Page 1 of 8
`
`Frontier Therapeutics Exhibit 1011
`
`

`
`16 The Open Rheumnrofogp Jorrrmrl, 2010, Volume 4
`
`patients treated with SC MTX than with oral MTX showed
`ACR20 (78% vs 70%) and ACR70 (41% vs 33%) responses.
`Patients with disease duration 2 12 months had even higher
`ACR20 response rates (89% for SC administration and 63%
`for oral). Tolerability did not differ between the two groups.
`
`In a phase I study, 12 healthy male subjects received
`15 mg MTX SC either as 50 mg/ml
`solution or as a
`10 mg/ml concentration. Both concentrations were shown to
`be bioequivalent with regard to AUC (medac, data on file).
`However,
`the rate of absorption expressed by Cum, was
`different with higher Cum concentrations achieved after
`administration of the higher concentrated solution. For the
`metabolite 7-hydroxy«MTX, similarity in rate and extent of
`absorption for SC administration was confirmed. Because of
`the bioequivalence of AUC of both concentrations, no
`difference in
`the efficacy and the safety of the two
`formulations was expected. Local tolerability was similar in
`both groups. Only three cases of mild erythema were
`observed (one with the concentration of 50 mgfml and two
`with the concentration of 10 mgfml). All events occurred
`immediately after injection and resolved within 2 hours after
`injection.
`
`The objectives of the subsequent study were the direct
`comparisons of local tolerability, usability, satisfaction and
`preference of
`two MTX solutions with
`different
`concentrations after SC administration in a larger number of
`patients with RA.
`
`STUDY PARTICIPANTS AND METHODS
`
`Objectives
`
`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 mgfml solution; need to apply needle) or the high-
`concentration formulation (HC) (0.4 ml of 50 mgfml pre-
`filled syringe; pre-attached needle) by repeated SC inject-
`ions.
`
`Miiiier-Ladrter er ml.
`
`Patients
`
`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 > l.5 x ULN); liver function test abnormalities
`(AST or ALT > 2 x ULN, bilirubin > 5 rngfdl); impaired
`haematopoiesis (platelets < 100 x l09l'l, leukocytes < 3.5 x
`10°/l), anaemia (haemoglobin < 30 gfdl); 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 capfdiaphragm with spermicide during
`the study and for at least 6 months thereafter; pregnant or
`breast-feeding women; any other subcutaneously adminis-
`tered drugs (e.g.
`insulin, heparin); concurrent vaccination
`with live vaccines.
`
`Previous therapy with other DMARDs and concomitant
`therapy with nonsteroidal antirheumatic drugs or corticoste-
`roids were permitted during the study: combination therapy
`with one or more DMARDS or a biological
`immuno-
`modulator (e.g. TNF-or blockers); drugs causing folate defic-
`iency (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.
`
`Secondary objectives included satisfaction, usability and
`local tolerability assessed by patients, physicians and study
`nurses.
`
`Assessment of Patient-Reported, Physician-Reported and
`Study Nursel'Physieian-Reported Outcomes
`
`Study Design
`
`controlled,
`comparative, within-patient
`open,
`This
`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 mgfml solution) once weekly for 3
`weeks followed by HC (0.4 ml of the 50 mgfml solution) for
`another three weeks. The physicians or the study nurses
`performed the first injection of every type of syringe (Isl and
`4"‘ injection within the study), the following two injections
`of every type of syringe were performed by the patients
`themselves (2'“i, 3"', 5”‘ and 6"‘
`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.
`
`Page 2 of 8
`Page 2 of 8
`
`Table 1 summarises questions and answers concerning
`patient-reported, physician-reported and study nursefphysi-
`cian-reported outcomes.
`
`Assessm ent of Safety
`
`least one dose of study
`All patients who received at
`medication were evaluated for the occurrence of adverse
`
`laboratory
`and clinical
`adverse events
`serious
`events,
`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 Medication
`
`Study drug consisted of the commercially available MTX
`medium-concentration formulation (10 mg/ml solution; need
`to apply a needle; metexa in Germany, metoject® in other
`countries, manufacturer: medac Gesellschaft
`fur klinisehe
`Spezialpraparate mbH, Hamburg, Germany) and a prefilled
`
`

`
`Compnrisorr of Tim M TX Prefltfed Sjrrirtgesfor S.C. Injection in RA
`
`The Open Rtrenmototogy Jortrrrot. 20M, Voinme 4 [7
`
`Table I.
