed an absence of erythema with HC treatment in 79.7% of patients compared to 71.1% with MC treatment, which was statistically significant (P = 0.0123) and tended to be confirmed by patients’ assessment.

For all laboratory categories (haematology and biochemistry), mean parameter changes were minor including those of liver function tests. Except for a mean decrease in CRP by 4 mg/l, mean changes were of no clinical relevance.