`
`Preference and Usability 0utcomes*
`
`f’atient—Reportcd Outcomes
`
`Overall preference [primary endpoint)
`
`"lV.hic}r ofthe pr'e-fi;’r'ed syringes’ u'r)t.o’dymr pr-efir'fi'onr now on? "
`Patient satisfaction
`
`"How woutdyot: assess. in stnrrmary. the smut’!/Forge syringe at the and ofthe strrdfy? "
`1!
`as
`»
`
`Five categories were suggested: “very poor", "poor", “no preference
`
`good” and “very good”.
`
`Syringe with or without pre-attached needle
`
`".-‘tour do your {tire the prenttached needle (smelt syringe} in cornpar‘is0n to one that stilt has to be attached {forge syringe)? "
`
`l-'ive categories were suggested: “great disadvantage”, “disadvantage“, “no difference”, “advantage", and “great advantage“.
`
`Usa bility of syringe volume
`
`“Do you,-‘eel comjiwrabte n-‘iii: rnefizct that the irgiection lfqrrid isfive times less in the smelt syringe than in the large syringe? "
`
`Five possible answers were suggested: “fully disagree“, “disagree“, ”indit1‘erenl", “agree" and “fully agree".
`
`Local tote.-rability
`
`Occurrence of erythema, swelling, itching, pain and haematoma assessed as “none”, ‘‘mild‘‘, ‘‘moderate’‘ or “severe“.
`
`Usability ofthe ll} mgtml syringe at the 2"“ and 3"“ injection (MC formulation) and ofthe 50 mglml syringe at the 5"'and 6"‘ injection (I-[(3
`formulation)
`
`Rated on a visual scale from 0 {not convenient = 0 mm) to 10 (very convenient = I00 mm).
`
`Physician-Reported Outcomes
`
`Usability of the II} mgfml syringe at the I" injection (MC formulation) and ofthe 50 mgfml syringe at the 4"‘ injection (HC formulation)
`
`Rated on a visual scale from 0 {not convenient = 0 mm) to I0 (very convenient = 100 mm).
`
`Local tolerabilily
`
`Occurrence of crythema, swelling, itching, pain and haematoma assessed as “none”, “mild”, “moderatc" or “severe”.
`
`Study NursetPhysician-Reported Outcomes
`
`Syringe with or without prc-attached needle
`
`"How do you like the pr'e-attached’ neetfle (Sinai! syringe) in cornparison to the one n'irr'ch stiff has to be attached (large syringe)? "
`
`Five categories were suggested: “great disadvantage", “disadvantage”, “no difference“, “advanlage", and “great advantage".
`
`Usability of syringe volume
`
`"Do yotrfee.-' eomfor‘tat5.-‘e with thefaet that the injection liquid r'.s'_,r'ive times fess in the smut? syringe than in the large syringe?"
`
`Five possible answers were suggested: “fully disagree", ”disagree”, “indilt'crcm". “agree” and “fully agree".
`
`Overall assessment of the small prefilled syringe
`
`1\
`Five categories were suggested: “very poor“, “poor ,
`
`“no preference", “good” and “very good".
`
`Overall assessment of the large prefrlled syringe
`
`u a
`Five categories were suggested: “very poor”, “poor", “no preference ,
`‘Original in German.
`
`good" and “very good”.
`
`syringe MTX high-concentration formulation (50 mgtml
`solution; pre-attached needle) (Fig. 1); both formulations
`were provided by mcdac Gmbl-I, Germany.
`
`the
`significance level would have 90% power to detect
`difference between the null hypothesis rate of 55% and the
`alternative rate of 70% with a sample size of I 10 patients.
`
`Statistical Analysis
`
`the proportion of patients
`i.c.
`The primary objective,
`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 0ne—gr'0up chi-square test with a 5% two-sided
`
`Page 3 of 8
`Page 3 of 8
`
`tolerability at the site of injection,
`To assess the local
`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 explorativc perspective. All other param cters
`were analysed descriptivcly using robust measures of
`iocation and dispersion such as medians and 1“ (Ql) and 3“
`quartiles (Q3).
`
`

`
`18 The Open R.F:er:mnto!0gi'Jonr11m', 2010, Volume 4
`
`Mailer-Lndrzer er 01.
`
`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 1 16 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 mgfweek and differed from those dosages given at study
`start. 85.1% of the patients received MTX dosages of 15 or
`20 mgfweek (6 patients received more than 20mg oral MTX,
`1 patient received 25 mg, the other ones 22.5 mg).
`
`Effi eacy
`
`Patient-Reported 0:: tea mes
`
`to quantify the
`The primary efficacy variable was
`decision of the patient for future MTX treatment (50 mgfml
`syringe vs
`10 mgfml
`syringe)
`following repeated SC
`injections of both formulations. At the end of the study,
`93.0% of all patients stated that they would prefer the HC
`formulation compared to 2.3% of the patients expressing a
`preference for the MC formulation (95% confidence interval:
`[87.1%;
`96.7%}). The
`result was highly statistically
`significant (P<0.0001).
`
`At the end of the study, overall assessment of the patients
`of the HC formulation was “good" and “very good” in
`90.6% of the patients compared to 1.6% with a “poor” and
`“very poor” overall assessment. The patients’
`overall
`assessment of the MC formulation was “good“ and “very
`good” in 34.4% of the patients compared to 17.2% with a
`“poor“ and “very poor” overall assessment (Fig. 2). This
`advantage in favour of the HC formulation was statistically
`significant (P<0.000 l ).
`
`39.1% of the patients assessed the usability of having a
`pre-attached needle with the small syringe (HC formulation)
`as an “advantage” and “great advantage” and 3.1% as a
`“disadvantage” and “great disadvantage".
`
`87.5% of the patients reported that the smaller volume in
`the HC formulation was more suitable (“agree” and “fully
`agree") compared to the larger volume with the MC
`formulation. 1.6% of the patients disagreed in this regard.
`
`global
`patient’s
`scale,
`analogue
`visual
`a
`Using
`assessment of syringe usability was 63.5 mm (Q1-Q3: 49-
`92) after MC administrations which increased significantly
`to 95.0 mm (Ql~Q3: 85-99) after administration of the HC
`formulation (P < 0.0001).
`
`Physician-Reported Outcomes
`
`Using a visual analogue scale, physician-reported global
`assessment of syringe usability was 82.0 mm (Ql»Q3: 59»
`100) at the time of administration of the MC formulation. A
`significant
`increase in to 96.0 mm (Q1-Q3: 86-100) was
`observed at time of HC administration (P < 0.0001).
`
`Study Nurse/Physicfnn~Reporled Outcomes
`
`All study nurses and physicians assessed the usability of
`having a pre-attached needle with the small syringe (HC
`formulation) as an “advantage” or “great advantage”.
`
`MTX 10 mgiml
`
`MTX 50 mglml
`
`(1). Comparison of the methotrexatc prcfillcd syringe
`Fig.
`I0 Inglml and 50 mglml true to scale. MTX=mcthotrcxatc.
`
`Ethics
`
`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.
`
`Funding
`
`The study was supported by medac Gesellschaft
`klinische Spezialpraparate mbH, Hamburg, Germany.
`
`fur
`
`RESULTS
`
`Patient Characteristics
`
`Of the 132 patients enrolled, one was excluded from the
`safety-analysis set (due to missing study visits U“, 2"" and
`4"‘ injection) and lack of any source data) and additional 3
`Page 4 of 8
`Page 4 of 8
`
`

`
`Compnrisorr ofTwo MTX Prefifled Syrirrgesfor S.C. Irfiecrion In RA
`
`Tire Open Rlreumarology Jaumrrl, 2010. Voimne 4 19
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0 %
`
`|:} MTX10 mgrml
`I MTX so mgrml
`
`Very good
`
`Good
`
`No
`preference
`
`Poor
`
`Very Poor
`
`Missing
`
`Fig. (2). Patients’ overall assessment of methotrcxatc prcfillcd syringe 10 mgfml and 50 mglml.
`
`100%
`
`90%
`
`30%
`
`T0%
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
` E] MTX 18 mgfrnl
`
`I rvrrx so mgfrnl
`
`0%
`
`Very good
`
`Good
`
`No preference
`
`Poor
`
`Fig. (3). Study nurses’ and physicians’ overall assessment of metholrexate prelilled syringe 10 mgfml and 50 mgfml.
`
`37.5% found that
`
`the smaller volume in
`
`the HC
`
`formulation was more suitable (“agree” and “fully agree”)
`compared to the larger volume with the MC formulation.
`12.5% saw no difference in this regard.
`
`At the end of the study, study nurses’ and investigators’
`overall assessment of the HC formulation was “good”
`(18.8%) and “very good” (81.2%). The overall assessment of
`the MC formulation was “good” in 31.3% of cases, “very
`good" in 12.5% and no preference in 50% (Fig. 3).
`
`Sa fety
`
`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
`
`Page 5 of 8
`Page 5 of 8
`
`for safety analysis. The number of patients experiencing
`adverse events was 14 (10.7%) and 15 (1 1.5%) 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-
`relatcd. 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
`
`

`
`20 The Open Rlrerrmamtagy Jortrrrnl, 2010. Valmne 4
`
`Table 2.
`
`Adverse Events
`
`MedDRA System Organ C|assi'Prcfcrr'cd Terms
`
`Number or patients with adverse events
`Gastrointestinal disorders
`
`Abdominal pain
`
`Abdominal pain upper
`Diarrhoea
`
`Mouth ulceration
`
`Nausea
`
`investigations
`Alanine aininolransfelase increased
`
`Aspartate aminotranslerase increased
`
`Gamma-glutamyltranslerase increased
`White blood cell count decreased
`
`General disorders and administration site conditions
`
`Fatigue
`
`Feeling abnonnal
`
`Injection site irritation
`
`Mueosai dryness
`Pair:
`
`Skin and subcutaneous tissue disorders
`
`Alopecia
`
`Erylhema
`
`Muscuioskcletal and connective tissue disorders
`
`Musculoskeletal pain
`
`Myalgia
`
`Pain in extremity
`
`Rheumatoid arthritis (worsening)
`
`Nervous system disorders
`
`Cervical root pain
`Dizziness
`
`Miifler-Lndtrer er a1.
`
`MTX Medium
`Concentration
`n=l3l
`n 0%)
`
`MTX High
`Concentration
`n=l3l
`n [%)
`
`I4 {I03}
`
`15 (115)
`
`25 (19_])
`
`2 ( I .5)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (0.3)
`
`0 (0.0)
`
`1 (0.8)
`
`l (0.8)
`
`Respiratory, thoracic and mediastinal disorders! Cough
`
`Infections and inf'cstationsi'()ral herpes
`
`Far and labyrinth disortiersfvcrtigc
`
`Injury, poisoning and procedural t:on1plicatior1sfFacial bones fiaeture
`Metabolism and nutrition disordersmnorexia
`
`Vascular disorders Extremity necrosis
`
`l (0.3)
`
`investigations occurring during HC
`system organ class
`treatment compared to no cases during MC treatment.
`
`examination. All events were considered unrelated to study
`medication by the investigator.
`
`reported: One
`events were
`adverse
`Three serious
`occurred during HC-treatment phase two days after the 5“
`injection {check bone fracture) and two others (back pain and
`left ear mastoiditis) within
`28 days
`after
`the
`final
`
`Three subjects discontinued study participation due to
`adverse events. These included coughing, dizziness and
`nauseafsicca symptomsfpain. All events were nomserious
`and considered as possibly reiated to study medication.
`
`Page 6 of 8
`Page 6 of 8
`
`

`
`Comparison of Two MIX Prefifled Syringesfor S. C. Injection in RA
`
`The Open Rhenmnroiogv Jcomal. 2010, Volume 4' 21
`
`tolerability including
`local
`With regard to overall
`erythema, swelling,
`itching, pain and haematorna 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 7l.l% with MC treatment, which
`was statistically significant (P = 0.0123) and tended to be
`confirmed by patients’ assessment.
`
`and
`(haematology
`categories
`laboratory
`all
`For
`biochemistry), mean
`parameter
`changes were minor
`including those of liver function tests. Except for a mean
`decrease in CR? by 4 mg/I, mean changes were of no clinical
`relevance.
`
`DISCUSSION
`
`The results of the study show that repeat dosing of the
`novel high«concentration (HC) MTX solution available in a
`prefilled syringe with a pre-attached needle yields
`a
`significantly better acceptance by patients and healthcare
`professionals than the medium-concentration (MC) solution
`with a syringe to which the needle still has to be attached.
`
`The MTX formulations differ also considerably with
`regard to usability and overall preference in numerous
`patients with RA who self-administered the prefitled MTX
`syringes. At
`the end of the study 93% of the patients
`preferred HC over MC as further treatment. Physicians’ and
`patients’ global assessments of syringe usability showed also
`highly statistically significant differences (P < 0.0001) in
`favour ofthe HC formulation.
`
`Reasons for this preference also include a smaller volume
`of administered drug, which improves
`the comfort of
`injection and may represent a psychological benefit for the
`patient.
`In
`addition,
`the
`pre-attached
`needle
`(HC
`formulation) allows a safer handling in comparison to the
`MC syringe, for which the needle must first be attached to
`the syringe body.
`
`A within patient-controlled design was considered the
`most appropriate approach to determine whether the switch
`to the newly available I-IC treatment has the ability to
`increase
`patient’s
`satisfaction of
`subcutaneous MTX
`treatment
`compared to
`the previously availabie MC
`treatment. Due to different sizes of syringes blinding of
`patients and nurses was not
`feasible within this trial.
`However, the study results may be biased due to the fact that
`the treatment sequence was not randomized. But, looking at
`the huge numerical advantage of HC,
`this bias can be
`considered to be negligible with respect to the overall study
`conclusion.
`
`Differences regarding local tolerability were slightly in
`favour of HC treatment. Erythema occurred significantly less
`often with HC treatment compared to MC treatment. Overall
`patient assessment was confirmed by physician and study
`nurse assessments who expressed similar preferences and
`conclusions as the patients. In general, quantity and quality
`of adverse
`events did not differ between the
`two
`formulations to a relevant extent.
`
`This study focused on safety and tolerability and not on
`efficacy. However,
`as
`the
`superior
`efficacy of SC
`administered MTX has been proven in a recent 6-month,
`
`Page 7 of 8
`Page 7 of 8
`
`in
`multicenter, randomized, double-blind, controlled trial
`comparison to oral MTX in 384 MTX-naive patients with
`active RA {5}, similar clinical results can be expected for the
`novel HC formulation. Parenteral MTX treatment
`is
`in
`
`guidelines which
`practice
`current
`accordance with
`recommend to consider a switch to the intramuscular or SC
`
`inadequate
`compliance,
`poor
`patients with
`in
`route
`effectiveness, or gastrointestinal side effects [8, 9}. Taking
`into account the evidence from other studies which have
`
`confirmed the improved usability and tolerability of SC
`administration of MTX also in comparison to intramuscular
`injection {2-4},
`the newly developed 50 mgfml prefilled
`syringe appears to be a highly preferred treatment option for
`patients with RA in need of MTX. This is supported by the
`strong appreciation of the patients as well as their attending
`healthcare professionals for its usability and toicrability.
`
`CONCLUSIONS
`
`A smaller volume of administered drug, the usability of
`being able to use a pre-attached needle with the small
`prefilled syringe and an improved local
`tolerability have
`contributed to the preference of the HC small syringe to
`apply subcutaneous MTX in active RA patients. This
`assessment was supported by similar assessments made by
`physicians and study nurses. With the exception of erythema
`which occurred significantly less often with I~lC treatment
`quality and quantity of adverse events did in general not
`differ between the two formulations.
`
`AC KNOWLEDGSMENTS
`
`The authors wish to thank all patients who participated in
`the trial and all rheumatologists and nursing staff of the
`participating centres who enrolled at least I patient:
`
`K. Rockwitz, Goslar; J. Brandt-Jiirgens, Berlin; R. Haux,
`Berlin; P. Kastner, Erfurt;
`.1. Braun, Heme; W. Demary,
`Hildesheim; K. Karberg, Berlin; M. Leidert, Liineburg; U.
`Miiller~Ladner, Bad Nauheim; H. Schulze-Koops, Mtinchen;
`C. Fiehn, Baden-Baden; B. Heilig, Heidelberg; C. Baerwald,
`Leipzig; M. Fleck, Bad Abbach; J. Kuipers, Bremen; G.
`Gauler, Osnabriick.
`
`The authors also wish to thank Sonja Btihm, medac
`Gmbl-l, for her excellent monitoring of the study and Martin
`Bornemann, who provided med ieal writing support on behalf
`of medac Gmbl--I.
`
`FINANCIAL DISC LDSURESICONFLICTS OF INTEREST
`
`UML has received consulting and speaker fees (less than
`10.000 USD) from medac Gmbl-I. CGS, UP and AB are
`employees of medac GmbH. All other authors have declared
`no conflicts of interest.
`
`KEY MESSAGES
`
`Patients, physicians and nursing staff prefer a high-
`concentration prefiiled syringe over a mediunuconcentration
`syringe for SC administration of MTX.
`
`Superior usability and overall satisfaction contributed to
`this preference. Local tolerability trended to be advantageous
`for HC and was partly significant for erythema.
`
`

`
`22 Tire Open Rherrmrrfalngy Journal, 2010, Volume 4
`
`REFERENCES
`
`[I]
`
`{2}
`
`[3]
`
`[4]
`
`[5|
`
`.ir., Reaman Git, et at. Pharmacokinetics of
`Baiis FM, Mirro J,
`subcutaneous methotrcxate. J Clin Oncol 1988: 6:
`l882—6.
`DA.
`Brooks
`PJ,
`Spruill WJ,
`Parish
`RC,
`Birclimorc
`Pharmacokinetics of methotrcxatc administered by intrarmiscular
`and subcutaneous injections in patients with rheumatoid arthritis.
`Arthritis Rheum 1990: 33: 91-4.
`Sander O. Htibner G, Rau R. Subcutaneous MTX - a reasonable
`addition of established modes ol‘ administration. Z Rheumatol
`1996; 55{Suppl I): Ill.
`Zackheim HS. Subcutaneous administration of methotrexate. J Am
`Acad Dermatol l992;26: I003.
`Braun .l, Ktistner P, Flaxcnberg P, at at. Comparison of the clinical
`efficacy and safety of subcutaneous versus oral administration of
`mcthotrexate in patients with active rheumatoid arthritis: Results of
`
`[6]
`
`{7}
`
`[3]
`
`[9]
`
`Ma‘Her~Lrrdner er in‘.
`
`a six-month, muiticenter, randomized, double-blind, controlled,
`phase IV trial. Arthritis Rheum 2008: 58: 73~8].
`Arnelt FC, Edwonhy SM, Bloch DA, er m‘. The American
`Rheumatism Association 1987 revised criteria for the classification
`ofrheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24.
`Wollenhaupt J, Alten R, Baekhaus M, et at. Recommendations for
`the treatment of rheumatoid arthritis. Results from a German
`consensus conference: Update 2009. Akt Rheumatol 2009; 34: 234-
`9.
`
`Pavy S, Constantin A, Pham T, 9! at. Methotrexatc therapy for
`rheumatoid arthritis: Clinical
`practice guidelines
`based
`on
`published evidence and expert opinion. Joint Bone Spine 2006; '13:
`388-95.
`at’. Evidence-based
`at
`IH, Manger B, Fleck M,
`'|‘arncr
`recommendations of a national group of experts on the use of
`methotrexate in inflammatory rheumatic diseases. Akt Rheumatol
`2009; 34: 59-66.
`
`
`
`Received: January 14, 2010
`
`Revised: January 29, 2010
`
`Accepted: February 8, 2010
`
`C3 Muller-Ladncr et all Licensee Bentham (Jprm.
`This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License {httpJlcreativeeontmons.org,i'|icensesfhy-nct
`3.00 which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
`
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